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  • 101.
    Granseth, Björn
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Andersson, Fredrik K
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Lindström, Sarah H
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    The initial stage of reversal learning is impaired in mice hemizygous for the vesicular glutamate transporter (VGluT1)2015Ingår i: Genes, Brain and Behavior, ISSN 1601-1848, E-ISSN 1601-183X, Vol. 14, nr 6, s. 477-485Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Behavioral flexibility is a complex cognitive function that is necessary for survival in changeable environments. Patients with schizophrenia or Parkinsons disease often suffer from cognitive rigidity, reducing their capacity to function in society. Patients and rodent models with focal lesions in the prefrontal cortex (PFC) show similar rigidity, owing to the loss of PFC regulation of subcortical reward circuits involved in behavioral flexibility. The vesicular glutamate transporter (VGluT1) is preferentially expressed at modulatory synapses, including PFC neurons that project to components of the reward circuit (such as the nucleus accumbens, NAc). VGluT1(+/-) mice display behavioral phenotypes matching many symptoms of schizophrenia, and VGluT1 expression is reduced in the PFC of patients with schizophrenia and Parkinsons disease. Thus, it appears likely that VGluT1-expressing synapses from PFC play a key role in behavioral flexibility. To examine this hypothesis, we studied behavioral flexibility in VGluT1(+/-) mice by testing reversal learning in a visual discrimination task. Here, we show that VGluT1(+/-) mice acquired the initial visual discrimination at the same rate as controls. However, they failed to suppress responses to the previously rewarded stimulus following reversal of reward contingencies. Thus, our genetic disruption of modulatory glutamatergic signaling, including that arising from PFC, appears to have impaired the first stage of reversal learning (extinguishing responses to previously rewarded stimuli). Our data show that this deficit stems from a preservative phenotype. These findings suggest that glutamatergic regulation from the cortex is important for behavioral flexibility and the disruption of this pathway may be relevant in diseases such as schizophrenia.

  • 102.
    Granseth, Björn
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet. Osaka University, Suita, Japan.
    Fukushima, Yuichi
    Osaka University, Suita, Japan.
    Sugo, Noriuki
    Osaka University, Suita, Japan.
    Lagnado, Leon
    Osaka University, Suita, Japan.
    Yamamoto, Nobuhiko
    Osaka University, Suita, Japan.
    Regulation of thalamocortical axon branching by BDNF and synaptic vesicle cycling2013Ingår i: Frontiers in Neural Circuits, ISSN 1662-5110, E-ISSN 1662-5110, Vol. 7, nr 202Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    During development, axons form branches in response to extracellular molecules. Little is known about the underlying molecular mechanisms. Here, we investigate how neurotrophin-induced axon branching is related to synaptic vesicle cycling for thalamocortical axons. The exogenous application of brain-derived neurotrophic factor (BDNF) markedly increased axon branching in thalamocortical co-cultures, while removal of endogenous BDNF reduced branching. Over-expression of a C-terminal fragment of AP180 that inhibits clathrin-mediated endocytosis affected the laminar distribution and the number of branch points. A dominant-negative synaptotagmin mutant that selectively targets synaptic vesicle cycling, strongly suppressed axon branching. Moreover, axons expressing the mutant synaptotagmin were resistant to the branch-promoting effect of BDNF. These results suggest that synaptic vesicle cycling might regulate BDNF induced branching during the development of the axonal arbor.

  • 103.
    Guan, Na N.
    et al.
    Department of Molecular Medicine and Surgery, Section of Urology, Karolinska Institutet, Stockholm, Sweden / Department of Urology, Karolinska University Hospital, Stockholm, Sweden / Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Sharma, Nimish
    Department of Molecular Medicine and Surgery, Section of Urology, Karolinska Institutet, Stockholm, Sweden / Department of Urology, Karolinska University Hospital, Stockholm, Sweden.
    Hallén‐Grufman, Katarina
    Department of Molecular Medicine and Surgery, Section of Urology, Karolinska Institutet, Stockholm, Sweden / Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Jager, Edwin W. H.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Sensor- och aktuatorsystem. Linköpings universitet, Tekniska fakulteten.
    Svennersten, Karl
    Department of Molecular Medicine and Surgery, Section of Urology, Karolinska Institutet, Stockholm, Sweden / Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    The role of ATP signalling in response to mechanical stimulation studied in T24 cells using new microphysiological tools2018Ingår i: Journal of Cellular and Molecular Medicine (Print), ISSN 1582-1838, E-ISSN 1582-4934, Vol. 22, nr 4, s. 2319-2328Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The capacity to store urine and initiate voiding is a valued characteristic of the human urinary bladder. To maintain this feature, it is necessary that the bladder can sense when it is full and when it is time to void. The bladder has a specialized epithelium called urothelium that is believed to be important for its sensory function. It has been suggested that autocrine ATP signalling contributes to this sensory function of the urothelium. There is well‐established evidence that ATP is released via vesicular exocytosis as well as by pannexin hemichannels upon mechanical stimulation. However, there are still many details that need elucidation and therefore there is a need for the development of new tools to further explore this fascinating field. In this work, we use new microphysiological systems to study mechanostimulation at a cellular level: a mechanostimulation microchip and a silicone‐based cell stretcher. Using these tools, we show that ATP is released upon cell stretching and that extracellular ATP contributes to a major part of Ca2+ signalling induced by stretching in T24 cells. These results contribute to the increasing body of evidence for ATP signalling as an important component for the sensory function of urothelial cells. This encourages the development of drugs targeting P2 receptors to relieve suffering from overactive bladder disorder and incontinence.

  • 104.
    Gustafsson, Gabriel
    et al.
    Uppsala Univ, Sweden.
    Loov, Camilla
    Massachusetts Gen Hosp, MA 02129 USA; Harvard Med Sch, MA 02115 USA.
    Persson, Emma
    Uppsala Univ, Sweden.
    Lazaro, Diana F.
    Univ Med Ctr Gottingen, Germany.
    Takeda, Shuko
    Massachusetts Gen Hosp, MA 02129 USA; Harvard Med Sch, MA 02115 USA.
    Bergstrom, Joakim
    Uppsala Univ, Sweden.
    Erlandsson, Anna
    Uppsala Univ, Sweden.
    Sehlin, Dag
    Uppsala Univ, Sweden.
    Balaj, Leonora
    Massachusetts Gen Hosp, MA 02129 USA; Massachusetts Gen Hosp, MA 02129 USA; Harvard Med Sch, MA 02115 USA.
    Gyorgy, Bence
    Massachusetts Gen Hosp, MA 02129 USA; Harvard Med Sch, MA 02115 USA.
    Hallbeck, Martin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi.
    Outeiro, Tiago F.
    Univ Med Ctr Gottingen, Germany; Max Planck Inst Expt Med, Germany; Newcastle Univ, England.
    Breakefield, Xandra O.
    Massachusetts Gen Hosp, MA 02129 USA; Harvard Med Sch, MA 02115 USA.
    Hyman, Bradley T.
    Massachusetts Gen Hosp, MA 02129 USA; Harvard Med Sch, MA 02115 USA.
    Ingelsson, Martin
    Uppsala Univ, Sweden; Massachusetts Gen Hosp, MA 02129 USA; Massachusetts Gen Hosp, MA 02129 USA; Harvard Med Sch, MA 02115 USA.
    Secretion and Uptake of -Synuclein Via Extracellular Vesicles in Cultured Cells2018Ingår i: Cellular and molecular neurobiology, ISSN 0272-4340, E-ISSN 1573-6830, Vol. 38, nr 8, s. 1539-1550Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In Parkinsons disease and other Lewy body disorders, the propagation of pathology has been accredited to the spreading of extracellular -synuclein (-syn). Although the pathogenic mechanisms are not fully understood, cell-to-cell transfer of -syn via exosomes and other extracellular vesicles (EVs) has been reported. Here, we investigated whether altered molecular properties of -syn can influence the distribution and secretion of -syn in human neuroblastoma cells. Different -syn variants, including -syn:hemi-Venus and disease-causing mutants, were overexpressed and EVs were isolated from the conditioned medium. Of the secreted -syn, 0.1-2% was associated with vesicles. The major part of EV -syn was attached to the outer membrane of vesicles, whereas a smaller fraction was found in their lumen. For -syn expressed with N-terminal hemi-Venus, the relative levels associated with EVs were higher than for WT -syn. Moreover, such EV-associated -syn:hemi-Venus species were internalized in recipient cells to a higher degree than the corresponding free-floating forms. Among the disease-causing mutants, A53T -syn displayed an increased association with EVs. Taken together, our data suggest that -syn species with presumably lost physiological functions or altered aggregation properties may shift the cellular processing towards vesicular secretion. Our findings thus lend further support to the tenet that EVs can mediate spreading of harmful -syn species and thereby contribute to the pathology in -synucleinopathies.

  • 105.
    Gustafsson, Per E.
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Barn- och ungdomspsykiatri. Linköpings universitet, Hälsouniversitetet.
    Gustafsson, Per A.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Barn- och ungdomspsykiatri. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Närsjukvården i centrala Östergötland, Barn- och ungdomspsykiatriska kliniken.
    Ivarsson, Tord
    Department of Child and Adolescent Psychiatry, Göteborg University, Göteborg, Sweden; The Regional Center for Child and Adolescent Psychiatry (R. BUP), Oslo, Norway.
    Nelson, Nina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Pediatrik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Linköping.
    Diurnal Cortisol Levels and Cortisol Response in Youths with Obsessive-Compulsive Disorder2008Ingår i: Neuropsychobiology, ISSN 0302-282X, E-ISSN 1423-0224, Vol. 57, nr 1-2, s. 14-21Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background/Aims: Recent results indicate a role of the hypothalamic-pituitary-adrenal (HPA) axis in the pathophysiology of obsessive-compulsive disorder (OCD). Although childhood onset is common, the HPA axis has scarcely been studied in young OCD subjects. Therefore, the present study aimed at examining basal and response levels of salivary cortisol in a sample of young OCD subjects.

    Methods: Twenty-three children and adolescents with DSM-IV OCD were compared to a reference group of school children (n = 240-336). The basal cortisol rhythm was measured through saliva samples 3 times/day. The cortisol response to a psychological stressor (exposure therapy in the OCD group and a fire alarm in the reference group) was also examined.

    Results: Compared to the reference group, OCD subjects displayed higher early-morning cortisol values (p = 0.005) with no difference between the late-morning and evening values. The cortisol levels in the OCD group diminished in response to the psychological stressor, compared to a positive response in the reference group (p < 0.001). No relation was found between cortisol and clinical parameters.

    Conclusion: These results support the idea that HPA hyperactivity, commonly found in adult OCD patients, is also present at an earlier stage of development, with specificity for the early-morning peak.

  • 106.
    Gómez-Climent, M. Á
    et al.
    Neurobiology Unit and Program in Basic and Applied Neurosciences, Cell Biology Department, Universitat de València, Spain.
    Hernández-González, S.
    Neurobiology Unit and Program in Basic and Applied Neurosciences, Cell Biology Department, Universitat de València, Spain.
    Shionoya, Kiseko
    CSGA, UMR CNRS 6265, INRA 1354, Université de Bourgogne, 15 rue Picardet, 21000 Dijon, France.
    Belles, M.
    Neurobiology Unit and Program in Basic and Applied Neurosciences, Cell Biology Department, Universitat de València, Spain.
    Alonso-Llosa, G.
    Neurobiology Unit and Program in Basic and Applied Neurosciences, Cell Biology Department, Universitat de València, Spain.
    Datiche, F.
    CSGA, UMR CNRS 6265, INRA 1354, Université de Bourgogne, 15 rue Picardet, 21000 Dijon, France.
    Nacher, J.
    Neurobiology Unit and Program in Basic and Applied Neurosciences, Cell Biology Department, Universitat de València, Spain.
    Olfactory bulbectomy, but not odor conditioned aversion, induces the differentiation of immature neurons in the adult rat piriform cortex2011Ingår i: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 181, nr 5, s. 18-27Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The piriform cortex layer II of young-adult rats presents a population of prenatally generated cells, which express immature neuronal markers, such as the polysialylated form of the neural cell adhesion molecule (PSA-NCAM) or doublecortin (DCX), and display structural characteristics of immature neurons. The number of PSA-NCAM/DCX expressing cells in this region decreases markedly as age progresses, suggesting that these cells differentiate or die. Since the piriform cortex receives a major input from the olfactory bulb and participates in olfactory information processing, it is possible that the immature neurons in layer II are affected by manipulations of the olfactory bulb or olfactory learning. It is not known whether these cells can be induced to differentiate and, if so, what would be their fate. In order to address these questions, we have performed unilateral olfactory bulbectomy (OBX) and an olfactory learning paradigm (taste-potentiated odor aversion, TPOA), in young-adult rats and have studied the expression of different mature and immature neuronal markers, as well as the presence of cell death. We have found that 14 h after OBX there was a dramatic decrease in the number of both PSA-NCAM and DCX expressing cells in piriform cortex layer II, whereas that of cells expressing NeuN, a mature neuronal marker, increased. By contrast, the number of cells expressing glutamate decarboxylase, isoform 67 (GAD67), a marker for interneurons, decreased slightly. Additionally, we have not found evidence of numbers of dying cells high enough to justify the disappearance of immature neurons. Analysis of animals subjected to TPOA revealed that this paradigm does not affect PSA-NCAM expressing cells. Our results strongly suggest that OBX can induce the maturation of immature neurons in the piriform cortex layer II and that these cells do not become interneurons. By contrast, these cells do not seem to play a crucial role in olfactory memory.

  • 107.
    Hakizimana, Pierre
    et al.
    Karolinska Institutet / Karolinska University Hospital, Stockholm, Sweden.
    Brownell, William E
    Jacob, Stefan
    Fridberger, Anders
    Karolinska Institutet / Karolinska University Hospital, Stockholm, Sweden.
    Sound-induced length changes in outer hair cell stereocilia2012Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 3Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Hearing relies on mechanical stimulation of stereocilia bundles on the sensory cells of the inner ear. When sound hits the ear, each stereocilium pivots about a neck-like taper near their base. More than three decades of research have established that sideways deflection of stereocilia is essential for converting mechanical stimuli into electrical signals. Here we show that mammalian outer hair cell stereocilia not only move sideways but also change length during sound stimulation. Currents that enter stereocilia through mechanically sensitive ion channels control the magnitude of both length changes and bundle deflections in a reciprocal manner: the smaller the length change, the larger is the bundle deflection. Thus, the transduction current is important for maintaining the resting mechanical properties of stereocilia. Hair cell stimulation is most effective when bundles are in a state that ensures minimal length change.

  • 108.
    Hallbeck, Martin
    et al.
    Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet.
    Nath, Sangeeta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neurovetenskap. Linköpings universitet, Hälsouniversitetet.
    Marcusson, Jan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neurovetenskap. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Närsjukvården i centrala Östergötland, Geriatriska kliniken.
    Neuron-to-Neuron Transmission of Neurodegenerative Pathology2013Ingår i: The Neuroscientist, ISSN 1073-8584, E-ISSN 1089-4098, Vol. 19, nr 6, s. 560-566Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    One of the hallmarks of neurodegenerative dementia diseases is the progressive loss of mental functions and the ability to manage activities of daily life. This progression is caused by the spread of the disease to more and more brain areas via anatomical connections. The pathophysiological process responsible for this spread of disease has long been sought after. There has been an increased understanding that the driving force of these neurodegenerative diseases could be the small, soluble intraneuronal accumulations of neurodegenerative proteins rather than the large, extracellular accumulations. Recently we have shown that the mechanism of spread of Alzheimer's disease most likely depends on the neuron-to-neuron spread of such soluble intraneuronal accumulations of -amyloid through neuritic connections. Similar transmissions have been shown for several other neurodegenerative proteins but little is known about the cellular mechanisms and about any potential strategies that might stop this spread. Resolving these questions requires good cellular models. We have established a unique model of synaptic transmission between human neuronal-like cells, something that has previously been difficult to target. This opens the possibility of developing potential inhibitors of progression of these devastating diseases.

  • 109.
    Halénius, Patric
    Linköpings universitet, Institutionen för datavetenskap.
    Trippelkodmodellen: hur barnhjärnor hanterar numeriska uppgifter2019Självständigt arbete på grundnivå (kandidatexamen), 12 poäng / 18 hpStudentuppsats (Examensarbete)
    Abstract [sv]

    Att kunna uppskatta antal är en grundläggande förmåga som återfinns hos många djur förutom männinskan. Trippelkodmodellen (TKM) för numerisk kognition säger att antal representeras på tre olika sätt, som (arabiska) siffror, som sifferord och som ickesymboliska magnituder, vilka associeras till separata, men delvis överlappande, neurala substrat. Denna studie undersökte för första gången alla tre koder samtidigt på barn. 10 barn mellan 10-12 år genomgick fMRT-skanning för att söka neurala korrelat till antalsuppfattning. Oberoende uppgift > kontroll-kontraster bekräftade delvis TKM, såsom funktionellt olika neurala substrat, ett fronto-parietalt nätverk och att barn nyttjar det ventrala uppmärksamhetsnätet mer än vuxna på grund av mindre automatisering. Därtill fanns aktiveringar i visuella områden V2 och V3 liksom i primära somatosensoriska området vilket överensstämmer med föreslagna kompletteringar av TKM. Parametriska kontraster kunde i viss mån bekräfta distanseffekten som innebär större kognitiv belastning vid särskiljning av närliggande antal jämfört med att skilja på tydligt olika antal.

  • 110.
    Hamilton, Paul
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Sacchet, Matthew D.
    Stanford Univ, CA 94305 USA.
    Hjornevik, Trine
    Oslo Univ Hosp, Norway; Norwegian Med Cyclotron Ctr, Norway; Stanford Univ, CA 94305 USA.
    Chin, Frederick T.
    Stanford Univ, CA 94305 USA.
    Shen, Bin
    Stanford Univ, CA 94305 USA.
    Kämpe, Robin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Park, Jun Hyung
    Stanford Univ, CA 94305 USA.
    Knutson, Brian D.
    Stanford Univ, CA USA.
    Williams, Leanne M.
    Stanford Univ, CA 94305 USA.
    Borg, Nicholas
    Stanford Univ, CA USA.
    Zaharchuk, Greg
    Stanford Univ, CA 94305 USA.
    Camacho, M. Catalina
    Univ Pittsburgh, PA 15260 USA.
    Mackey, Sean
    Stanford Univ, CA 94305 USA.
    Heilig, Markus
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Närsjukvården i centrala Östergötland, Psykiatriska kliniken.
    Drevets, Wayne C.
    Janssen Res and Dev LLC, NJ USA.
    Glover, Gary H.
    Stanford Univ, CA 94305 USA.
    Gambhir, Sanjiv S.
    Stanford Univ, CA 94305 USA.
    Gotlib, Ian H.
    Stanford Univ, CA USA.
    Striatal dopamine deficits predict reductions in striatal functional connectivity in major depression: a concurrent C-11-raclopride positron emission tomography and functional magnetic resonance imaging investigation2018Ingår i: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 8, artikel-id 264Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Major depressive disorder (MDD) is characterized by the altered integration of reward histories and reduced responding of the striatum. We have posited that this reduced striatal activation in MDD is due to tonically decreased stimulation of striatal dopamine synapses which results in decremented propagation of information along the corticostriatal-pallido-thalamic (CSPT) spiral. In the present investigation, we tested predictions of this formulation by conducting concurrent functional magnetic resonance imaging (fMRI) and C-11-raclopride positron emission tomography (PET) in depressed and control (CTL) participants. We scanned 16 depressed and 14 CTL participants with simultaneous fMRI and C-11-raclopride PET. We estimated raclopride binding potential (BPND), voxel-wise, and compared MDD and CTL samples with respect to BPND in the striatum. Using striatal regions that showed significant between-group BPND differences as seeds, we conducted whole-brain functional connectivity analysis using the fMRI data and identified brain regions in each group in which connectivity with striatal seed regions scaled linearly with BPND from these regions. We observed increased BPND in the ventral striatum, bilaterally, and in the right dorsal striatum in the depressed participants. Further, we found that as BPND increased in both the left ventral striatum and right dorsal striatum in MDD, connectivity with the cortical targets of these regions (default-mode network and salience network, respectively) decreased. Deficits in stimulation of striatal dopamine receptors in MDD could account in part for the failure of transfer of information up the CSPT circuit in the pathophysiology of this disorder.

