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  • 51.
    Ciganovic, Nikola
    et al.
    Imperial Coll London, England.
    Warren, Rebecca L.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten.
    Keceli, Batu
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Jacob, Stefan
    Karolinska Inst, Sweden.
    Fridberger, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Reichenbach, Tobias
    Imperial Coll London, England; Univ Calif Santa Barbara, CA 93106 USA.
    Static length changes of cochlear outer hair cells can tune low-frequency hearing2018Ingår i: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 14, nr 1, artikel-id e1005936Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The cochlea not only transduces sound-induced vibration into neural spikes, it also amplifies weak sound to boost its detection. Actuators of this active process are sensory outer hair cells in the organ of Corti, whereas the inner hair cells transduce the resulting motion into electric signals that propagate via the auditory nerve to the brain. However, how the outer hair cells modulate the stimulus to the inner hair cells remains unclear. Here, we combine theoretical modeling and experimental measurements near the cochlear apex to study the way in which length changes of the outer hair cells deform the organ of Corti. We develop a geometry-based kinematic model of the apical organ of Corti that reproduces salient, yet counter-intuitive features of the organs motion. Our analysis further uncovers a mechanism by which a static length change of the outer hair cells can sensitively tune the signal transmitted to the sensory inner hair cells. When the outer hair cells are in an elongated state, stimulation of inner hair cells is largely inhibited, whereas outer hair cell contraction leads to a substantial enhancement of sound-evoked motion near the hair bundles. This novel mechanism for regulating the sensitivity of the hearing organ applies to the low frequencies that are most important for the perception of speech and music. We suggest that the proposed mechanism might underlie frequency discrimination at low auditory frequencies, as well as our ability to selectively attend auditory signals in noisy surroundings