  • 111.
    Hamlin, Lina
    et al.
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Mackerlova, Ludmila
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Blomqvist, Anders
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Ericson, Ann-Charlott
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Cellbiologi. Linköpings universitet, Medicinska fakulteten.
    AMPA-selective glutamate receptor subunits and their relation to glutamate-and GABA-like immunoreactive terminals in the nucleus submedius of the rat1996Ingår i: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 217, nr 2-3, s. 149-52Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Glutamate plays an important role in supraspinal nociceptive systems. Thus, glutamate is present in the nucleus submedius of the medial thalamus, a major relay for nociceptive information. In this study, immunoreactivity for the four subunits (GluR1-4) of alpha-amino-3-hydroxy-5-methyl-4-isoxasoleproprionate (AMPA) receptors was examined by a preembedding immunohistochemical method in order to evaluate the presence of this glutamate receptor subtype in the nucleus submedius. Combining the preembedding method with a postembedding immunogold technique, we found that AMPA receptor-like immunoreactivity was present postsynaptically to glutamatergic terminals but not to terminals containing gamma-aminobutyric acid (GABA). These findings suggest a role for AMPA receptors in excitatory synaptic transmission in the nucleus submedius of the rat thalamus.

  • 112.
    Hanson, Michaela
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    Jojola, Susan M.
    AFB International, 3 Research Park Drive, St. Charles, MO 63304, USA.
    Rawson, Nancy E.
    AFB International, 3 Research Park Drive, St. Charles, MO 63304, USA.
    Crowe, Melissa
    AFB International, 3 Research Park Drive, St. Charles, MO 63304, USA.
    Laska, Matthias
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    Facial expressions and other behavioral responses to pleasant andunpleasant tastes in cats (Felis silvestris catus)2016Ingår i: Applied Animal Behaviour Science, ISSN 0168-1591, E-ISSN 1872-9045, Vol. 181, s. 129-136Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The goal of the present study was to assess how cats react to tastes previously reported to be preferredor avoided relative to water. To this end, the facial and behavioral reactions of 13 cats to differentconcentrations of l-Proline and quinine monohydrochloride (QHCl) as well as mixtures with differentconcentrations of the two substances were assessed using a two-bottle preference test of short duration.The cats were videotaped and the frequency and duration of different behaviors were analyzed. Significantdifferences in the cats’ behavior in response to the taste quality of the different solutions included,but were not limited to, Tongue Protrusions (p < 0.039), Mouth smacks (p = 0.008) and Nose Licks (p = 0.011)with four different stimulus concentrations. The cats responded to preferred taste by keeping their Eyeshalf-closed (p = 0.017) for significantly longer periods of time with four different stimulus concentrationscompared to a water control. When encountering mixtures containing l-Proline and QHCl the cats performedTongue protrusion gapes (p < 0.038) significantly more frequently with three different stimulusconcentrations compared to an l-Proline control. A stepwise increase in the concentration of l-Prolinefrom 5 mM to 500 mM in mixtures with 50 M QHCl did not overcome the negative impact of the bittertaste on intake. The results of the present study suggest that behavioral responses provide an additionaldimension and may be more informative than consumption data alone to assess whether cats perceivetastes as pleasant or unpleasant. Thus, the analysis of behavioral responses to different taste qualitiesmay be a useful tool to assess and improve the acceptance of commercial food by cats.

  • 113.
    Hansson, Anita C.
    et al.
    Heidelberg Univ, Germany.
    Koopmann, Anne
    Heidelberg Univ, Germany.
    Uhrig, Stefanie
    Heidelberg Univ, Germany.
    Buhler, Sina
    Heidelberg Univ, Germany.
    Domi, Esi
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten. Univ Camerino, Italy.
    Kiessling, Eva
    Heidelberg Univ, Germany.
    Ciccocioppo, Roberto
    Univ Camerino, Italy.
    Froemke, Robert C.
    NYU, NY USA.
    Grinevich, Valery
    German Canc Res Ctr, Germany.
    Kiefer, Falk
    Heidelberg Univ, Germany.
    Sommer, Wolfgang H.
    Heidelberg Univ, Germany; Heidelberg Univ, Germany.
    Vollstaedt-Klein, Sabine
    Heidelberg Univ, Germany.
    Spanagel, Rainer
    Heidelberg Univ, Germany.
    Oxytocin Reduces Alcohol Cue-Reactivity in Alcohol-Dependent Rats and Humans2018Ingår i: Neuropsychopharmacology, ISSN 0893-133X, E-ISSN 1740-634X, Vol. 43, nr 6, s. 1235-1246Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Approved pharmacological treatments for alcohol use disorder are limited in their effectiveness, and new drugs that can easily be translated into the clinic are warranted. One of those candidates is oxytocin because of its interaction with several alcohol-induced effects. Alcoholdependent rats as well as post-mortem brains of human alcoholics and controls were analyzed for the expression of the oxytocin system by qRT-PCR, in situ hybridizaton, receptor autoradiography ([(125)l]OVTA binding), and immunohistochemistry. Alcohol self administration and cue-induced reinstatement behavior was measured after intracerebroventicular injection of 10 nM oxytocin in dependent rats. Here we show a pronounced upregulation of oxytocin receptors in brain tissues of alcohol dependent rats and deceased alcoholics, primarily in frontal and striatal areas. This upregulation stems most likely from reduced oxytocin expression in hypothalamic nuclei. Pharmacological validaton showed that oxytocin reduced cue-induced reinstatement response in dependent rats-an effect that was not observed in nondependent rats. Finally, a clinical pilot study (German clinical trial number DRKS00009253) using functional magnetic resonance imaging in heavy social male drinkers showed that intranasal oxytocin (24 IU) decreased neural cue-reactivity in brain networks similar to those detected in dependent rats and humans with increased oxytocin receptor expression. These studies suggest that oxytocin might be used as an anticraving medication and thus may positvely affect treatment outcomes in alcoholics.

  • 114.
    He, Min
    et al.
    Harvard Medical Sch, MA USA; Shanxi Medical University, Peoples R China.
    Storr-Paulsen, Thomas
    Harvard Medical Sch, MA USA; Aarhus University Hospital NBG, Denmark.
    Wang, Annie L.
    Harvard Medical Sch, MA USA.
    Ghezzi, Chiara E.
    Tufts University, MA 02155 USA.
    Wang, Siran
    Tufts University, MA 02155 USA.
    Fullana, Matthew
    Case Western Reserve University, OH 44106 USA.
    Karamichos, Dimitrios
    University of Oklahoma, OK USA.
    Utheim, Tor P.
    Harvard Medical Sch, MA USA; University of Oslo, Norway; Vestre Viken Hospital Trust, Norway; University of Coll Southeast Norway, Norway.
    Islam, Rakibul
    Harvard Medical Sch, MA USA; University of Oslo, Norway.
    Griffith, May
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Karolinska Institute, Sweden.
    Islam, Mohammad Mirazul Mirazul
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Karolinska Institute, Sweden.
    Hodges, Robin R.
    Harvard Medical Sch, MA USA.
    Wnek, Gary E.
    Case Western Reserve University, OH 44106 USA.
    Kaplan, David L.
    Tufts University, MA 02155 USA.
    Dartt, Darlene A.
    Harvard Medical Sch, MA USA.
    Artificial Polymeric Scaffolds as Extracellular Matrix Substitutes for Autologous Conjunctival Goblet Cell Expansion2016Ingår i: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 57, nr 14, s. 6134-6146Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    PURPOSE. We fabricated and investigated polymeric scaffolds that can substitute for the conjunctival extracellular matrix to provide a substrate for autologous expansion of human conjunctival goblet cells in culture. METHODS. We fabricated two hydrogels and two silk films: (1) recombinant human collagen (RHC) hydrogel, (2) recombinant human collagen 2-methacryloylxyethyl phosphorylcholine (RHC-MPC) hydrogel, (3) arginine-glycine-aspartic acid (RGD) modified silk, and (4) poly-D-lysine (PDL) coated silk, and four electrospun scaffolds: (1) collagen, (2) poly(acrylic acid) (PAA), (3) poly(caprolactone) (PCL), and (4) poly(vinyl alcohol) (PVA). Coverslips and polyethylene terephthalate (PET) were used for comparison. Human conjunctival explants were cultured on scaffolds for 9 to 15 days. Cell viability, outgrowth area, and the percentage of cells expressing markers for stratified squamous epithelial cells (cytokeratin 4) and goblet cells (cytokeratin 7) were determined. RESULTS. Most of cells grown on all scaffolds were viable except for PCL in which only 3.6 +/- 2.2% of the cells were viable. No cells attached to PVA scaffold. The outgrowth was greatest on PDL-silk and PET. Outgrowth was smallest on PCL. All cells were CK7-positive on RHCMPC while 84.7 +/- 6.9% of cells expressed CK7 on PDL-silk. For PCL, 87.10 +/- 3.17% of cells were CK7-positive compared to PET where 67.10 +/- 12.08% of cells were CK7-positive cells. CONCLUSIONS. Biopolymer substrates in the form of hydrogels and silk films provided for better adherence, proliferation, and differentiation than the electrospun scaffolds and could be used for conjunctival goblet cell expansion for eventual transplantation once undifferentiated and stratified squamous cells are included. Useful polymer scaffold design characteristics have emerged from this study.

  • 115.
    He, Wenxuan
    et al.
    Oregon Health and Science University, Portland, USA.
    Fridberger, Anders
    Karolinska Institutet / Karolinska University Hospital, Stockholm, Sweden.
    Porsov, Edward
    Oregon Health and Science University, Portland, USA.
    Grosh, Karl
    University of Michigan, Ann Arbor, MI, USA .
    Ren, Tianying
    Oregon Health and Science University, Portland, USA.
    Reverse wave propagation in the cochlea2008Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 105, nr 7, s. 2729-2733Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Otoacoustic emissions, sounds generated by the inner ear, are widely used for diagnosing hearing disorders and studying cochlear mechanics. However, it remains unclear how emissions travel from their generation sites to the cochlear base. The prevailing view is that emissions reach the cochlear base via a backward-traveling wave, a slow-propagating transverse wave, along the cochlear partition. A different view is that emissions propagate to the cochlear base via the cochlear fluids as a compressional wave, a fast longitudinal wave. These theories were experimentally tested in this study by measuring basilar membrane (BM) vibrations at the cubic distortion product (DP) frequency from two longitudinal locations with a laser interferometer. Generation sites of DPs were varied by changing frequencies of primary tones while keeping the frequency ratio constant. Here, we show that BM vibration amplitude and phase at the DP frequency are very similar to responses evoked by external tones. Importantly, the BM vibration phase at a basal location leads that at a more apical location, indicating a traveling wave that propagates in the forward direction. These data are in conflict with the backward- traveling-wave theory but are consistent with the idea that the emission comes out of the cochlea predominantly through compressional waves in the cochlear fluids.

  • 116. He, Wenxuan
    et al.
    Fridberger, Anders
    Karolinska Institutet / Karolinska University Hospital, Stockholm, Sweden.
    Porsov, Edward
    Ren, Tianying
    Fast reverse propagation of sound in the living cochlea2010Ingår i: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 98, nr 11, s. 2497-2505Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The auditory sensory organ, the cochlea, not only detects but also generates sounds. Such sounds, otoacoustic emissions, are widely used for diagnosis of hearing disorders and to estimate cochlear nonlinearity. However, the fundamental question of how the otoacoustic emission exits the cochlea remains unanswered. In this study, emissions were provoked by two tones with a constant frequency ratio, and measured as vibrations at the basilar membrane and at the stapes, and as sound pressure in the ear canal. The propagation direction and delay of the emission were determined by measuring the phase difference between basilar membrane and stapes vibrations. These measurements show that cochlea-generated sound arrives at the stapes earlier than at the measured basilar membrane location. Data also show that basilar membrane vibration at the emission frequency is similar to that evoked by external tones. These results conflict with the backward-traveling-wave theory and suggest that at low and intermediate sound levels, the emission exits the cochlea predominantly through the cochlear fluids.

  • 117.
    Hegoburu, Chloe
    et al.
    Team “Olfaction: From Coding to Memory”, Lyon Neuroscience Research Center, INSERM U1028, CNRS UMR5292, Lyon, France / University Lyon 1, Lyon, France.
    Shionoya, Kiseko
    Team “Olfaction: From Coding to Memory”, Lyon Neuroscience Research Center, INSERM U1028, CNRS UMR5292, Lyon, France / University Lyon 1, Lyon, France.
    Garcia, Samuel
    Team “Olfaction: From Coding to Memory”, Lyon Neuroscience Research Center, INSERM U1028, CNRS UMR5292, Lyon, France / University Lyon 1, Lyon, France.
    Messaoudi, Belkacem
    Team “Olfaction: From Coding to Memory”, Lyon Neuroscience Research Center, INSERM U1028, CNRS UMR5292, Lyon, France / University Lyon 1, Lyon, France.
    Thevenet, Marc
    Team “Olfaction: From Coding to Memory”, Lyon Neuroscience Research Center, INSERM U1028, CNRS UMR5292, Lyon, France / University Lyon 1, Lyon, France.
    Mouly, Anne-Marie
    Team “Olfaction: From Coding to Memory”, Lyon Neuroscience Research Center, INSERM U1028, CNRS UMR5292, Lyon, France / University Lyon 1, Lyon, France.
    The RUB Cage: Respiration–Ultrasonic Vocalizations–Behavior Acquisition Setup for Assessing Emotional Memory in Rats2011Ingår i: Frontiers in Behavioral Neuroscience, ISSN 1662-5153, E-ISSN 1662-5153, Vol. 5, s. 1-13, artikel-id 25Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In animals, emotional memory is classically assessed through pavlovian fear conditioning in which a neutral novel stimulus (conditioned stimulus) is paired with an aversive unconditioned stimulus. After conditioning, the conditioned stimulus elicits a fear response characterized by a wide range of behavioral and physiological responses. Despite the existence of this large repertoire of responses, freezing behavior is often the sole parameter used for quantifying fear response, thus limiting emotional memory appraisal to this unique index. Interestingly, respiratory changes and ultrasonic vocalizations (USV) can occur during fear response, yet very few studies investigated the link between these different parameters and freezing. The aim of the present study was to design an experimental setup allowing the simultaneous recording of Respiration, USV and Behavior (RUB Cage), and the offline synchronization of the collected data for fine-grain second by second analysis. The setup consisted of a customized plethysmograph for respiration monitoring, equipped with a microphone capturing USV, and with four video cameras for behavior recording. In addition, the bottom of the plethysmograph was equipped with a shock-floor allowing foot-shock delivery, and the top received tubing for odor presentations. Using this experimental setup we first described the characteristics of respiration and USV in different behaviors and emotional states. Then we monitored these parameters during contextual fear conditioning and showed that they bring complementary information about the animal’s anxiety state and the strength of aversive memory. The present setup may be valuable in providing a clearer appraisal of the physiological and behavioral changes that occur during acquisition as well as retrieval of emotional memory.

  • 118.
    Heilig, Markus
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Närsjukvården i centrala Östergötland, Psykiatriska kliniken.
    Alkohol, droger och hjärnan: tro och vetande utifrån modern neurovetenskap2015Bok (Övrigt vetenskapligt)
    Abstract [sv]

    Alkohol, droger och hjärnan beskriver framsteg inom hjärnforskningen som gjort det möjligt att bättre förstå alkohol- och drogproblem. Boken är skriven från författarens perspektiv som läkare och forskare och visar hur vetenskapens framsteg pekar ut vägar mot empatisk, rationell behandling som alternativ till moraliserande attityder och vårdideologiska strider.

    Missbruksproblem är mycket vanliga, och nästan varje familj har erfarenhet av någon som drabbats. Svenskars användningsmönster av alkohol har förändrats. After Work-ölen och mitt-i-veckan-drinken är förhållandevis nya i svensk dryckeskultur, samtidigt som traditionen av tungt helgdrickande finns kvar. Dessa dryckesbeteenden aktualiserar behovet av fördjupad kunskap och vetenskapligt grundade behandlingsmetoder. För att nå dit behöver forskningens resultat nå ut utanför akademiska kretsar.

  • 119.
    Heilig, Markus
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Närsjukvården i centrala Östergötland, Psykiatriska kliniken.
    Barbier, Estelle
    Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap.
    Johnstone, A. L.
    University of Miami, FL 33136 USA.
    Tapocik, J.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Meinhardt, M. W.
    Heidelberg University, Germany.
    Pfarr, S.
    Heidelberg University, Germany.
    Wahlestedt, C.
    University of Miami, FL 33136 USA.
    Sommer, W. H.
    Heidelberg University, Germany.
    Reprogramming of mPFC transcriptome and function in alcohol dependence2017Ingår i: Genes, Brain and Behavior, ISSN 1601-1848, E-ISSN 1601-183X, Vol. 16, nr 1, s. 86-100Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Despite its limited immediate reinforcement value, alcohol has a potent ability to induce neuroadaptations that promote its incentive salience, escalation of voluntary alcohol intake and aversion-resistant alcohol seeking. A constellation of these traits, collectively called post-dependent, emerges following brain exposure to repeated cycles of intoxication and withdrawal. The medial prefrontal cortex (mPFC) and its subdivisions exert top-down regulation of approach and avoidance behaviors, including those that lead to alcohol intake. Here, we review an emerging literature which indicates that a reprogramming of mPFC function occurs with prolonged exposure of the brain to cycles of alcohol intoxication and withdrawal. This reprogramming results in molecular dysregulations that contribute to the post-dependent syndrome. Convergent evidence has identified neuroadaptations resulting in altered glutamatergic and BDNF-mediated signaling, and for these pathways, direct evidence for a mechanistic role has been obtained. Additional evidence points to a dysregulation of pathways involving calcium homeostasis and neurotransmitter release. Recent findings indicate that global DNA hypermethylation is a key factor in reprogramming the mPFC genome after a history of dependence. As one of the results of this epigenetic remodeling, several histone modifying epigenetic enzymes are repressed. Among these, PR-domain zinc-finger protein 2, a methyltransferase that selectively mono-methylates histone H3 at lysine 9 has been functionally validated to drive several of the molecular and behavioral long-term consequences of alcohol dependence. Information processing within the mPFC involves formation of dynamic neuronal networks, or functional ensembles that are shaped by transcriptional responses. The epigenetic dysregulations identified by our molecular studies are likely to alter this dynamic processing in multiple ways. In summary, epigenetic molecular switches in the mPFC appear to be turned on as alcoholism develops. Strategies to reverse these processes may offer targets for disease-modifying treatments.

  • 120.
    Heilig, Markus
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Centrum för social och affektiv neurovetenskap (CSAN). Region Östergötland, Närsjukvården i centrala Östergötland, Psykiatriska kliniken.
    Epstein, David H.
    NIDA, MD 21044 USA.
    Nader, Michael A.
    Wake Forest School Med, NC 27157 USA.
    Shaham, Yavin
    NIDA, MD 21044 USA.
    Time to connect: bringing social context into addiction neuroscience2016Ingår i: Nature Reviews Neuroscience, ISSN 1471-003X, E-ISSN 1471-0048, Vol. 17, nr 9, s. 592-599Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Research on the neural substrates of drug reward, withdrawal and relapse has yet to be translated into significant advances in the treatment of addiction. One potential reason is that this research has not captured a common feature of human addiction: progressive social exclusion and marginalization. We propose that research aimed at understanding the neural mechanisms that link these processes to drug seeking and drug taking would help to make addiction neuroscience research more clinically relevant.

  • 121.
    Heilig, Markus
    et al.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Thorsell, Annika
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Sommer, Wolfgang H.
    Central Institute of Mental Health, Mannheim, Germany.
    Hansson, Anita C.
    Central Institute of Mental Health, Mannheim, Germany.
    Ramchandani, Vijay A.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    George, David T.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Hommer, Daniel
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Barr, Christina S.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Translating the neuroscience of alcoholism into clinical treatments: from blocking the buzz to curing the blues2010Ingår i: Neuroscience and Biobehavioral Reviews, ISSN 0149-7634, E-ISSN 1873-7528, Vol. 35, nr 2, s. 334-344Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Understanding the pathophysiology of addictive disorders is critical for development of new treatments. A major focus of addiction research has for a long time been on systems that mediate acute positively reinforcing effects of addictive drugs, most prominently the mesolimbic dopaminergic (DA) system and its connections. This research line has been successful in shedding light on the physiology of both natural and drug reward, but has not led to therapeutic breakthroughs. The role of classical reward systems is perhaps least clear in alcohol addiction. Here, recent work is summarized that points to some clinically important conclusions. First, important pharmacogenetic differences exist with regard to positively reinforcing effects of alcohol and the ability of this drug to activate classical reward pathways. This offers an opportunity for personalized treatment approaches in alcoholism. Second, brain stress and fear systems become pathologically activated in later stages of alcoholism and their activation is a major influence in escalation of alcohol intake, sensitization of stress responses, and susceptibility to relapse. These findings offer a new category of treatment mechanisms. Corticotropin-releasing hormone (CRH) signaling through CRH1 receptors is a major candidate target in this category, but recent data indicate that antagonists for substance P (SP) neurokinin 1 (NK1) receptors may have a similar potential.

  • 122.
    Hilke, Susanne
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet.
    Galanin and NPY in the rodent brain: rapid effects of 17beta-estradiol and possible roles in hippocampal plasticity2005Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    The neuropeptides galanin and neuropeptide Y (NPY) play an important role in the reproduction of rodents, e.g. by modulating the release of gonadal hormones, the nutritional status by effects on feeding behavior and also by influencing mating behavior. There are age- and gender- differences in galanin- and NPY- like immunoreactivities (LIs) in brain areas important for higher functions including the hippocampal formation (HiFo) and cortex, that are related to the concentrations of 17β-estradiol.

    Neuropeptides in general are currently not considered critical in normal integrative neuronal functions but are rather thought to act as slow modulators during periods of stress or injury. In the present thesis we attempted to investigate, if the normal cyclical changes in the female sex-hormone 17β-estradiol can affect neurotransmission in brain areas important for memory, cognition and mood. We studied not only ”long term” (days and weeks) but also ”short-term” (one hour) effects on galanin and NPY concentrations in 17β-estradiol-primed ovariectomized (ovx) rats and mice.

    Radioimmunoassay (RIA) of galanin-LI in extracts of brain tissues from ”long-term” 17β-estradiol-treated ovx rats showed that its effects on galanin are dependent on boththe dose and on duration. Galanin - and NPY-LI in brain tissues of young ovx rats and mice increased in response to 17β-estradiol treatment in the HiFo, frontal cortex and striatum already within hours. This effect was not blocked by Tamoxifen® in rats. The mechanism of the 17β-estradiol effects on galanin levels in the rat HiFo may be related to decreased release of galanin into the extracellular fluid, since galanin-LI decreased in microdialysis samples two hours after a single injection of 17β-estradiol. Species differences were observed with regards to galanin, possibly due to tissue and species differences in the distribution of estrogen receptors.

    In the HiFo and caudate nucleus of mice, we found an increase in NPY-transcript after two hours by means of insitu hybridization, perhaps a compensatory up-regulation of NPY mRNA after increased 17β-estradiol-induced release in these areas. Taken together with no effects of Tamoxifen® on the levels on galanin in the HiFo of rats, the short duration, and the fact that the density of classical estrogen receptors seems to be limited in the striatum, we suggest that these effects are mediated through a membrane-related mechanism perhaps not involving the classical ER route.

    With an antiserum raised against the C-terminal end of the first 16 aminoacids of galanin- the sequence important for binding of intact galanin to its receptor - we found a novel compound which appears to be a homologue to galanin. Chromatographical analysis revealed that it was not galanin(1-29) or the galanin related peptide, galaninlike peptide (GALP), but appeared with immunohistochemistry in the galanin systems in the brain and was further influenced by 17β-estradiol in the HiFo and frontal cortex in a similar manner as galanin(1-29).

    In conclusion, tissue concentrations of galanin, a putative galanin homologue and NPY can be altered already after one hour by 17β-estradiol treatment e.i. in the HiFo. These ”short-term” effects are most likely to be due to effects on estrogen-primed peptide release which might influence mechanisms important for memory, cognition and mood.

    Delarbeten
    1. Estrogen induces a rapid increase in galanin levels in female rat hippocampal formation: possibly a nongenomic/indirect effect
    Öppna denna publikation i ny flik eller fönster >>Estrogen induces a rapid increase in galanin levels in female rat hippocampal formation: possibly a nongenomic/indirect effect
    Visa övriga...
    2005 (Engelska)Ingår i: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 21, nr 8, s. 2089-2099Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Administration of 17β-estradiol to ovariectomized rats increased the concentrations of galanin-like immunoreactivity (LI) in the hippocampal formation by 215% (P < 0.001) within 1 h. An increase of 125% (P < 0.05) was observed in the same brain region in the proestrous phase of a normal estrous cycle. Tamoxifen® did not block the 17β-estradiol-induced increase in the concentration of galanin-LI but resulted in a 62% decrease in the hypothalamus within 1 h. In vivo microdialysis in the dorsal hippocampal formation showed a decrease of extracellular galanin-LI (P < 0.001) 1−2 h after treatment with 17β-estradiol, indicating a decreased release of galanin. For comparision, we studied the concentrations of neuropeptide Y, which were not influenced significantly in any of the regions studied. Taken together our results suggest that 17β-estradiol inhibits galanin release, presumably from noradrenergic nerve terminals, and primarily via a nongenomic/indirect action, not necessarily involving the classical nuclear receptors ER-α or ER-β. These rapid estrogen-induced changes in galanin release could influence transmitter signalling and plasticity in the hippocampal formation.

    Nyckelord
    estrogen receptors, immunohistochemistry, in situ hybridization, microdialysis, radioimmunoassay
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-13379 (URN)10.1111/j.1460-9568.2005.04050.x (DOI)
    Tillgänglig från: 2005-09-29 Skapad: 2005-09-29 Senast uppdaterad: 2017-12-13
    2. Galanin in the hippocampal formation of female rats: effects of 17beta estradiol
    Öppna denna publikation i ny flik eller fönster >>Galanin in the hippocampal formation of female rats: effects of 17beta estradiol
    Visa övriga...
    2005 (Engelska)Ingår i: Neuropeptides, ISSN 0143-4179, Vol. 39, nr 3, s. 253-257Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    17β-Estradiol induced an increase in tissue concentrations of galanin in the hippocampal formation of ovariectomized rats. This increase was dose- and time dependent, and occurred already 60 min after steroid administration and was not blocked by Tamoxifen®. There was also an increase in galanin in the pro-estrous phase in regularly cycling rats. The estrogen-induced rapid increase may at least in part be due to decreased release of galanin as demonstrated by in vivo microdialysis studies. Thus, sex steroid hormones may influence signalling molecules in brain areas of importance for cognitive functions.

    Nyckelord
    Estrogen receptors; Radioimmunoassay; Microdialysis; Immunohistochemistry; In situ hybridization
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-13380 (URN)10.1016/j.npep.2005.01.002 (DOI)
    Tillgänglig från: 2005-09-29 Skapad: 2005-09-29
    3. Rapid versus prolonged treatment with 17beta estradiol induces different effects on galanin and neuropeptide Y concentrations in the brain of ovariectomized mice
    Öppna denna publikation i ny flik eller fönster >>Rapid versus prolonged treatment with 17beta estradiol induces different effects on galanin and neuropeptide Y concentrations in the brain of ovariectomized mice
    Visa övriga...
    Manuskript (Övrigt vetenskapligt)
    Identifikatorer
    urn:nbn:se:liu:diva-13381 (URN)
    Tillgänglig från: 2005-09-29 Skapad: 2005-09-29 Senast uppdaterad: 2010-01-13
    4. A short estrogen-responsive N-terminal galanin homologue found in rat brain and gut with antiserum raised against rat galanin(1-16)
    Öppna denna publikation i ny flik eller fönster >>A short estrogen-responsive N-terminal galanin homologue found in rat brain and gut with antiserum raised against rat galanin(1-16)
    2007 (Engelska)Ingår i: Neurochemical Research, ISSN 0364-3190, Vol. 31, nr 2, s. 177-188Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Galanin-like peptide (GALP) is currently the only known galanin(1-29) homologue. However, three different galanin receptors, of which GalR3 exhibits comparatively low affinity for galanin(1-29), and molecular heterogeneity of immunoreactive galanin are arguments for presence of other endogenous galanin homologues. Since antibodies recognize three-dimensional structures of 3–5 amino acids in a peptide, we raised antibodies in rabbits against galanin(1-16) conjugated to bovine serum albumin, looking for the presence of endogenous N-terminal galanin homologues in rat tissues. The antiserum selected had 7,830 times higher avidity for galanin(1-16) compared to galanin(1-29). A single immunoreactive component with a Stokes radius of about 8 amino acids was found. Immunohistochemistry strongly suggested that this immunoreactivity is localised in the same neurons as galanin(1-29). Furthermore, its concentration was increased in response to estrogen treatment in the same brain regions as galanin(1-29), although not as rapidly. The present results indicate the presence of a novel endogenous N-terminal galanin homologue.

    Nyckelord
    Hippocampus, HPLC, Hypothalamus, Immunohistochemistry, Radioimmunoassay
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-13382 (URN)10.1007/s11064-005-9007-5 (DOI)
    Tillgänglig från: 2005-09-29 Skapad: 2005-09-29 Senast uppdaterad: 2009-08-18
  • 123.
    Hokfelt, Tomas
    et al.
    Karolinska Inst, Sweden.
    Barde, Swapnali
    Karolinska Inst, Sweden.
    Xu, Zhi-Qing David
    Karolinska Inst, Sweden; Capital Med Univ, Peoples R China.
    Kuteeva, Eugenia
    Karolinska Inst, Sweden; Atlas Antibodies AB, Sweden.
    Ruegg, Joelle
    Karolinska Inst, Sweden; Ctr Mol Med, Sweden; Swetox, Sweden.
    Le Maitre, Erwan
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Risling, Marten
    Karolinska Inst, Sweden.
    Kehr, Jan
    Pronexus Analyt AB, Sweden; Karolinska Inst, Sweden.
    Ihnatko, Robert
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten.
    Theodorsson, Elvar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Palkovits, Miklos
    Semmelweis Univ, Hungary.
    Deakin, William
    Univ Manchester, England.
    Bagdy, Gyorgy
    Semmelweis Univ, Hungary; Semmelweis Univ, Hungary; Semmelweis Univ, Hungary.
    Juhasz, Gabriella
    Univ Manchester, England; Semmelweis Univ, Hungary; Semmelweis Univ, Hungary.
    Prudhomme, H. Josee
    Douglas Hosp, Canada.
    Mechawar, Naguib
    Douglas Hosp, Canada; McGill Univ, Canada.
    Diaz-Heijtz, Rochellys
    Karolinska Inst, Sweden.
    Ogren, Sven Ove
    Karolinska Inst, Sweden.
    Neuropeptide and Small Transmitter Coexistence: Fundamental Studies and Relevance to Mental Illness2018Ingår i: Frontiers in Neural Circuits, ISSN 1662-5110, E-ISSN 1662-5110, Vol. 12, artikel-id 106Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Neuropeptides are auxiliary messenger molecules that always co-exist in nerve cells with one or more small molecule (classic) neurotransmitters. Neuropeptides act both as transmitters and trophic factors, and play a role particularly when the nervous system is challenged, as by injury, pain or stress. Here neuropeptides and coexistence in mammals are reviewed, but with special focus on the 29/30 amino acid galanin and its three receptors GalR1, -R2 and -R3. In particular, galanins role as a co-transmitter in both rodent and human noradrenergic locus coeruleus (LC) neurons is addressed. Extensive experimental animal data strongly suggest a role for the galanin system in depression-like behavior. The translational potential of these results was tested by studying the galanin system in postmortem human brains, first in normal brains, and then in a comparison of five regions of brains obtained from depressed people who committed suicide, and from matched controls. The distribution of galanin and the four galanin system transcripts in the normal human brain was determined, and selective and parallel changes in levels of transcripts and DNA methylation for galanin and its three receptors were assessed in depressed patients who committed suicide: upregulation of transcripts, e.g., for galanin and GalR3 in LC, paralleled by a decrease in DNA methylation, suggesting involvement of epigenetic mechanisms. It is hypothesized that, when exposed to severe stress, the noradrenergic LC neurons fire in bursts and release galanin from their soma/dendrites. Galanin then acts on somato-dendritic, inhibitory galanin autoreceptors, opening potassium channels and inhibiting firing. The purpose of these autoreceptors is to act as a brake to prevent overexcitation, a brake that is also part of resilience to stress that protects against depression. Depression then arises when the inhibition is too strong and long lasting - a maladaption, allostatic load, leading to depletion of NA levels in the forebrain. It is suggested that disinhibition by a galanin antagonist may have antidepressant activity by restoring forebrain NA levels. A role of galanin in depression is also supported by a recent candidate gene study, showing that variants in genes for galanin and its three receptors confer increased risk of depression and anxiety in people who experienced childhood adversity or recent negative life events. In summary, galanin, a neuropeptide coexisting in LC neurons, may participate in the mechanism underlying resilience against a serious and common disorder, MDD. Existing and further results may lead to an increased understanding of how this illness develops, which in turn could provide a basis for its treatment.

  • 124.
    Ingberg, Edvin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Challenges in experimental stroke research: The 17β-estradiol example2016Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Ischemic stroke causes millions of deaths around the world each year, and surviving patients often suffer from long-term disability. Hundreds of promising drug candidates have been identified in animal models, but the clinical trials have repeatedly failed. Lack of methodological quality in the animal studies, e.g. low statistical power as a result of small group sizes in combination with high outcome variability and high mortality, has been suggested to in part explain the lack of translational success. In the meta-analytical Papers II and Paper V, we therefore investigated how method parameters impact infarct size variation and mortality in rodent stroke studies. These findings can help researchers to optimize their animal models or to more exactly predict variability and mortality given a certain experimental setup.

    The relation between ischemic stroke and estrogens is complex. Premenopausal women have a lower risk of stroke than men of the same age, suggesting that female sex hormones provide protection against cerebrovascular events. The idea of a beneficial effect on the brain of estrogens was also supported by epidemiological studies showing that estrogens given as postmenopausal hormone replacement therapy decreased the risk of stroke. However, subsequent clinical trials reported the opposite, an increased risk. Interestingly, discrepancies exist also in the animal stroke literature. The majority of the rodent studies on the effects of estrogens have shown protection, but there are also several examples of increased damage. Based on experimental results and a meta-analysis, it was hypothesized that differences in hormone administration methods and their resulting plasma concentrations of estrogens might explain the previous discordant animal findings. Paper I investigated the commonly used methods for 17β-estradiol administration and found that the popular slow-release pellets produced high and unpredictable serum concentrations. A novel method with 17β-estradiol administered orally in Nutella® was also evaluated with promising results. Paper III extracted data regarding methodological choices from all previously published estrogen-stroke studies, and showed through metaanalysis that slow-release pellets are more prone to render estrogens damaging. Finally, Paper IV tested whether estrogens could both exert neuroprotection and promote detrimental effects merely depending on dose and irrespective of the administration route. Surprisingly, and in contrast to the hypothesis, a significant negative correlation was found between 17β-estradiol dose group and infarct size meaning that the higher the dose, the smaller the infarcts.

    In summary, this thesis does not confirm the hypothesis of dose-related neuroprotective vs neurodamaging effects of estrogens on ischemic stroke. If high estrogen doses/plasma concentrations per se can cause increased stroke damage, such a phenomenon is not very robust, and seems to depend on tight dose ranges and/or other experimental circumstances. Although not directly applicable to the clinical situation, hopefully in a long-term perspective these findings may contribute in elucidating when estrogens are beneficial and when they are harmful. Further, it adds to the growing literature on how the quality of experimental stroke research can be increased to try to overcome translational difficulties.

    Delarbeten
    1. Methods for long-term 17β-estradiol administration to mice
    Öppna denna publikation i ny flik eller fönster >>Methods for long-term 17β-estradiol administration to mice
    2012 (Engelska)Ingår i: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 175, nr 1, s. 188-193Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Rodent models constitute a cornerstone in the elucidation of the effects and biological mechanisms of 17β-estradiol. However, a thorough assessment of the methods for long-term administration of 17β-estradiol to mice is lacking. The fact that 17β-estradiol has been demonstrated to exert different effects depending on dose emphasizes the need for validated administration regimens. Therefore, 169 female C57BL/6 mice were ovariectomized and administered 17β-estradiol using one of the two commonly used subcutaneous methods; slow-release pellets (0.18 mg, 60-day release pellets; 0.72 mg, 90-day release pellets) and silastic capsules (with/without convalescence period, silastic laboratory tubing, inner/outer diameter: 1.575/3.175 mm, filled with a 14 mm column of 36 μg 17β-estradiol/mL sesame oil), or a novel peroral method (56 μg 17β-estradiol/day/kg body weight in the hazelnut cream Nutella). Forty animals were used as ovariectomized and intact controls. Serum samples were obtained weekly for five weeks and 17β-estradiol concentrations were measured using radioimmunoassay. The peroral method resulted in steady concentrations within – except on one occasion – the physiological range and the silastic capsules produced predominantly physiological concentrations, although exceeding the range by maximum a factor three during the first three weeks. The 0.18 mg pellet yielded initial concentrations an order of magnitude higher than the physiological range, which then decreased drastically, and the 0.72 mg pellet produced between 18 and 40 times higher concentrations than the physiological range during the entire experiment. The peroral method and silastic capsules described in this article constitute reliable modes of administration of 17β-estradiol, superior to the widely used commercial pellets.

    Ort, förlag, år, upplaga, sidor
    Elsevier, 2012
    Nyckelord
    Estradiol; Slow-release pellets; Silastic capsule; Per os; Uterine weight
    Nationell ämneskategori
    Farmaceutiska vetenskaper
    Identifikatorer
    urn:nbn:se:liu:diva-107100 (URN)10.1016/j.ygcen.2011.11.014 (DOI)000299065800022 ()22137913 (PubMedID)2-s2.0-84855192470 (Scopus ID)
    Tillgänglig från: 2014-06-05 Skapad: 2014-06-05 Senast uppdaterad: 2018-01-11Bibliografiskt granskad
    2. Method parameters’ impact on mortality and variability in rat stroke experiments: a meta-analysis
    Öppna denna publikation i ny flik eller fönster >>Method parameters’ impact on mortality and variability in rat stroke experiments: a meta-analysis
    2013 (Engelska)Ingår i: BMC neuroscience (Online), ISSN 1471-2202, E-ISSN 1471-2202, Vol. 14, nr 41Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Background

    Even though more than 600 stroke treatments have been shown effective in preclinical studies, clinically proven treatment alternatives for cerebral infarction remain scarce. Amongst the reasons for the discrepancy may be methodological shortcomings, such as high mortality and outcome variability, in the preclinical studies. A common approach in animal stroke experiments is that A) focal cerebral ischemia is inflicted, B) some type of treatment is administered and C) the infarct sizes are assessed. However, within this paradigm, the researcher has to make numerous methodological decisions, including choosing rat strain and type of surgical procedure. Even though a few studies have attempted to address the questions experimentally, a lack of consensus regarding the optimal methodology remains.

    Methods

    We therefore meta-analyzed data from 502 control groups described in 346 articles to find out how rat strain, procedure for causing focal cerebral ischemia and the type of filament coating affected mortality and infarct size variability.

    Results

    The Wistar strain and intraluminal filament procedure using a silicone coated filament was found optimal in lowering infarct size variability. The direct and endothelin methods rendered lower mortality rate, whereas the embolus method increased it compared to the filament method.

    Conclusions

    The current article provides means for researchers to adjust their middle cerebral artery occlusion (MCAo) protocols to minimize infarct size variability and mortality.

    Ort, förlag, år, upplaga, sidor
    BioMed Central, 2013
    Nyckelord
    Brain infarction, Middle cerebral artery occlusion, Rats, Methods, Mortality, Variability
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-93981 (URN)10.1186/1471-2202-14-41 (DOI)000318616000001 ()23548160 (PubMedID)
    Anmärkning

    Funding Agencies|County Council of Ostergotland, Sweden||

    Tillgänglig från: 2013-06-13 Skapad: 2013-06-13 Senast uppdaterad: 2017-12-06Bibliografiskt granskad
    3. Impact of methodology on estrogens’ effects on cerebral ischemia in rats: an updated meta-analysis
    Öppna denna publikation i ny flik eller fönster >>Impact of methodology on estrogens’ effects on cerebral ischemia in rats: an updated meta-analysis
    2014 (Engelska)Ingår i: BMC neuroscience (Online), ISSN 1471-2202, E-ISSN 1471-2202, Vol. 15, nr 22Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    BACKGROUND:

    Although most animal stroke studies have demonstrated potent neuroprotective effects of estrogens, there are a number of articles reporting the opposite. In 2009, we made the case that this dichotomy was related to administered estrogen dose. Several other suggestions for the discordant results have also been propagated, including the age of the experimental animals and the length of hypoestrogenicity prior to estrogen administration. These two suggestions have gained much popularity, probably because of their kinship with the window of opportunity hypothesis, which is commonly used to explain the analogous dichotomy among human studies. We were therefore encouraged to perform an updated meta-analysis, and to improve it by including all relevant variables in a large multiple regression model, where the impact of confounders could be controlled for.

    RESULTS:

    The multiple regression model revealed an indisputable impact of estrogen administration mode on the effects of estrogens in ischemic stroke. Subcutaneous slow-release pellets differed from the injection and silastic capsule treatments in terms of impact of estrogens on ischemic stroke, showing that the first mentioned were more prone to render estrogens damaging. Neither the use of elderly animals nor the adoption of longer wash-out periods influenced estrogens' effects on experimental ischemic stroke in rats.

    CONCLUSIONS:

    We conclude that the discordant results regarding estrogens' effects in rat models of ischemic stroke are a consequence of differences in estrogen administration modes. These results are not only of importance for the ongoing debate regarding menopausal hormone therapy, but also have an important bearing on experimental stroke methodology and the apparent translational roadblock for suggested stroke interventions.

    Ort, förlag, år, upplaga, sidor
    BioMed Central, 2014
    Nyckelord
    Cerebral ischemia; Estradiol; Estrogens; Meta-analysis; Rats; Stroke
    Nationell ämneskategori
    Medicinska och farmaceutiska grundvetenskaper
    Identifikatorer
    urn:nbn:se:liu:diva-106875 (URN)10.1186/1471-2202-15-22 (DOI)000334885400001 ()24495535 (PubMedID)
    Tillgänglig från: 2014-05-28 Skapad: 2014-05-23 Senast uppdaterad: 2018-01-11Bibliografiskt granskad
    4. Effects of high and low 17β-estradiol doses on focal cerebral ischemia in rats
    Öppna denna publikation i ny flik eller fönster >>Effects of high and low 17β-estradiol doses on focal cerebral ischemia in rats
    2016 (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    The majority of the numerous animal studies of the effects of estrogens on cerebral ischemia have reported neuroprotective results, but a few have shown increased damage. Differences in hormone administration methods, resulting in highly different 17β-estradiol levels, may explain the discrepancies in previously reported effects. The objective of the present study was to test the hypothesis that it is the delivered dose per se, and not the route and method of administration, that determines the effect, and that high doses are damaging while lower doses are protective. One hundred and twenty ovariectomized female Wistar rats (n=40 per group) were randomized into three groups, subcutaneously administered different doses of 17β-estradiol and subjected to transient middle cerebral artery occlusion. The modifi ed sticky tape test was performed after 24 h and the rats were subsequently sacrifi ced for infarct size measurements. In contrast to our hypothesis, a signifi cant negative correlation between 17β-estradiol dose and infarct size was found (p=0.018). Thus, no support was found for the hypothesis that 17β-estradiol can be both neuroprotective and neurotoxic merely depending on dose. In fact, on the contrary, the fi ndings indicate that the higher the dose of 17β-estradiol, the smaller the infarct.

    Nationell ämneskategori
    Klinisk medicin Mikrobiologi inom det medicinska området
    Identifikatorer
    urn:nbn:se:liu:diva-123890 (URN)
    Tillgänglig från: 2016-01-13 Skapad: 2016-01-13 Senast uppdaterad: 2018-01-10Bibliografiskt granskad
    5. Method parameters’ impact on mortality and variability in mouse stroke experiments: a meta-analysis
    Öppna denna publikation i ny flik eller fönster >>Method parameters’ impact on mortality and variability in mouse stroke experiments: a meta-analysis
    Visa övriga...
    2016 (Engelska)Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Although hundreds of promising substances have been tested in clinical trials, thrombolysis currently remains the only specifi c pharmacological treatment for ischemic stroke. Poor quality, e.g. low statistical power, in the preclinical studies has been suggested to play an important role in these failures. Therefore, it would be attractive to use animal models optimized to minimize unnecessary mortality and outcome variability, or at least to be able to power studies more exactly by predicting variability and mortality given a certain experimental setup. The possible combinations of methodological parameters are innumerous, and an experimental comparison of them all is therefore not feasible. As an alternative approach, we extracted data from 334 experimental mouse stroke articles and, using a hypothesis-driven meta-analysis, investigated the method parameters’ impact on infarct size variability and mortality. The use of Swiss and C57BL6 mice as well as permanent occlusion of the middle cerebral artery rendered the lowest variability of the infarct size while the emboli methods increased variability. The use of Swiss mice increased mortality. Our study offers guidance for researchers striving to optimize mouse stroke models.

    Ort, förlag, år, upplaga, sidor
    Nature Publishing Group, 2016
    Nationell ämneskategori
    Klinisk medicin Mikrobiologi inom det medicinska området
    Identifikatorer
    urn:nbn:se:liu:diva-123892 (URN)10.1038/srep21086 (DOI)000370034300001 ()
    Anmärkning

    Funding agencies:  County Council of Ostergotland, Sweden

    Vid tiden för disputation förelåg publikationen endast som manuskript

    Tillgänglig från: 2016-01-13 Skapad: 2016-01-13 Senast uppdaterad: 2018-01-10Bibliografiskt granskad
  • 125.
    Isacsson, Nils
    et al.
    Linköpings universitet, Institutionen för beteendevetenskap och lärande.
    Kolbeinsson, Örn
    Linköpings universitet, Institutionen för beteendevetenskap och lärande.
    Prediction of treatment response in Social Anxiety Disorder, what does the brain tell us that questionnaires do not?: Using brain activity related to self- and other-referential criticism to predict treatment response to Internet- delivered Cognitive Behaviour Therapy for Social Anxiety Disorder2016Självständigt arbete på avancerad nivå (masterexamen), 20 poäng / 30 hpStudentuppsats (Examensarbete)
    Abstract [en]

    Predicting who will benefit from what in the treatment of psychiatric disorders is incremental to future development of psychological treatments. In the current study functional magnetic resonance imaging (fMRI) data from participants with social anxiety disorder (SAD) was used to elucidate whether neural responses to negative evaluation could predict treatment response in SAD. Nine weeks prior to Internet- delivered Cognitive Behaviour Therapy (ICBT) onset, participants viewed negative social stimuli directed either at themselves or an significant other during fMRI scanning. Regression analyses including the differential activations for other-referential criticism in contrast to self-referential criticism in the posterior mid cingulate cortex (pMCC) and the lingual gyrus (LG) predicted 34% of treatment change as measured by residual gain scores on the Liebowitz Social Anxiety Scale Self-Report (LSAS-SR) in our sample. The final regression model, combining these measures with behavioural measures, which by themselves explained 27% of the variance, resulted in a model explaining 50% of the variance regarding treatment response. This lends additional support to the notion that further elucidating the neurobiological underpinnings of core processes in SAD, as well as the neural correlates of treatment response to CBT, would be of great value in predicting treatment outcome. 

  • 126.
    Jacob, Stefan
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Johansson, Cecilia
    Karolinska Institutet, Stockholm, Sweden.
    Fridberger, Anders
    Karolinska Institutet, Stockholm, Sweden.
    Noise-induced alterations in cochlear mechanics, electromotility, and cochlear amplification2013Ingår i: Pflügers Archiv: European Journal of Physiology, ISSN 0031-6768, E-ISSN 1432-2013, Vol. 465, nr 6, s. 907-917Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Loud sounds are a common cause of hearing loss. Very intense sounds may result in permanent hearing loss, but lower levels typically cause a transient decrease in auditory sensitivity. Studies have arrived at different conclusions as regards the physiological mechanisms underlying such temporary threshold shifts. Here, we investigated the effect of acoustic overstimulation on the mechanics of the low-frequency areas of the guinea pig cochlea. We demonstrate that brief loud sound exposure results in an increased phase lag and a paradoxical frequency-specific increase of sound-evoked displacement. Despite the increased displacement, electrically evoked motion is reduced. Because electromotility is important for amplifying low-level sounds, this change was associated with a decrease in measures of cochlear amplification. These changes recovered over the course of 30-40 min. Overstimulation also caused an increase in cytoplasmic calcium levels of both hair cells and supporting cells. These data suggest that reduced organ of Corti stiffness contributes to temporary threshold shifts.

  • 127. Jacob, Stefan
    et al.
    Johansson, Cecilia
    Ulfendahl, Mats
    Fridberger, Anders
    Karolinska Institutet / Karolinska University Hospital, Stockholm, Sweden.
    A digital heterodyne laser interferometer for studying cochlear mechanics2009Ingår i: Journal of Neuroscience Methods, ISSN 0165-0270, E-ISSN 1872-678X, Vol. 179, nr 2, s. 271-277Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Laser interferometry is the technique of choice for studying the smallest displacements of the hearing organ. For low intensity sound stimulation, these displacements may be below 1 nm. This cannot be reliably measured with other presently available techniques in an intact organ of Corti. In a heterodyne interferometer, light is projected against an object of study and motion of the target along the optical axis causes phase and frequency modulations of the back-reflected light. To recover object motion, the reflected light is made to interfere with a reference beam of artificially altered frequency, producing a beating signal. In conventional interferometers, this carrier signal is demodulated with analog electronics. In this paper, we describe a digital implementation of the technique, using direct carrier sampling. In order to obtain the necessary reference signal for demodulation we introduce an additional third light path. Together, this results in lower noise and reduces the cost of the system.

    Within the hearing organ, different structures may move in different directions. It is therefore necessary to precisely measure the angle of incidence of the laser light, and to precisely localize the anatomical structure where the measurement is performed. Therefore, the interferometer is integrated with a laser scanning confocal microscope that permits us to map crucial morphometric parameters in each experiment. We provide key construction parameters and a detailed performance characterization. We also show that the system accurately measures the diminutive vibrations present in the apical turn of the cochlea during low-level sound stimulation.

  • 128. Jacob, Stefan
    et al.
    Pienkowski, Martin
    Fridberger, Anders
    Karolinska Institutet / Karolinska University Hospital, Stockholm, Sweden.
    The endocochlear potential alters cochlear micromechanics2011Ingår i: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 100, nr 11, s. 2586-2594Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Acoustic stimulation gates mechanically sensitive ion channels in cochlear sensory hair cells. Even in the absence of sound, a fraction of these channels remains open, forming a conductance between hair cells and the adjacent fluid space, scala media. Restoring the lost endogenous polarization of scala media in an in vitro preparation of the whole cochlea depolarizes the hair cell soma. Using both digital laser interferometry and time-resolved confocal imaging, we show that this causes a structural refinement within the organ of Corti that is dependent on the somatic electromotility of the outer hair cells (OHCs). Specifically, the inner part of the reticular lamina up to the second row of OHCs is pulled toward the basilar membrane, whereas the outer part (third row of OHCs and the Hensen's cells) unexpectedly moves in the opposite direction. A similar differentiated response pattern is observed for sound-evoked vibrations: restoration of the endogenous polarization decreases vibrations of the inner part of the reticular lamina and results in up to a 10-fold increase of vibrations of the outer part. We conclude that the endogenous polarization of scala media affects the function of the hearing organ by altering its geometry, mechanical and electrical properties.

  • 129.
    Jacob, Stefan
    et al.
    Karolinska Institutet / Karolinska University Hospital, Stockholm, Sweden.
    Tomo, Igor
    Karolinska Institutet / Karolinska University Hospital, Stockholm, Sweden.
    Fridberger, Anders
    Karolinska Institutet / Karolinska University Hospital, Stockholm, Sweden.
    Boutet de Monvel, Jacques
    Karolinska Institutet / Karolinska University Hospital, Stockholm, Sweden.
    Ulfendahl, Mats
    Karolinska Institutet / Karolinska University Hospital, Stockholm, Sweden.
    Rapid confocal imaging for measuring sound-induced motion of the hearing organ in the apical region2007Ingår i: Journal of Biomedical Optics, ISSN 1083-3668, E-ISSN 1560-2281, Vol. 12, nr 2, s. 021005-1-021005-6Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We describe a novel confocal image acquisition system capable of measuring the sound-evoked motion of the organ of Corti. The hearing organ is imaged with a standard laser scanning confocal microscope during sound stimulation. The exact temporal relation between each image pixel and the sound stimulus is quantified. The motion of the structures under study is obtained by fitting a Fourier series to the time dimension of a continuous sequence of acquired images. Previous versions of this acquisition system used a simple search to find pixels with similar phase values. The Fourier series approach permits substantially faster image acquisition with reduced noise levels and improved motion estimation. The system is validated by imaging various vibrating samples attached to a feedback-controlled piezoelectric translator. When using a rigid sample attached to the translator, the system is capable of measuring motion with peak-to-peak amplitudes smaller than 50 nm with an error below 20% at frequencies between 50 and 600 Hz. Examples of image sequences from the inner ear are given, along with detailed performance characteristics of the method.

  • 130.
    Jakola, Asgeir Store
    et al.
    Department of Neurosurgery, Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Neurosurgery, St. Olavs Hospital, Trondheim, Norway; Institute of Neuroscience and Physiology, Department of Clinical Neuroscience, University of Gothenburg, Sahlgrenska Academy, Gothenburg, Sweden.
    Werlenius, Katja
    Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden; Institute of Clinical Sciences, University of Gothenburg, Sahlgrenska Academy, Gothenburg, Sweden.
    Mudaisi, Munila
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Hylin, Sofia
    Department of Neurology, Karolinska University Hospital, Stockholm, Sweden.
    Kinhult, Sara
    Department of Oncology, Skåne University Hospital, Lund, Sweden.
    Bartek, Jiri
    Department of Neurosurgery, Karolinska University Hospital, Stockholm, Sweden; Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
    Salvesen, Øyvind
    Department of Public Health and Nursing, Norwegian University of Science and Technology, Trondheim, Norway.
    Carlsen, Sven Magnus
    Department of Cancer Research and Molecular medicine, Norwegian University of Science and Technology, Trondheim, Norway; Department of Endocrinology, St. Olavs Hospital, Trondheim, Norway.
    Strandéus, Michael
    Department of Oncology, County Hospital Ryhov, Jönköping, Sweden.
    Lindskog, Magnus
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden; Section of Oncology, Akademiska University Hospital, Uppsala, Sweden.
    Löfgren, David
    Department of Oncology, Örebro University Hospital, Örebro, Sweden.
    Rydenhag, Bertil
    Department of Neurosurgery, Sahlgrenska University Hospital, Gothenburg, Sweden; Institute of Neuroscience and Physiology, Department of Clinical Neuroscience, University of Gothenburg, Sahlgrenska Academy, Gothenburg, Sweden.
    Carstam, Louise
    Department of Neurosurgery, Sahlgrenska University Hospital, Gothenburg, Sweden; Institute of Neuroscience and Physiology, Department of Clinical Neuroscience, University of Gothenburg, Sahlgrenska Academy, Gothenburg, Sweden.
    Gulati, Sasha
    Department of Neurosurgery, St. Olavs Hospital, Trondheim, Norway; Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway.
    Solheim, Ole
    Department of Neurosurgery, St. Olavs Hospital, Trondheim, Norway; Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway.
    Bartek, Jiri
    Department of Medical Biochemistry and Biophysics, Division of Genome Biology, Science for Life Laboratory,, Karolinska Institute, Stockholm, Sweden; Research Center, Danish Cancer Society, Copenhagen, Denmark.
    Solheim, Tora
    European Palliative Care Research Centre (PRC), Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway; Cancer Clinic, St. Olavs Hospital, Trondheim, Norway.
    Disulfiram repurposing combined with nutritional copper supplement as add-on to chemotherapy in recurrent glioblastoma (DIRECT): Study protocol for a randomized controlled trial2018Ingår i: F1000 Research, E-ISSN 2046-1402, Vol. 7, artikel-id 1797Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Disulfiram (DSF) is a well-tolerated, inexpensive, generic drug that has been in use to treat alcoholism since the 1950s. There is now independent preclinical data that supports DSF as an anticancer agent, and experimental data suggest that copper may increase its anti-neoplastic properties. There is also some clinical evidence that DSF is a promising anticancer agent in extracranial cancers. In glioblastoma, DSF induced O 6-methylguanine methyltransferase (MGMT) inhibition may increase response to alkylating chemotherapy. A recent phase I study demonstrated the safety of DSF in glioblastoma patients when DSF was administered at doses below 500 mg/day together with chemotherapy. We plan to assess the effects of DSF combined with nutritional copper supplement (DSF-Cu) as an adjuvant to alkylating chemotherapy in glioblastoma treatment. Methods: In an academic, industry independent, multicenter, open label randomized controlled phase II/III trial with parallel group design (1:1) we will assess the efficacy and safety of DSF-Cu in glioblastoma treatment. The study will include 142 patients at the time of first recurrence of glioblastoma where salvage therapy with alkylating chemotherapy is planned. Patients will be randomized to treatment with or without DSF-Cu. Primary end-point is survival at 6 months. Secondary end-points are overall survival, progression free survival, quality of life, contrast enhancing tumor volume and safety. Discussion: There is a need to improve the treatment of recurrent glioblastoma. Results from this randomized controlled trial with DSF-Cu in glioblastoma will serve as preliminary evidence of the future role of DSF-Cu in glioblastoma treatment and a basis for design and power estimations of future studies. In this publication we provide rationale for our choices and discuss methodological issues. Trial registration: The study underwent registration in EudraCT 2016-000167-16 (Date: 30.03.2016,) and Clinicaltrials.gov NCT02678975 (Date: 31.01.2016) before initiating the study.

  • 131.
    Jamali, Reza
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Peripheral Hypoglycaemic Neuropathy in Type 1 Diabetic Rats: Morphologic and Metabolic Studies2006Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Hyperglycaemia caused by insulin deficiency is believed to play a major role in the de-velopment of neuropathy in diabetic patients. The clinical and pathological features of diabetic neuropathy vary considerably, although sensory and autonomic dysfunctions are the most common characteristics. Normalisation of the blood glucose level by ef-fective insulin treatment decreases the incidence of diabetic neuropathy in patients. However, intensive insulin therapy may result in more frequent hypoglycaemic epi-sodes than are provoked by less ambitious diabetes control. Neuropathy might also be induced by severe hypoglycaemia in diabetes or insulinoma. Accordingly, it seems that the diversity in clinical symptoms of diabetic neuropathy may be due to the combined effects of hyperglycaemia and hypoglycaemia. Based on that assumption, the general aim of this project was to study the relationship between severe hypoglycaemia and pe-ripheral neuropathy in diabetic rats. To understand how the development of neuropathy is related to glycaemic control, we needed to be aware of the glucose dynamics in the animal model that we used. The aim was to ascertain whether the diabetic rats were similar to type 1 diabetic patients with regard to such dynamics. To achieve that goal, we used a MiniMed continuous glucose monitoring system (CGMS®) to measure sub-cutaneous glucose in freely moving rats over a period of 72 hours. The glucose monitor worked well, and it showed that the insulin-treated diabetic BB/Wor rats with a hyper-glycaemic insulin regimen have a glycaemic status similar to that of type 1 diabetic patients with poor glycaemic control. The diabetic rats with a hypoglycaemic regimen generally had low blood glucose levels.

    Prolonged hypoglycaemia led to axonal de- and regeneration of large myelinated fibres in vagus nerve destined to the laryngeal muscle. Axonal de- and regeneration was also observed in the gastrocnemius and sural nerves, although the frequency of degeneration was much lower in the sural nerve. Small myelinated and unmyelinated nerve fibres were normal in these nerves. These results suggest that hypoglycaemia preferentially damages muscle-related nerve fibres. In contrast, in the diabetic rats exposed to pro-longed hyperglycaemia, only the sural nerve exhibited decreased myelinated fibre diameter in the absence of obvious axonal degeneration.

    In situ glucose measurements by microdialysis showed that the glucose concentrations in blood and subcutaneous tissue were similar in healthy, diabetic hyperglycaemic, and diabetic hypoglycaemic rats. In the healthy and hyperglycaemic animals, the lowest glucose level was found in the peripheral nerve. Moreover, in controls, the glucose level was lower in muscle than in blood. In hypoglycaemic rats, there were no signifi-cant differences in glucose concentrations between different tissues.

    Delarbeten
    1. Continuous monitoring of the subcutaneous glucose level in freely moving normal and diabetic rats and in humans with Type I diabetes
    Öppna denna publikation i ny flik eller fönster >>Continuous monitoring of the subcutaneous glucose level in freely moving normal and diabetic rats and in humans with Type I diabetes
    2002 (Engelska)Ingår i: Diabetes Technology and Therapeutics, ISSN 1520-9156, Vol. 4, nr 3, s. 305-312Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Laboratory animals are extensively used in diabetic research. However, it is not known whether the glucose dynamics in laboratory animals are similar to the dynamics in humans. The aim of the present study is to see whether the Medtronic MiniMed continuous subcutaneous glucose monitoring system can be used to record fluctuations of the glucose level in freely moving normal and insulin-treated diabetic rats. The monitoring system was applied during 3 days to normal and diabetic hyperglycemic and hypoglycemic rats treated with insulin implants. Corresponding data from type 1 diabetic patients with poor glycemic control were selected retrospectively in order to note the similarities and differences. In normal rats the subcutaneous glucose level varied slightly (median = 111 mg/dL). In hyperglycemic rats the subcutaneous glucose values fluctuated markedly around a median of 226 mg/dL. The fluctuations formed a short-wave pattern with a low amplitude, superimposed on a long-wave pattern with a high amplitude. The subcutaneous glucose profile seen in type 1 diabetic patients (median = 180 mg/dL) was similar to that observed in hyperglycemic rats. In hypoglycemic rats, the subcutaneous glucose level fluctuated moderately around a median of 55 mg/dL. In these rats the fluctuations formed a short-wave pattern with low amplitude, without any obvious long-wave pattern. The subcutaneous glucose values conformed to corresponding blood glucose measurements. We conclude that the Medtronic MiniMed continuous glucose monitoring system can be used to record the subcutaneous glucose level over time in freely moving rats.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-14187 (URN)10.1089/152091502760098447 (DOI)
    Tillgänglig från: 2007-01-09 Skapad: 2007-01-09 Senast uppdaterad: 2016-02-29
    2. Hypoglycaemia causes degeneration of large myelinated nerve fibres in the vagus nerve of insulin-treated diabetic ΒB/Wor rats
    Öppna denna publikation i ny flik eller fönster >>Hypoglycaemia causes degeneration of large myelinated nerve fibres in the vagus nerve of insulin-treated diabetic ΒB/Wor rats
    2005 (Engelska)Ingår i: Acta Neuropathologica, ISSN 0001-6322, Vol. 109, nr 2, s. 198-206Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The aim of this study was to find out whether dysglycaemia causes neuropathy in the vagus nerve of insulin-treated diabetic BB/Wor rats. Specimens were collected from the left vagus nerve proximal and distal to the level of recurrent laryngeal branch and from the recurrent branch itself in control rats and diabetic BB/Wor rats subjected to hyper- or hypoglycaemia. Myelinated and unmyelinated axons were counted and myelinated axon diameters were measured by electron microscopy. In controls, the vagus nerve proximal to the recurrent branch exhibited three regions in terms of fibre composition: part A was mainly composed of large myelinated axons, part B contained small myelinated and unmyelinated axons, and part C contained mainly unmyelinated axons. The distal level resembled part C at the proximal level and the recurrent branch resembled parts A and B. In hyperglycaemic rats, a normal picture was found at the proximal and distal levels of the vagus nerve and in the recurrent branch. In hypoglycaemic rats, signs of past and ongoing degeneration and regeneration of large myelinated axons were found at the proximal and distal levels and in the recurrent branch. We conclude that hypoglycaemia elicits degenerative alterations in large myelinated axons in the vagus and recurrent laryngeal nerves in diabetic BB/Wor rats. The absence of signs of neuropathy in unmyelinated and small myelinated axons suggests that the sensory and autonomic components of the nerve are less affected. In contrast, the hyperglycaemic rats examined here did not show obvious degenerative alterations.

    Nyckelord
    Diabetes mellitus, Hypoglycaemia, Neuropathy, Vagus nerve, BB/Wor rat
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-14188 (URN)10.1007/s00401-004-0932-1 (DOI)
    Tillgänglig från: 2007-01-09 Skapad: 2007-01-09 Senast uppdaterad: 2016-02-29
    3. Differential neuropathies in hyperglycemic and hypoglycemic diabetic rats
    Öppna denna publikation i ny flik eller fönster >>Differential neuropathies in hyperglycemic and hypoglycemic diabetic rats
    2006 (Engelska)Ingår i: Journal of Neuropathology & Experimental Neurology, ISSN 0022-3069, Vol. 65, nr 12, s. 1118-1125Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    We investigated the effects of hyperglycemia and hypoglycemia on development of peripheral neuropathy in somatic motor and sensory nerves in type 1 diabetic BB/Wor rats. The animals were maintained in a hyper- or hypoglycemic state by treatment with insulin for 3 months. Nondiabetic siblings served as controls. Qualitative analysis of the gastrocnemius and sural nerves by light and electron microscopy revealed signs of Wallerian-type axonal degeneration and regeneration of large myelinated fibers in the hypoglycemic but not the hyperglycemic animals. Degeneration was more common in the gastrocnemius nerve than in the sural nerve. In hypoglycemic rats, myelinated fibers in both the gastrocnemius and sural nerves had significantly shorter internodes and smaller diameters. The decreased fiber diameter was related (r = -0.9) to the duration of severe hypoglycemia (≤2.5 mmol/L). Myelinated fiber occupancy was also decreased without any significant changes in fiber counts in both the gastrocnemius and sural nerves. In hyperglycemic rats, myelinated fibers in the sural nerve but not the gastrocnemius nerve had smaller diameters compared with controls. We conclude that hypoglycemia has a more severe impact on somatic motor nerves than on somatic sensory nerves, whereas hyperglycemia affects only somatic sensory nerves.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-14189 (URN)10.1097/01.jnen.0000248546.13176.d4 (DOI)
    Tillgänglig från: 2007-01-09 Skapad: 2007-01-09 Senast uppdaterad: 2016-02-29
    4. Simultaneous glucose measurement in blood, peripheral nerve, muscle and skin in control and diabetic rats
    Öppna denna publikation i ny flik eller fönster >>Simultaneous glucose measurement in blood, peripheral nerve, muscle and skin in control and diabetic rats
    Manuskript (Övrigt vetenskapligt)
    Identifikatorer
    urn:nbn:se:liu:diva-14190 (URN)
    Tillgänglig från: 2007-01-09 Skapad: 2007-01-09 Senast uppdaterad: 2010-01-13
  • 132.
    Jastrzebska, Kamila
    et al.
    Polish Academic Science, Poland.
    Walczak, Magdalena
    Jagiellonian University, Poland.
    Eligiusz Cieslak, Przemyslaw
    Polish Academic Science, Poland.
    Szumiec, Lukasz
    Polish Academic Science, Poland.
    Turbasa, Mateusz
    Polish Academic Science, Poland.
    Engblom, David
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Blasiak, Tomasz
    Jagiellonian University, Poland.
    Rodriguez Parkitna, Jan
    Polish Academic Science, Poland.
    Loss of NMDA receptors in dopamine neurons leads to the development of affective disorder-like symptoms in mice2016Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, artikel-id 37171Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The role of changes in dopamine neuronal activity during the development of symptoms in affective disorders remains controversial. Here, we show that inactivation of NMDA receptors on dopaminergic neurons in adult mice led to the development of affective disorder-like symptoms. The loss of NMDA receptors altered activity and caused complete NMDA-insensitivity in dopamine-like neurons. Mutant mice exhibited increased immobility in the forced swim test and a decrease in social interactions. Mutation also led to reduced saccharin intake, however the preference of sweet taste was not significantly decreased. Additionally, we found that while mutant mice were slower to learn instrumental tasks, they were able to reach the same performance levels, had normal sensitivity to feedback and showed similar motivation to exert effort as control animals. Taken together these results show that inducing the loss of NMDA receptor-dependent activity in dopamine neurons is associated with development of affective disorder-like symptoms.

  • 133.
    Johnstone, Andrea L.
    et al.
    Univ Miami, FL 33136 USA; Univ Miami, FL 33136 USA; EpiCypher Inc, NC USA.
    Andrade, Nadja S.
    Univ Miami, FL 33136 USA.
    Barbier, Estelle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Khomtchouk, Bohdan B.
    Univ Miami, FL 33136 USA; Univ Chicago, IL 60637 USA.
    Rienas, Christopher A.
    Univ Miami, FL 33136 USA.
    Lowe, Kenneth
    Univ Miami, FL 33136 USA.
    Van Booven, Derek J.
    Univ Miami, FL 33136 USA.
    Domi, Esi
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Esanov, Rustam
    Univ Miami, FL 33136 USA.
    Vilca, Samara
    Univ Miami, FL 33136 USA.
    Tapocik, Jenica D.
    NIAAA, MD USA.
    Rodriguez, Keli
    EpiCypher Inc, NC USA.
    Maryanski, Danielle
    EpiCypher Inc, NC USA.
    Keogh, Michael Christopher
    EpiCypher Inc, NC USA.
    Meinhardt, Marcus W.
    Heidelberg Univ, Germany.
    Sommer, Wolfgang H.
    Heidelberg Univ, Germany.
    Heilig, Markus
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Närsjukvården i centrala Östergötland, Psykiatriska kliniken inkl beroendekliniken.
    Zeier, Zane
    Univ Miami, FL 33136 USA.
    Wahlestedt, Claes
    Univ Miami, FL 33136 USA.
    Dysregulation of the histone demethylase KDM6B in alcohol dependence is associated with epigenetic regulation of inflammatory signaling pathways2019Ingår i: Addiction Biology, ISSN 1355-6215, E-ISSN 1369-1600, artikel-id UNSP e12816Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Epigenetic enzymes oversee long-term changes in gene expression by integrating genetic and environmental cues. While there are hundreds of enzymes that control histone and DNA modifications, their potential roles in substance abuse and alcohol dependence remain underexplored. A few recent studies have suggested that epigenetic processes could underlie transcriptomic and behavioral hallmarks of alcohol addiction. In the present study, we sought to identify epigenetic enzymes in the brain that are dysregulated during protracted abstinence as a consequence of chronic and intermittent alcohol exposure. Through quantitative mRNA expression analysis of over 100 epigenetic enzymes, we identified 11 that are significantly altered in alcohol-dependent rats compared with controls. Follow-up studies of one of these enzymes, the histone demethylase KDM6B, showed that this enzyme exhibits region-specific dysregulation in the prefrontal cortex and nucleus accumbens of alcohol-dependent rats. KDM6B was also upregulated in the human alcoholic brain. Upregulation of KDM6B protein in alcohol-dependent rats was accompanied by a decrease of trimethylation levels at histone H3, lysine 27 (H3K27me3), consistent with the known demethylase specificity of KDM6B. Subsequent epigenetic (chromatin immunoprecipitation [ChIP]-sequencing) analysis showed that alcohol-induced changes in H3K27me3 were significantly enriched at genes in the IL-6 signaling pathway, consistent with the well-characterized role of KDM6B in modulation of inflammatory responses. Knockdown of KDM6B in cultured microglial cells diminished IL-6 induction in response to an inflammatory stimulus. Our findings implicate a novel KDM6B-mediated epigenetic signaling pathway integrated with inflammatory signaling pathways that are known to underlie the development of alcohol addiction.

  • 134.
    Jonsson, Amanda
    Linköpings universitet, Institutionen för teknik och naturvetenskap, Fysik och elektroteknik. Linköpings universitet, Tekniska fakulteten.
    Organic electronics for precise delivery of neurotransmitters2016Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Organic electronic materials, that is, carbon-based compounds that conduct electricity, have emerged as candidates for improving the interface between conventional electronics and biological systems. The softness of these materials matches the elasticity of biological tissue better than conventional electronic conductors, allowing better contact to tissue, and the mixed ionic-electronic conductivity can improve the signal transduction between electronic devices and electrically excitable cells. This improved communication between electronics and tissue can significantly enhance, for example, electrical stimulation for therapy and electrical recording for diagnostics.

    The ionic conductivity of organic electronic materials makes it possible to achieve ion-specific ionic currents, where the current consists of migration of specific ions. These ions can be charged signalling substances, such as neurotransmitters, that can selectively activate or inhibit cells that contain receptors for these substances. This thesis describes the development of chemical delivery devices, where delivery is based on such ion-specific currents through ionically and electronically conducting polymers. Delivery is controlled by electrical signals, and allows release of controlled amounts of neurotransmitters, or other charged compounds, to micrometer-sized regions.

    The aims of the thesis have been to improve spatial control and temporal resolution of chemical delivery, with the ultimate goal of selective interaction with individual cells, and to enable future therapies for disorders of the nervous system. Within the thesis, we show that delivery can alleviate pain through local delivery to specific regions of the spinal cord in an animal model of neuropathic pain, and that epilepsy-related signalling can be suppressed in vitro. We also integrate the delivery device with electrodes for sensing, to allow simultaneous electrical recording and delivery at the same position. Finally, we improve the delay from electrical signal to chemical delivery, approaching the time domain of synaptic signaling, and construct devices with several individually controlled release sites.

    Delarbeten
    1. Therapy using implanted organic bioelectronics
    Öppna denna publikation i ny flik eller fönster >>Therapy using implanted organic bioelectronics
    Visa övriga...
    2015 (Engelska)Ingår i: Science Advances, ISSN 2375-2548, Vol. 1, nr 4, artikel-id e1500039Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Many drugs provide their therapeutic action only at specific sites in the body, but are administered in ways that cause the drug’s spread throughout the organism. This can lead to serious side effects. Local delivery from an implanted device may avoid these issues, especially if the delivery rate can be tuned according to the need of the patient. We turned to electronically and ionically conducting polymers to design a device that could be implanted and used for local electrically controlled delivery of therapeutics. The conducting polymers in our device allow electronic pulses to be transduced into biological signals, in the form of ionic and molecular fluxes, which provide a way of interfacing biology with electronics. Devices based on conducting polymers and polyelectrolytes have been demonstrated in controlled substance delivery to neural tissue, biosensing, and neural recording and stimulation. While providing proof of principle of bioelectronic integration, such demonstrations have been performed in vitro or in anesthetized animals. Here, we demonstrate the efficacy of an implantable organic electronic delivery device for the treatment of neuropathic pain in an animal model. Devices were implanted onto the spinal cord of rats, and 2 days after implantation, local delivery of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) was initiated. Highly localized delivery resulted in a significant decrease in pain response with low dosage and no observable side effects. This demonstration of organic bioelectronics-based therapy in awake animals illustrates a viable alternative to existing pain treatments, paving the way for future implantable bioelectronic therapeutics. Keywords

    Ort, förlag, år, upplaga, sidor
    American Association of the Advances of Science, 2015
    Nyckelord
    pain, neuromodulation, in vivo, organic electronics, bioelectronics
    Nationell ämneskategori
    Textil-, gummi- och polymermaterial Medicinska material och protesteknik Annan medicinsk bioteknologi
    Identifikatorer
    urn:nbn:se:liu:diva-117968 (URN)10.1126/sciadv.1500039 (DOI)000216593600006 ()
    Projekt
    OBOE miljö
    Forskningsfinansiär
    VINNOVA, 2010-00507
    Tillgänglig från: 2015-05-19 Skapad: 2015-05-19 Senast uppdaterad: 2018-03-09
    2. Controlling Epileptiform Activity with Organic Electronic Ion Pumps
    Öppna denna publikation i ny flik eller fönster >>Controlling Epileptiform Activity with Organic Electronic Ion Pumps
    Visa övriga...
    2015 (Engelska)Ingår i: Advanced Materials, ISSN 0935-9648, E-ISSN 1521-4095, Vol. 27, nr 20, s. 3138-3144Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    In treating epilepsy, the ideal solution is to act at a seizure's onset, but only in the affected regions of the brain. Here, an organic electronic ion pump is demonstrated, which directly delivers on-demand pure molecules to specific brain regions. State-of-the-art organic devices and classical pharmacology are combined to control pathological activity in vitro, and the results are verified with electrophysiological recordings.

    Ort, förlag, år, upplaga, sidor
    Wiley-VCH Verlag, 2015
    Nyckelord
    Organic Bioelectronics, Organic Electronic Ion Pump, PEDOT:PSS, Neuroengineering
    Nationell ämneskategori
    Neurologi
    Identifikatorer
    urn:nbn:se:liu:diva-119247 (URN)10.1002/adma.201500482 (DOI)000354823600002 ()25866154 (PubMedID)
    Anmärkning

    Funding Agencies|European Union [602102]; A*MIDEX [A_M-AAP-ID-13-24-130531-16.31-BERNARD-HLS]; Swedish Innovation Office (VINNOVA); Swedish Research Council [621-2011-3517]; Knut and Alice Wallenberg Foundation [2012.0302]; National Science Foundation [DMR-1105253]; ANR [ANR-13-BSV5-0019-01]; Fondation pour la Recherche Medicale [DBS20131128446]; Fondation de lAvenir; Onnesjo Foundation; Region PACA; Microvitae Technologies; Orthogonal, Inc.; Marie Curie Fellowships

    Tillgänglig från: 2015-06-15 Skapad: 2015-06-12 Senast uppdaterad: 2017-11-22
    3. Bioelectronic neural pixel: Chemical stimulation and electrical sensing at the same site
    Öppna denna publikation i ny flik eller fönster >>Bioelectronic neural pixel: Chemical stimulation and electrical sensing at the same site
    Visa övriga...
    2016 (Engelska)Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 113, nr 34, s. 9440-9445Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Local control of neuronal activity is central to many therapeutic strategies aiming to treat neurological disorders. Arguably, the best solution would make use of endogenous highly localized and specialized regulatory mechanisms of neuronal activity, and an ideal therapeutic technology should sense activity and deliver endogenous molecules at the same site for the most efficient feedback regulation. Here, we address this challenge with an organic electronic multifunctional device that is capable of chemical stimulation and electrical sensing at the same site, at the single-cell scale. Conducting polymer electrodes recorded epileptiform discharges induced in mouse hippocampal preparation. The inhibitory neurotransmitter, γ-aminobutyric acid (GABA), was then actively delivered through the recording electrodes via organic electronic ion pump technology. GABA delivery stopped epileptiform activity, recorded simultaneously and colocally. This multifunctional “neural pixel” creates a range of opportunities, including implantable therapeutic devices with automated feedback, where locally recorded signals regulate local release of specific therapeutic agents.

    Ort, förlag, år, upplaga, sidor
    National Academy of Sciences, 2016
    Nationell ämneskategori
    Elektroteknik och elektronik
    Identifikatorer
    urn:nbn:se:liu:diva-130851 (URN)10.1073/pnas.1604231113 (DOI)000381860800035 ()27506784 (PubMedID)
    Anmärkning

    Funding agencies:We thank Gaelle Rondeau and the staff of the clean room in Centre Microelectronique de Provence (CMP) for technical support during fabrication. The research leading to these results has received funding from the European Union's Seventh Framework Programme (FP7/2007-2013) under Grant Agreement 602102 (EPITARGET) and Initiative of Excellence Aix-Marseilles project MIDOE (A_M-AAP-ID-13-24-130531-16.31-BERNARD-HLS). Funding was also provided by the Swedish Innovation Office (2010-00507), the Swedish Research Council (621-2011-3517), and the Knut and Alice Wallenberg Foundation (KAW Scholar, 2012.0302). The authors also thank the National Science Foundation Grant DMR-1105253 for partial support of this work, the French National Research Agency (ANR) through the project PolyProbe (ANR-13-BSV5-0019-01), Fondation pour la Recherche Medicale under Grant Agreements DBS20131128446 and ARF20150934124, Fondation de l'Avenir, the Onnesjo Foundation, the Region Provence-Alpes-Cote d'Azur, and Microvitae Technologies. J.R. and L.K. acknowledge support from Marie Curie Fellowships. The fabrication of the device was performed, in part, at CMP.

    Tillgänglig från: 2016-08-26 Skapad: 2016-08-26 Senast uppdaterad: 2017-11-21Bibliografiskt granskad
    4. Chemical delivery array with millisecond neurotransmitter release
    Öppna denna publikation i ny flik eller fönster >>Chemical delivery array with millisecond neurotransmitter release
    Visa övriga...
    2016 (Engelska)Ingår i: Science Advances, ISSN 2375-2548, Vol. 2, nr 11, artikel-id e1601340Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Technologies that restore or augment dysfunctional neural signaling represent a promising route to deeper understanding and new therapies for neurological disorders. Because of the chemical specificity and subsecond signaling of the nervous system, these technologies should be able to release specific neurotransmitters at specific locations with millisecond resolution. We have previously demonstrated an organic electronic lateral electrophoresis technology capable of precise delivery of charged compounds, such as neurotransmitters. However, this technology, the organic electronic ion pump, has been limited to a single delivery point, or several simultaneously addressed outlets, with switch-on speeds of seconds. We report on a vertical neurotransmitter delivery device, configured as an array with individually controlled delivery points and a temporal resolution of 50 ms. This is achieved by supplementing lateral electrophoresis with a control electrode and an ion diode at each delivery point to allow addressing and limit leakage. By delivering local pulses of neurotransmitters with spatiotemporal dynamics approaching synaptic function, the high-speed delivery array promises unprecedented access to neural signaling and a path toward biochemically regulated neural prostheses.

    Ort, förlag, år, upplaga, sidor
    Washington: American Association for the Advancement of Science (A A A S), 2016
    Nationell ämneskategori
    Atom- och molekylfysik och optik Datorteknik Övrig annan teknik Biomedicinsk laboratorievetenskap/teknologi Signalbehandling
    Identifikatorer
    urn:nbn:se:liu:diva-133161 (URN)10.1126/sciadv.1601340 (DOI)000391267800033 ()27847873 (PubMedID)
    Tillgänglig från: 2016-12-12 Skapad: 2016-12-12 Senast uppdaterad: 2018-01-13Bibliografiskt granskad
  • 135.
    Jonsson, Emma H.
    et al.
    Univ Gothenburg, Sweden.
    Kotilahti, Kalle
    Aalto Univ, Finland.
    Heiskala, Juha
    Univ Helsinki, Finland.
    Wasling, Helena Backlund
    Univ Gothenburg, Sweden.
    Olausson, Håkan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Neurofysiologiska kliniken US. Univ Gothenburg, Sweden.
    Croy, Ilona
    Tech Univ Dresden, Germany.
    Mustaniemi, Hanna
    Aalto Univ, Finland.
    Hiltunen, Petri
    Aalto Univ, Finland.
    Tuulari, Jetro J.
    Univ Turku, Finland.
    Scheinin, Noora M.
    Univ Turku, Finland; Turku Univ Hosp, Finland.
    Karlsson, Linnea
    Univ Turku, Finland; Turku Univ Hosp, Finland.
    Karlsson, Hasse
    Univ Turku, Finland; Turku Univ Hosp, Finland.
    Nissila, Ilkka
    Aalto Univ, Finland.
    Affective and non-affective touch evoke differential brain responses in 2-month-old infants2018Ingår i: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 169, s. 162-171Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Caressing touch is an effective way to communicate emotions and to create social bonds. It is also one of the key mediators of early parental bonding. The caresses are generally thought to represent a social form of touching and indeed, slow, gentle brushing is encoded in specialized peripheral nerve fibers, the C-tactile (CT) afferents. In adults, areas such as the posterior insula and superior temporal sulcus are activated by affective, slow stroking touch but not by fast stroking stimulation. However, whether these areas are activated in infants, after social tactile stimulation, is unknown. In this study, we compared the total hemoglobin responses measured with diffuse optical tomography (DOT) in the left hemisphere following slow and fast stroking touch stimulation in 16 2-month-old infants. We compared slow stroking (optimal CT afferent stimulation) to fast stroking (non-optimal CT stimulation). Activated regions were delineated using two methods: one based on contrast between the two conditions, and the other based on voxel-based statistical significance of the difference between the two conditions. The first method showed a single activation cluster in the temporal cortex with center of gravity in the middle temporal gyrus where the total hemoglobin increased after the slow stroking relative to the fast stroking (p = 0.04 uncorrected). The second method revealed a cluster in the insula with an increase in total hemoglobin in the insular cortex in response to slow stroking relative to fast stroking (p = 0.0005 uncorrected; p = 0.04 corrected for multiple comparisons). These activation clusters encompass areas that are involved in processing of affective, slow stroking touch in the adult brain. We conclude that the infant brain shows a pronounced and adult-like response to slow stroking touch compared to fast stroking touch in the insular cortex but the expected response in the primary somatosensory cortex was not found at this age. The results imply that emotionally valent touch is encoded in the brain in adult-like manner already soon after birth and this suggests a potential for involvement of touch in bonding with the caretaker.

  • 136.
    Jonsson, Maria
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Nyström, Sofie
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Sandberg, Alexander
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Carlback, Marcus
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Michno, Wojciech
    Univ Gothenburg, Sweden.
    Hanrieder, Jorg
    Univ Gothenburg, Sweden; UCL, England.
    Starkenberg, Annika
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten.
    Nilsson, Peter
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Thor, Stefan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten.
    Hammarström, Per
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Aggregated A beta 1-42 Is Selectively Toxic for Neurons, Whereas Glial Cells Produce Mature Fibrils with Low Toxicity in Drosophila2018Ingår i: Cell Chemical Biology, ISSN 2451-9456, E-ISSN 2451-9448, Vol. 25, nr 5, s. 595-610Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The basis for selective vulnerability of certain cell types for misfolded proteins (MPs) in neurodegenerative diseases is largely unknown. This knowledge is crucial for understanding disease progression in relation to MPs spreading in the CNS. We assessed this issue in Drosophila by cell-specific expression of human A beta 1-42 associated with Alzheimers disease. Expression of A beta 1-42 in various neurons resulted in concentration-dependent severe neurodegenerative phenotypes, and intraneuronal ringtangle-like aggregates with immature fibril properties when analyzed by aggregate-specific ligands. Unexpectedly, expression of A beta 1-42 from a pan-glial driver produced a mild phenotype despite massive brain load of A beta 1-42 aggregates, even higher than in the strongest neuronal driver. Glial cells formed more mature fibrous aggregates, morphologically distinct from aggregates found in neurons, and was mainly extracellular. Our findings implicate that A beta 1-42 cytotoxicity is both cell and aggregate morphotype dependent.

  • 137.
    Kalafateli, Aimilia Lydia
    et al.
    Univ Gothenburg, Sweden.
    Vallof, Daniel
    Univ Gothenburg, Sweden.
    Jornulf, Julia Winsa
    Univ Gothenburg, Sweden.
    Heilig, Markus
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Närsjukvården i centrala Östergötland, Psykiatriska kliniken.
    Jerlhag, Elisabet
    Univ Gothenburg, Sweden.
    A cannabinoid receptor antagonist attenuates ghrelin-induced activation of the mesolimbic dopamine system in mice2018Ingår i: Physiology and Behavior, ISSN 0031-9384, E-ISSN 1873-507X, Vol. 184, s. 211-219Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Ghrelin has been attributed various physiological processes including food intake and reward regulation, through activation of the mesolimbic dopamine system. Reward modulation involves the mesolimbic dopamine system, consisting of the ventral tegmental area (VTA) dopamine neurons targeting nucleus accumbens (NAc), a system that ghrelin activates through VTA-dependent mechanisms. In the first study, we found that systemic intraperitoneal (ip) administration of rimonabant attenuated intracerebroventricular (icv) ghrelins ability to cause locomotor stimulation and NAc dopamine release in mice. Ghrelin-induced (icv) chow intake was not altered by rimonabant administration (ip). Finally, we showed that bilateral VTA administration of rimonabant blocks the ability of intra-VTA administered ghrelin to increase locomotor activity, but does not affect food intake in mice. Collectively, these data indicate clear dissociation between regulation of food intake and activation of the mesolimbic dopamine system.

  • 138.
    Kanno, Takahiro
    et al.
    Department of Physiology, Hirosaki University School of Medicine, Hirosaki, Japan.
    Ma, Xiasong
    Department of Physiological Sciences, Lund University, Lund, Sweden.
    Barg, Sebastian
    Department of Physiological Sciences, Lund University, Lund, Sweden.
    Eliasson, Lena
    Department of Physiological Sciences, Lund University, Lund, Sweden.
    Galvanovskis, Juris
    Department of Physiological Sciences, Lund University, Lund, Sweden.
    Göpel, Sven
    Department of Physiological Sciences, Lund University, Lund, Sweden.
    Larsson, Max
    Department of Physiological Sciences, Lund University, Lund, Sweden.
    Renström, Erik
    Department of Physiological Sciences, Lund University, Lund, Sweden.
    Rorsman, Patrik
    Department of Physiological Sciences, Lund University, Lund, Sweden.
    Large dense-core vesicle exocytosis in pancreatic beta-cells monitored by capacitance measurements.2004Ingår i: Methods, ISSN 1046-2023, E-ISSN 1095-9130, Vol. 33, nr 4, s. 302-311Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    This article discusses the currently used methodologies for monitoring exocytosis as changes in cell capacitance. Details are given on composition of solutions, experimental protocols, and how the observed responses can be interpreted physiologically. The concepts are illustrated by examples from our own work on insulin-releasing pancreatic beta-cells. Finally, we consider the feasibility of applying capacitance measurements to endocrine cells in intact pancreatic islets, where the cells are electrically coupled to each other.

  • 139.
    Karlsson, Camilla
    et al.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Zook, Michelle
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Ciccocioppo, Roberto
    University of Camerino, Italy.
    Gehlert, Donald R.
    Eli Lilly, Indianapolis, IN, USA.
    Thorsell, Annika
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Heilig, Markus
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Cippitelli, Andrea
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Melanin-concentrating hormone receptor 1 (MCH1-R) antagonism: reduced appetite for calories and suppression of addictive-like behaviors2012Ingår i: Pharmacology, Biochemistry and Behavior, ISSN 0091-3057, E-ISSN 1873-5177, Vol. 102, nr 3, s. 400-406Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    RATIONALE: The hypothalamic neuropeptide melanin-concentrating hormone and its MCH1 receptor have been implicated in regulation of feeding and energy homeostasis, as well as modulation of reward-related behaviors. Here, we examined whether the MCH system plays a role both in caloric and motivational aspects of sugar intake.

    MATERIALS AND METHODS: The non-peptide MCH1-R antagonist GW803430 (3, 10, 30 mg/kg, i.p.) was first tested on self-administration under a fixed ratio schedule of reinforcement of both a caloric (10% w/v sucrose) and a non-caloric (0.06% w/v saccharin) sweet solution. GW803430 was then tested for its ability to alter motivational properties and seeking of sucrose. Lastly, the drug was tested to concurrently examine its effects on the escalated consumption of both sugar and food in animals following intermittent sugar access.

    RESULTS: The MCH1-R antagonist reduced sucrose- but not saccharin-reinforced lever pressing, likely reflecting a decreased appetite for calories in GW803430-treated rats. GW803430 reduced sucrose self-administration under a progressive ratio schedule, and suppressed cue-induced reinstatement of sucrose seeking, suggesting effects on rewarding properties of sucrose. GW803430 attenuated food intake in rats on intermittent access to sucrose at all doses examined (3, 10, 30 mg/kg), while reduction of sugar intake was weaker in magnitude.

    CONCLUSION: Together, these observations support an involvement of the MCH system in regulation of energy balance as well as mediation of sucrose reward. MCH may be an important regulator of sugar intake by acting on both caloric and rewarding components.

  • 140.
    Karlsson, Rose-Marie
    et al.
    National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
    Choe, Jessica S.
    National Institute of Mental Health, NIH, Bethesda, MD, USA .
    Cameron, Heather A
    National Institute of Mental Health, NIH, Bethesda, MD, USA.
    Thorsell, Annika
    National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
    Crawley, Jacqueline N
    National Institute of Mental Health, NIH, Bethesda, MD, USA.
    Holmes, Andrew
    National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
    Heilig, Markus
    National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
    The neuropeptide Y Y1 receptor subtype is necessary for the anxiolytic-like effects of neuropeptide Y, but not the antidepressant-like effects of fluoxetine, in mice2008Ingår i: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 195, nr 4, s. 547-557Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    RATIONALE: Neuropeptide Y (NPY) is implicated in the pathophysiology of affective illness. Multiple receptor subtypes (Y1R, Y2R, and Y5R) have been suggested to contribute to NPY's effects on rodent anxiety and depression-related behaviors.

    OBJECTIVES: To further elucidate the role of Y1R in (1) NPY's anxiolytic-like effects and (2) fluoxetine's antidepressant-like and neurogenesis-inducing effects.

    METHODS: Mice lacking Y1R were assessed for spontaneous anxiety-like behavior (open field, elevated plus-maze, and light/dark exploration test) and Pavlovian fear conditioning, and for the anxiolytic-like effects of intracerebroventricularly (icv)-administrated NPY (elevated plus-maze). Next, Y1R -/- were assessed for the antidepressant-like effects of acute fluoxetine in the forced swim test and chronic fluoxetine in the novelty-induced hypophagia test, as well as for chronic fluoxetine-induced hippocampal neurogenesis.

    RESULTS: Y1R -/- exhibited largely normal baseline behavior as compared to +/+ littermate controls. Intraventricular administration of NPY in Y1R -/- mice failed to produce the normal anxiolytic-like effect in the elevated plus-maze test seen in +/+ mice. Y1R mutant mice showed higher immobility in the forced swim test and longer latencies in the novelty-induced hypophagia test. In addition, Y1R -/- mice responded normally to the acute and chronic effects of fluoxetine treatment in the forced swim test and the novelty-induced hypophagia test, respectively, as well as increased neuronal precursor cell proliferation in the hippocampus.

    CONCLUSIONS: These data demonstrate that Y1R is necessary for the anxiolytic-like effects of icv NPY, but not for the antidepressant-like or neurogenesis-inducing effects of fluoxetine. The present study supports targeting Y1R as a novel therapeutic target for anxiety disorders.

  • 141.
    Kastbom, Åsa A.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Sexual behaviour, debut and identity among Swedish Schoolchildren2015Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [sv]

    Barns och ungdomars sexuella beteenden är ett område som engagerar både föräldrar och professionella men det är ett förhållandevis outforskat område. Kanske mycket på grund av att det är ett tabubelagt område och att finns en hel del metodologiska hinder och etiska betänkligheter vid sådan forskning.

    Ett sexualiserat beteende kan vara tecken på sexuella övergrepp och det är därför viktigt att beskriva vad som är vanligt förekommande och förväntade sexuella beteenden hos barn och unga tillika vilka beteenden som är ovanliga och som kanske behöver utredas vidare. En tidig sexuell debut (debut före 14 års ålder) kan ses som ett riskbeteende i sig men även ett beteende kopplat till andra riskbeteenden som alkoholkonsumtion eller antisociala beteenden. Att vänta med den sexuella debuten beskrivs ibland som något önskvärt men det är inte särskilt väl utforskat. Därför är det viktigt att ta reda på vilka konsekvenser en tidig eller sen sexuell debut får för individen och vilka andra beteenden som är kopplade till en tidig eller sen sexuell debut.

    Ett annat viktigt område när det gäller ungdomar och sexualitet är sexuell identitet och dess konsekvenser. Ungdomar med en sexuell identitet som homo-, bisexuell eller transperson (HBT) beskrivs i tidigare forskning ofta uppleva en lägre livskvalitet samt oftare ha erfarenhet av barnmisshandel än jämnåriga med heterosexual identitet.

    Studierna i denna avhandling hade fyra huvudsyften: 1), att undersöka sexuella beteenden hos barn i åldrarna 7 till 13 år 2,) att undersöka sambanden mellan en tidig sexuell debut (yngre än 14 år) och sociodemografi, sexuella erfarenheter, hälsa, erfarenhet av barnmisshandel och beteende vid 18 års ålder 3), sen sexuell debut (ingen frivillig erfarenhet av oral-, vaginaleller analsex vid 18 års ålder) och sociodemografi, sexuella erfarenheter, hälsa, erfarenhet av barnmisshandel och beteende vid 18 års ålder samt 4), att beskriva relationen mellan sexuell identitet och sociodemografi, sexuellt beteende, hälsa, erfarenheter av barnmisshandel och nuvarande beteenden hos svenska 18-åringar.

    Föräldrarna till 418 barn i åldern 7 till 13 år svarade på en enkät angående deras barns generella och sexuella beteenden. För att undersöka ungdomars sexuella beteenden, debut och identitet genomfördes en undersökning bland 3432 svenska gymnasieelever i 18-års ålder. Dessutom svarade 362 medlemmar i Svenska Förbundet för homosexuellas, bisexuellas och transpersoners rättigheter (RFSL), med en medelåder på 21.4 år, på samma enkät.

    Det visade sig att många sexuella beteenden bland 7 till 13-åringarna var vanligt förekommande och att de varierade i frekvens med ålder och kön. Problematiska eller oroväckande sexuella beteenden (som till exempel att kyssa vuxna med tungan, imitera samlag, onanera inför andra, röra andras könsorgan med munnen och så vidare) rapporterades inte av några föräldrar eller var mycket ovanliga. En tidig sexuell debut (yngre än 14 år) korrelerade positivt med högre antal sex partner, erfarenhet av oral- och analsex, rökning, drog- och alkoholanvändning och antisocialt beteende, såsom våldsbenägenhet, att ljuga, stjäla och sova borta utan att föräldrarna vet om det. Flickor med en tidig sexuell debut hade större erfarenhet av sexuella övergrepp än flickor med senare debut. Pojkar med en tidig sexuell debut hade oftare en svag känsla av sammanhang, låg självkänsla, psykisk ohälsa, erfarenhet av sexuella övergrepp, att sälja sex eller fysisk misshandel jämfört med pojkar med en senare debut.

    Knappt en fjärdedel (24,6%) av de 3380 ungdomarna hade inte haft frivillig sexuell debut (oral-, anal- eller vaginalsex) vid 18 års ålder. Ungdomar med sen sexuell debut hade oftare en pappa-barn relation som byggde på en hög grad av omsorg. De hade oftare föräldrar födda utanför Europa, låg sexuell lust, låg pornografikonsumtion, låg alkohol- och tobakskonsumtion, få antisociala beteenden och mer sällan erfarenhet av sexuella övergrepp än 18-åringar som redan debuterat sexuellt.

    Ungdomarna med sexuell identitet som homo- eller bisexuella hade oftare en föräldra-barn relation som byggde på låg omsorg och hög kontroll än sina heterosexuella kamrater. De homo-och bisexuella ungdomarna använde också mer alkohol och droger jämfört med de heterosexuella ungdomarna. Multivariat analys visade ett positivt samband mellan homo- och bisexualitet och erfarenhet av analsex, sexuell lust, erfarenhet av sexuella övergrepp, misshandel och erfarenhet att sälja sex. Det var mer än dubbelt så vanligt att ha erfarenhet av sexuella övergrepp och fysisk misshandel hos de med en sexuell minoritets identitet.

    En av slutsatserna blev att översexualiserade eller problematiska sexuella beteenden är sällsynta hos barn i 7-13 års ålder. Det är viktig kunskap för professionella som arbetar med barn och som ofta får frågor kring barns olika beteenden och måste avgöra om det är förväntade och vanligt förekommande beteenden eller beteenden som ska leda till någon form av utredning, Om ett barn visar ett översexualiserat eller annorlunda sexuellt beteende ska det observeras och undersökas vidare av professionella med kunskap om barn och dess utveckling.

    Tidig sexuell debut verkar vara förknippad med andra problematiska beteenden under senare tonåren. Detta kan också tyda på att den tidiga debuten för vissa barn är associerat med en ökad sårbarhet, som också måste identifieras och tillgodoses av olika yrkeskategorier som arbetar med barn och ungdomar.

    Det finns olika anledningar till varför vissa ungdomar inte haft sexuell debut vid 18 års ålder. Faktorer som familjestabilitet och kulturell bakgrund spelade roll. Ungdomar med sen sexuell debut rapporterade färre antisociala handlingar, var mindre benägna att röka och dricka alkohol, hade mindre sexuell lust och mindre erfarenhet av sexuella övergrepp. Ytterligare studier behövs för att undersöka om det finns något samband mellan personlighetsdrag och sen sexuell debut.

    Ungdomar med en sexuell identitet som homo- eller bisexuell skulle kunna anses ha en lägre livskvalitet jämfört med heterosexuella kamrater men ytterligare studier måste göras för att ytterligare utforska möjliga orsaker. Det visade sig vara mycket vanligare med erfarenhet av såväl fysisk misshandel som sexuella övergrepp bland dessa ungdomar. Vuxna och framför allt professionella behöver bli mer medvetna om denna grupps sårbarhet, den ökade risken för erfarenhet av barnmisshandel och kunna erbjuda olika former av stöd.

    Delarbeten
    1. Parents' reports on 7-12-years old childrens sexual behavior
    Öppna denna publikation i ny flik eller fönster >>Parents' reports on 7-12-years old childrens sexual behavior
    2011 (Engelska)Ingår i: Journal of Sexual Medicine, ISSN 1743-6095, E-ISSN 1743-6109, Vol. 8, nr Suppl. 3, s. 270-270Artikel i tidskrift, Meeting abstract (Övrigt vetenskapligt) Published
    Abstract [en]

    Aim: To understand if a sexual behaviour in a child is a sign of sexual abuse or neglect we need to investigate sexual behaviours among chil-dren. In the present study we investigated Swedish children age 7–12 to determine what constitutes usual and unusual sexual behaviours.

    Methods: Parents of 418 children answered questionnaires about their child’s behaviour, both general and sexual, and about their own attitudes.

    Results: We found that most sexual behaviours we asked about are common, and are in part related to or vary with age and gender. A small number of sexual behaviours were found to be very unusual in this normative group of children.

    Conclusion: Behaviours usually referred to as sexualized and problematic and perhaps a sign of sexual abuse or neglect were very rare in this normative sample of children 7–12 years of age.

    Ort, förlag, år, upplaga, sidor
    Malden , MA, USA: Blackwell Publishing, 2011
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-69889 (URN)10.1111/j.1743-6109.2011.02325.x (DOI)000291345300747 ()
    Konferens
    Proceedings from the 20th World Congress of Sexual Health, Glasgow, United Kingdom, June 12-16 2011
    Anmärkning

    Meeting Abstract: 746

    Tillgänglig från: 2011-08-09 Skapad: 2011-08-08 Senast uppdaterad: 2017-12-08Bibliografiskt granskad
    2. Sexual debut before the age of 14 leads to poorer psychosocial health and risky behaviour in later life
    Öppna denna publikation i ny flik eller fönster >>Sexual debut before the age of 14 leads to poorer psychosocial health and risky behaviour in later life
    Visa övriga...
    2015 (Engelska)Ingår i: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 104, nr 1, s. 91-100Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Aim: This study investigated the relationship between sexual debut before 14 years of age and socio-demographics, sexual experience, health, experience of child abuse and behaviour at 18 years of age.

    Methods: A sample of 3432 Swedish high school seniors completed a survey about sexuality, health and abuse at the age of 18.

    Results: Early debut was positively correlated with risky behaviours, such as the number of partners, experience of oral and anal sex, health behaviours, such as smoking, drug and alcohol use, and antisocial behaviour, such as being violent, lying, stealing and running away from home. Girls with an early sexual debut had significantly more experience of sexual abuse. Boys with an early sexual debut were more likely to have a weak sense of coherence, low self-esteem and poor mental health, together with experience of sexual abuse, selling sex and physical abuse. A multiple logistic regression model showed that a number of antisocial acts and health behaviours remained significant, but early sexual debut did not increase the risk of psychiatric symptoms, low self-esteem or low sense of coherence at 18 years of age.

    Conclusion: Early sexual debut was associated with problematic behaviours during later adolescence, and this vulnerability requires attention from parents and healthcare providers.

    Ort, förlag, år, upplaga, sidor
    John Wiley & Sons, 2015
    Nyckelord
    Child abuse; Drug use; Risky behaviour; Sexual behaviour; Sexual debut
    Nationell ämneskategori
    Klinisk medicin
    Identifikatorer
    urn:nbn:se:liu:diva-113719 (URN)10.1111/apa.12803 (DOI)000346987300025 ()25213099 (PubMedID)
    Tillgänglig från: 2015-01-30 Skapad: 2015-01-29 Senast uppdaterad: 2017-12-05
    3. Differences in sexual behavior, health, and history of child abuse among school students who had and had not engaged in sexual activity by the age of 18 years: a cross-sectional study
    Öppna denna publikation i ny flik eller fönster >>Differences in sexual behavior, health, and history of child abuse among school students who had and had not engaged in sexual activity by the age of 18 years: a cross-sectional study
    Visa övriga...
    2016 (Engelska)Ingår i: Adolescent Health, Medicine and Therapeutics, ISSN 1179-318X, Vol. 7, s. 1-11Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Background: Empirical research about late sexual debut and its consequences is limited, and further research is needed.

    Objective: To explore how students who had not had intercourse by the age of 18 years differed in terms of sociodemographic factors, physical and psychological health, sexual behavior, and history of sexual abuse from those who had.

    Materials and methods: This is a cross-sectional survey involving 3,380 Swedish 18-year-olds. Descriptive analyses were used to investigate different types of sexual behavior. Ordinal data concerning alcohol consumption, self-esteem, sexual and physical abuse, parental relationships, sense of coherence, and health were analyzed, and multiple regression was carried out to identify the most important factors associated with no sexual debut.

    Results: Just under a quarter of the adolescents had not had oral, anal, or vaginal sex by the age of 18 years, and they comprised the index group. They were characterized by being more likely to have caring fathers, parents born outside Europe, lower pornography consumption, lower alcohol and tobacco consumption, less antisocial behavior, and above all lower sexual desire (sometimes, adjusted odds ratio [aOR] 3.8; never/seldom, aOR 13.3) and fewer experiences of sexual abuse (aOR 25.5). Family structure and culture matters when it comes to the age of sexual debut.

    Conclusion: Adolescents with no sexual debut at 18 years of age seemed to live a more stable and cautious life than more sexual experienced peers, exemplified by fewer antisocial acts, less smoking and alcohol/drug consumption, less sexual desire, and less experience of sexual abuse.

    Ort, förlag, år, upplaga, sidor
    Dove Medical Press Ltd.(Dovepress), 2016
    Nyckelord
    Adolescents, sexual abuse, sexual behavior, late sexual debut
    Nationell ämneskategori
    Klinisk medicin
    Identifikatorer
    urn:nbn:se:liu:diva-123026 (URN)10.2147/AHMT.S95493 (DOI)26811695 (PubMedID)
    Forskningsfinansiär
    Myndigheten för ungdoms- och civilsamhällesfrågor (MUCF)
    Anmärkning

    At the time for thesis presentation publication was in status: Manuscript

    Tillgänglig från: 2015-12-02 Skapad: 2015-12-02 Senast uppdaterad: 2017-12-01Bibliografiskt granskad
    4. Comparing quality of life between Swedish adolescents and young adults from sexual minorities and heterosexual groups
    Öppna denna publikation i ny flik eller fönster >>Comparing quality of life between Swedish adolescents and young adults from sexual minorities and heterosexual groups
    Visa övriga...
    2015 (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Objectives: To investigate the relationship between sexual identity and socio- demographics, sexual experience, health, experience of child abuse, sexual exploitation and present behavior among Swedish adolescents and young adults.

    Methods: A cross-sectional survey with 3,503 adolescents completing a  survey  about their sexuality, health and abuse at a mean age of 18.3 years. In addition, 362 members of the Swedish Federation for Lesbian, Gay, Bisexual and Transgender Rights completed the same survey at a mean age of 21.4 years.

    Results: Sexual minority respondents were more likely to say that their parental relationship was based on low care and high overprotection and they used alcohol and other drugs to a significantly higher extent than their heterosexual peers. Multivariate analysis showed a positive correlation between sexual minority and  low  self-esteem, poor mental health and experience of sexual abuse, physical abuse and sexual exploitation.

    Conclusion: The sexual minority group had a lower quality of life than their heterosexual peers and professionals need to be more aware that they are more vulnerable in a number of respects, including an increased risk of having experienced child abuse, and offer them different forms of support.

    Nyckelord
    Sexual minority, child abuse, health, self-esteem
    Nationell ämneskategori
    Klinisk medicin
    Identifikatorer
    urn:nbn:se:liu:diva-123027 (URN)
    Tillgänglig från: 2015-12-02 Skapad: 2015-12-02 Senast uppdaterad: 2015-12-02Bibliografiskt granskad
  • 142.
    Keita, Åsa
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten.
    Söderholm, Johan D
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US.
    Mucosal permeability and mast cells as targets for functional gastrointestinal disorders2018Ingår i: Current opinion in pharmacology (Print), ISSN 1471-4892, E-ISSN 1471-4973, Vol. 43, s. 66-71Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    The intestinal mucosa is constantly exposed to harmful lumina! content, and uptake is closely controlled and regulated by neuro-immune factors. If control is broken, it might lead to ongoing enhanced mucosal permeability, potentially resulting in functional gastrointestinal disorders. The importance of mast cells in the regulation of the mucosal barrier has become obvious, and increased numbers and more activated mast cells have been observed in irritable bowel syndrome, functional dyspepsia and gastroesophageal reflux disease. To target the disturbed mucosal permeability, directly or via mast cells, is therefore currently of major interest. For example, administration of mast cell stabilizers and probiotics have shown promising effects in patients with functional gastrointestinal disorders.

  • 143.
    Kilman, Lisa
    et al.
    Linköpings universitet, Institutionen för beteendevetenskap och lärande, Handikappvetenskap. Linköpings universitet, Filosofiska fakulteten. Linköpings universitet, Institutet för handikappvetenskap (IHV).
    Zekveld, Adriana A.
    Linköpings universitet, Institutionen för beteendevetenskap och lärande. Linköpings universitet, Filosofiska fakulteten. Linköpings universitet, Institutet för handikappvetenskap (IHV). ENT/Audiology and EMGO+ Institute for Health and Care Research, VU University Medical Center, Amsterdam, Netherlands.
    Hällgren, Mathias
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Institutet för handikappvetenskap (IHV).
    Rönnberg, Jerker
    Linköpings universitet, Institutionen för beteendevetenskap och lärande, Handikappvetenskap. Linköpings universitet, Filosofiska fakulteten. Linköpings universitet, Institutet för handikappvetenskap (IHV).
    Episodic long-term memory by native and non-native stories masked by speech2015Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    The purpose of the current study was to investigate how well normal-hearing adults recalled Swedish (native) and English (non-native) fictional stories masked by speech in Swedish and English. Each story was 15 min long and divided into three parts of 5 min each. One part was masked by Swedish speech, one by English speech and one was presented unmasked as a baseline. Audibility was rated immediately after listening to each fragment. Episodic long-term memory was assessed using 24 multiple choice questions (4AFC). Every 8 questions corresponded to 5 min of recorded story and included 4 simple and 4 complex questions. Participants also performed complex span test of working memory capacity and proficiency tests in Swedish and English. The main result was that the stories in quiet were significantly better recalled than the stories masked by Swedish. Although the stimuli were correctly identified at the perceptual level, challenging listening

  • 144.
    Kilman, Lisa
    et al.
    Linköpings universitet, Institutionen för beteendevetenskap och lärande, Handikappvetenskap. Linköpings universitet, Filosofiska fakulteten. Linköpings universitet, Institutet för handikappvetenskap (IHV).
    Zekveld, Adriana A.
    Linköpings universitet, Institutionen för beteendevetenskap och lärande. Linköpings universitet, Filosofiska fakulteten. Linköpings universitet, Institutet för handikappvetenskap (IHV). ENT/Audiology and EMGO+ Institute for Health and Care Research, VU University Medical Center, Amsterdam, Netherlands.
    Hällgren, Mathias
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Öron- näsa- och halskliniken US.
    Rönnberg, Jerker
    Linköpings universitet, Institutionen för beteendevetenskap och lärande, Handikappvetenskap. Linköpings universitet, Filosofiska fakulteten. Linköpings universitet, Institutet för handikappvetenskap (IHV).
    Subjective ratings of masker disturbance during the perception of native and non-native speech2015Ingår i: Frontiers in Psychology, ISSN 1664-1078, E-ISSN 1664-1078, Vol. 6, artikel-id 1065Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The aim of the present study was to address how 43 normal-hearing (NH) and hearing-impaired (HI) listeners subjectively experienced the disturbance generated by four masker conditions (i.e., stationary noise, fluctuating noise, Swedish two-talker babble and English two-talker babble) while listening to speech in two target languages, i.e., Swedish (native) or English (non-native). The participants were asked to evaluate their noise-disturbance experience on a continuous scale from 0 to 10 immediately after having performed each listening condition. The data demonstrated a three-way interaction effect between target language, masker condition, and group (HI versus NH). The HI listeners experienced the Swedish-babble masker as significantly more disturbing for the native target language (Swedish) than for the non-native language (English). Additionally, this masker was significantly more disturbing than each of the other masker types during the perception of Swedish target speech. The NH listeners, on the other hand, indicated that the Swedish speech-masker was more disturbing than the stationary and the fluctuating noise-maskers for the perception of English target speech. The NH listeners perceived more disturbance from the speech maskers than the noise maskers. The HI listeners did not perceive the speech maskers as generally more disturbing than the noise maskers. However, they had particular difficulty with the perception of native speech masked by native babble, a common condition in daily-life listening conditions. These results suggest that the characteristics of the different maskers applied in the current study seem to affect the perceived disturbance differently in HI and NH listeners. There was no general difference in the perceived disturbance across conditions between the HI listeners and the NH listeners.

  • 145.
    Klawonn, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Molecular Mechanisms of Reward and Aversion2017Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Various molecular pathways in the brain shape our understanding of good and bad, as well as our motivation to seek and avoid such stimuli. This work evolves around how systemic inflammation causes aversion; and why general unpleasant states such as sickness, stress, pain and nausea are encoded by our brain as undesirable; and contrary to these questions, how drugs of abuse can subjugate the motivational neurocircuitry of the brain. A common feature of these various disease states is involvement of the motivational neurocircuitry - from mesolimbic to striatonigral pathways. Having an intact motivational system is what helps us evade negative outcomes and approach natural positive reinforcers, which is essential for our survival. During disease-states the motivational neurocircuitry may be overthrown by the molecular mechanisms that originally were meant to aid us.

    In study I, to investigate how inflammation is perceived as aversive, we used a behavioral test based on Pavlovian place conditioning with the aversive inflammatory stimulus E. coli lipopolysaccharide (LPS). Using a combination of cell-type specific gene deletions, pharmacology, and chemogenetics, we uncovered that systemic inflammation triggered aversion by MyD88-dependent activation of the brain endothelium followed by COX1-mediated cerebral prostaglandin E2 (PGE2) synthesis. Moreover, we showed that inflammation-induced PGE2 targeted EP1 receptors on striatal dopamine D1 receptor–expressing neurons and that this signaling sequence induced aversion through GABA-mediated inhibition of dopaminergic cells. Finally, inflammation-induced aversion was not an indirect consequence of fever or anorexia but constituted an independent inflammatory symptom triggered by a unique molecular mechanism. Collectively, these findings demonstrate that PGE2-mediated modulation of the dopaminergic circuitry is a key mechanism underlying inflammation-induced aversion.

    In study II, we investigate the role of peripheral IFN-γ in LPS induced conditioned place aversion by employing a strategy based on global and cell-type specific gene deletions, combined with measures of gene-expression. LPS induced IFN-ɣ expression in the blood, and deletion of IFN-ɣ or its receptor prevented conditioned place aversion (CPA) to LPS. LPS increased the expression of chemokine Cxcl10 in the striatum of normal mice. This induction was absent in mice lacking IFN-ɣ receptors or Myd88 in blood brain barrier endothelial cells. Furthermore, inflammation-induced aversion was blocked in mice lacking Cxcl10 or its receptor Cxcr3. Finally, mice with a selective deletion of the IFN-ɣ receptor in brain endothelial cells did not develop inflammation-induced aversion. Collectively, these findings demonstrate that circulating IFN-ɣ binding to receptors on brain endothelial cells which induces Cxcl10, is a central link in the signaling chain eliciting inflammation-induced aversion.

    In study III, we explored the role of melanocortin 4 receptors (MC4Rs) in aversive processing using genetically modified mice in CPA to various stimuli. In normal mice, robust aversions were induced by systemic inflammation, nausea, pain and kappa opioid receptor-induced dysphoria. In sharp contrast, mice lacking MC4Rs displayed preference towards most of the aversive stimuli, but were indifferent to pain. The unusual flip from aversion to reward in mice lacking MC4Rs was dopamine-dependent and associated with a change from decreased to increased activity of the dopamine system. The responses to aversive stimuli were normalized when MC4Rs were re-expressed on dopamine D1 receptor-expressing cells or in the striatum of mice otherwise lacking MC4Rs. Furthermore, activation of arcuate nucleus proopiomelanocortin neurons projecting to the ventral striatum increased the activity of striatal neurons in a MC4R-dependent manner and elicited aversion. Our findings demonstrate that melanocortin signaling through striatal MC4Rs is critical for assigning negative motivational valence to harmful stimuli.

    The neurotransmitter acetylcholine has been implied in reward learning and drug addiction. However, the role of cholinergic receptor subtypes in such processes remains elusive. In study IV we investigated the function of muscarinic M4Rs on dopamine D1R expressing neurons and acetylcholinergic neurons, using transgenic mice in various reward-enforced behaviors and in a “waiting”-impulsivity test. Mice lacking M4-receptors from D1-receptor expressing neurons exhibited an escalated reward seeking phenotype towards cocaine and natural reward, in Pavlovian conditioning and an operant self-administration task, respectively. In addition, the M4-D1RCre mice showed impaired waiting impulsivity in the 5-choice-serial-reaction-time-task. On the contrary, mice without M4Rs in acetylcholinergic neurons were unable to learn positive reinforcement to natural reward and cocaine, in an operant runway paradigm and in Pavlovian conditioning.  Immediate early gene expression mirrored the behavioral findings arising from M4R-D1R knockout, as cocaine induced cFos and FosB was significantly increased in the forebrain of M4-D1RCre mice, whereas it remained normal in the M4R-ChatCre mice. Our study illustrates that muscarinic M4Rs on specific neural populations, either cholinergic or D1R-expressing, are pivotal for learning processes related to both natural reward and drugs of abuse, with opposing functionality.

    Delarbeten
    1. Prostaglandin-dependent modulation of dopaminergic neurotransmission elicits inflammation-induced aversion in mice
    Öppna denna publikation i ny flik eller fönster >>Prostaglandin-dependent modulation of dopaminergic neurotransmission elicits inflammation-induced aversion in mice
    Visa övriga...
    2016 (Engelska)Ingår i: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 126, nr 2, s. 695-705Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Systemic inflammation causes malaise and general feelings of discomfort. This fundamental aspect of the sickness response reduces the quality of life for people suffering from chronic inflammatory diseases and is a nuisance during mild infections like common colds or the flu. To investigate how inflammation is perceived as unpleasant and causes negative affect, we used a behavioral test in which mice avoid an environment that they have learned to associate with inflammation-induced discomfort. Using a combination of cell-type-specific gene deletions, pharmacology, and chemogenetics, we found that systemic inflammation triggered aversion through MyD88-dependent activation of the brain endothelium followed by COX1-mediated cerebral prostaglandin E-2 (PGE(2)) synthesis. Further, we showed that inflammation-induced PGE(2) targeted EP1 receptors on striatal dopamine D1 receptor-expressing neurons and that this signaling sequence induced aversion through GABA-mediated inhibition of dopaminergic cells. Finally, we demonstrated that inflammation-induced aversion was not an indirect consequence of fever or anorexia but that it constituted an independent inflammatory symptom triggered by a unique molecular mechanism. Collectively, these findings demonstrate that PGE(2)-mediated modulation of the dopaminergic motivational circuitry is a key mechanism underlying the negative affect induced by inflammation.

    Ort, förlag, år, upplaga, sidor
    AMER SOC CLINICAL INVESTIGATION INC, 2016
    Nationell ämneskategori
    Klinisk medicin
    Identifikatorer
    urn:nbn:se:liu:diva-126263 (URN)10.1172/JCI83844 (DOI)000370677300029 ()26690700 (PubMedID)
    Anmärkning

    Funding Agencies|European Research Council (ERC); Swedish Medical Research Council; Knut and Alice Wallenberg foundation; Swedish Brain Foundation; County Council of Ostergotland; Swedish Cancer Foundation; Veterans Administration Merit award; NIH [NS33987, NS72337]

    Tillgänglig från: 2016-03-21 Skapad: 2016-03-21 Senast uppdaterad: 2019-04-29Bibliografiskt granskad
    2. Interferon-ɣ mediated signaling in the brain endothelium is critical for inflammation-induced aversion
    Öppna denna publikation i ny flik eller fönster >>Interferon-ɣ mediated signaling in the brain endothelium is critical for inflammation-induced aversion
    2018 (Engelska)Ingår i: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 67, s. 54-58Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Systemic inflammation elicits malaise and a negative affective state. The mechanism underpinning the aversive component of inflammation include cerebral prostaglandin synthesis and modulation of dopaminergic reward circuits, but the messengers that mediate the signaling between the peripheral inflammation and the brain have not been sufficiently characterized. Here we investigated the role of interferon-ɣ (IFN-ɣ) in the aversive response to systemic inflammation induced by a low dose (10μg/kg) of lipopolysaccharide (LPS) in mice. LPS induced IFN-ɣ expression in the blood and deletion of IFN-ɣ or its receptor prevented the development of conditioned place aversion to LPS. LPS induced expression of the chemokine Cxcl10 in the striatum of normal mice, but this induction was absent in mice lacking IFN-ɣ receptors or Myd88 in blood brain barrier endothelial cells. Furthermore, inflammation-induced aversion was blocked in mice lacking Cxcl10 or its receptor Cxcr3. Finally, mice with a selective deletion of the IFN-ɣ receptor in brain endothelial cells did not develop inflammation-induced aversion, demonstrating that the brain endothelium is the critical site of IFN-ɣ action. Collectively, these findings show that circulating IFN-ɣ that binds to receptors on brain endothelial cells and induces Cxcl10, is a central link in the signaling chain eliciting inflammation-induced aversion.

    Ort, förlag, år, upplaga, sidor
    Maryland Heights: Academic Press, 2018
    Nyckelord
    Aversion; Behavior; Chemokines; Depression; Endothelium; Interferon; Lipopolysaccharide; Sickness
    Nationell ämneskategori
    Farmakologi och toxikologi Neurovetenskaper Immunologi inom det medicinska området Immunologi Cell- och molekylärbiologi
    Identifikatorer
    urn:nbn:se:liu:diva-143812 (URN)10.1016/j.bbi.2017.08.020 (DOI)000416879100007 ()28864260 (PubMedID)2-s2.0-85028972384 (Scopus ID)
    Anmärkning

    Funding agencies: European Research Council; Swedish Medical Research Council; Knut and Alice Wallenberg foundation; Swedish Brain foundation; Parkinsonstiftelsen; Region Ostergotland

    Tillgänglig från: 2017-12-19 Skapad: 2017-12-19 Senast uppdaterad: 2019-04-10Bibliografiskt granskad
  • 146.
    Klawonn, Anna
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Fritz, Michael
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Nilsson, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Bonaventura, Jordi
    NIDA, MD USA.
    Shionoya, Kiseko
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Mirrasekhian, Elahe
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Karlsson, Urban
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Jaarola, Maarit
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Granseth, Björn
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Blomqvist, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Michaelides, Michael
    NIDA, MD USA; Johns Hopkins Sch Med, MD USA.
    Engblom, David
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Motivational valence is determined by striatal melanocortin 4 receptors2018Ingår i: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 128, nr 7, s. 3160-3170Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    It is critical for survival to assign positive or negative valence to salient stimuli in a correct manner. Accordingly, harmful stimuli and internal states characterized by perturbed homeostasis are accompanied by discomfort, unease, and aversion. Aversive signaling causes extensive suffering during chronic diseases, including inflammatory conditions, cancer, and depression. Here, we investigated the role of melanocortin 4 receptors (MC4Rs) in aversive processing using genetically modified mice and a behavioral test in which mice avoid an environment that they have learned to associate with aversive stimuli. In normal mice, robust aversions were induced by systemic inflammation, nausea, pain, and. opioid receptorinduced dysphoria. In sharp contrast, mice lacking MC4Rs displayed preference or indifference toward the aversive stimuli. The unusual flip from aversion to reward in mice lacking MC4Rs was dopamine dependent and associated with a change from decreased to increased activity of the dopamine system. The responses to aversive stimuli were normalized when MC4Rs were reexpressed on dopamine D1 receptor-expressing cells or in the striatum of mice otherwise lacking MC4Rs. Furthermore, activation of arcuate nucleus proopiomelanocortin neurons projecting to the ventral striatum increased the activity of striatal neurons in an MC4R-dependent manner and elicited aversion. Our findings demonstrate that melanocortin signaling through striatal MC4Rs is critical for assigning negative motivational valence to harmful stimuli.

  • 147.
    Klawonn, Anna
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten. Stanford Univ, CA 94305 USA.
    Wilhelms, Daniel
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Närsjukvården i centrala Östergötland, Akutkliniken.
    Lindström, Sarah
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten.
    Singh, Anand Kumar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Baylor Coll Med, TX 77030 USA.
    Jaarola, Maarit
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Wess, Jurgen
    NIH, MD 20892 USA.
    Fritz, Michael
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten. Stanford Univ, CA 94305 USA.
    Engblom, David
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Muscarinic M4 Receptors on Cholinergic and Dopamine D1 Receptor-Expressing Neurons Have Opposing Functionality for Positive Reinforcement and Influence Impulsivity2018Ingår i: Frontiers in Molecular Neuroscience, ISSN 1662-5099, Vol. 11, artikel-id 139Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The neurotransmitter acetylcholine has been implicated in reward learning and drug addiction. However, the roles of the various cholinergic receptor subtypes on different neuron populations remain elusive. Here we study the function of muscarinic M4 receptors (M4Rs) in dopamine D1 receptor (D1R) expressing neurons and cholinergic neurons (expressing choline acetyltransferase; ChAT), during various reward-enforced behaviors and in a "waiting"-impulsivity test. We applied cell-type-specific gene deletions targeting M4Rs in D1RCre or ChATCre mice. Mice lacking M4Rs in D1R-neurons displayed greater cocaine seeking and drug-primed reinstatement than their littermate controls in a Pavlovian conditioned place preference (CPP) paradigm. Furthermore, the M4R-D1RCre mice initiated significantly more premature responses (PRs) in the 5-choice-serial-reaction-time-task (5CSRTT) than their littermate controls, indicating impaired waiting impulse control. In contrast, mice lacking M4Rs in cholinergic neurons did not acquire cocaine Pavlovian conditioning. The M4R-ChATCre mice were also unable to learn positive reinforcement to either natural reward or cocaine in an operant runway paradigm. Immediate early gene (IEG) expression (cFos and FosB) induced by repeated cocaine injections was significantly increased in the forebrain of M4R-D1RCre mice, whereas it remained normal in the M4R-ChATCre mice. Our study illustrates that muscarinic M4Rs on specific neural populations, either cholinergic or D1R-expressing, are pivotal for learning processes related to both natural reward and drugs of abuse, with opposing functionality. Furthermore, we found that neurons expressing both M4Rs and D1Rs are important for signaling impulse control.

  • 148.
    Konsman, Jan Pieter
    et al.
    Laboratoire de Neurobiologie Intégrative, Centre National de la Recherche Scientifique FRE 2723 / Institut National de la Recherche Agronomique UR 1244, Institut François Magendie, Bordeaux, France.
    Vigues, Stephan
    Division of Endocrinology, National Institute for Biological Standards and Control, Herts, United Kingdom.
    Mackerlova, Ludmila
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Bristow, Adrian
    Division of Endocrinology, National Institute for Biological Standards and Control, Herts, United Kingdom.
    Blomqvist, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Rat Brain Vascular Distribution of Interleukin-1 Type-1 Receptor Immunoreactivity: Relationship to Patterns of Inducible Cyclooxygenase Expression by Peripheral Inflammatory Stimuli2004Ingår i: Journal of Comparative Neurology, ISSN 0021-9967, E-ISSN 1096-9861, Vol. 472, nr 1, s. 113-129Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Interleukin-1ß (IL-1ß) is thought to act on the brain to induce fever, neuroendocrine activation, and behavioral changes during disease through induction of prostaglandins at the blood-brain barrier (BBB). However, despite the fact that IL-1ß induces the prostaglandin-synthesizing enzyme cyclooxygenase-2 (COX-2) in brain vascular cells, no study has established the presence of IL-1 receptor type 1 (IL-1R1) protein in these cells. Furthermore, although COX inhibitors attenuate expression of the activation marker c-Fos in the preoptic and paraventricular hypothalamus after administration of IL-1ß or bacterial lipopolysaccharide (LPS), they do not alter c-Fos induction in other structures known to express prostaglandin receptors. The present study thus sought to establish whether IL-1R1 protein is present and functional in the rat cerebral vasculature. In addition, the distribution of IL-1R1 protein was compared to IL-1ß- and LPS-induced COX-2 expression. IL-1R1-immunoreactive perivascular cells were mostly found in choroid plexus and meninges. IL-1R1-immunoreactive vessels were seen throughout the brain, but concentrated in the preoptic area, subfornical organ, supraoptic hypothalamus, and to a lesser extent in the paraventricular hypothalamus, cortex, nucleus of the solitary tract, and ventrolateral medulla. Vascular IL-1R1-ir was associated with an endothelial cell marker, not found in arterioles, and corresponded to the induction patterns of phosphorylated c-Jun and inhibitory-factor kappaB mRNA upon IL-1ß stimulation, and colocalized with peripheral IL-1ß- or LPS-induced COX-2 expression. These observations indicate that functional IL-1R1s are expressed in endothelial cells of brain venules and suggest that vascular IL-1R1 distribution is an important factor determining BBB prostaglandin-dependent activation of brain structures during infection. © 2004 Wiley-Liss, Inc.

  • 149.
    Koppel, Lina
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Institutionen för ekonomisk och industriell utveckling, Nationalekonomi. Linköpings universitet, Filosofiska fakulteten.
    Andersson, David
    Linköpings universitet, Institutionen för ekonomisk och industriell utveckling, Nationalekonomi. Linköpings universitet, Filosofiska fakulteten. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Morrison, India
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Västfjäll, Daniel
    Linköpings universitet, Institutionen för beteendevetenskap och lärande, Psykologi. Linköpings universitet, Filosofiska fakulteten. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Institutionen för ekonomisk och industriell utveckling, Nationalekonomi. Decis Research, OR USA.
    Tinghög, Gustav
    Linköpings universitet, Institutionen för ekonomisk och industriell utveckling, Nationalekonomi. Linköpings universitet, Filosofiska fakulteten. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för hälso- och sjukvårdsanalys. Linköpings universitet, Medicinska fakulteten.
    The (Null) Effect of Affective Touch on Betrayal Aversion, Altruism, and Risk Taking2017Ingår i: Frontiers in Behavioral Neuroscience, ISSN 1662-5153, E-ISSN 1662-5153, Vol. 11, artikel-id 251Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Pleasant touch is thought to increase the release of oxytocin. Oxytocin, in turn, has been extensively studied with regards to its effects on trust and prosocial behavior, but results remain inconsistent. The purpose of this study was to investigate the effect of touch on economic decision making. Participants (n = 120) were stroked on their left arm using a soft brush (touch condition) or not at all (control condition; varied within subjects), while they performed a series of decision tasks assessing betrayal aversion (the Betrayal Aversion Elicitation Task), altruism (donating money to a charitable organization), and risk taking (the Balloon Analog Risk Task). We found no significant effect of touch on any of the outcome measures, neither within nor between subjects. Furthermore, effects were not moderated by gender or attachment. However, attachment avoidance had a significant effect on altruism in that those who were high in avoidance donated less money. Our findings contribute to the understanding of affective touch-and, by extension, oxytocin-in social behavior, and decision making by showing that touch does not directly influence performance in tasks involving risk and prosocial decisions. Specifically, our work casts further doubt on the validity of oxytocin research in humans.

  • 150.
    Kullberg, Agneta
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för samhällsmedicin. Linköpings universitet, Medicinska fakulteten.
    Odzakovic, Elzana
    Linköpings universitet, Institutionen för samhälls- och välfärdsstudier, Avdelningen för omvårdnad. Linköpings universitet, Medicinska fakulteten.
    Walking interviews as a research method with people living with dementia in their local community2018Ingår i: Social research methods in dementia studies: inclusion and innovation / [ed] John Keady, Lars-Christer Hydén, Ann Johnson, Caroline Swarbrick, Abingdon, Oxon: Routledge, 2018, s. 23-37Kapitel i bok, del av antologi (Övrigt vetenskapligt)
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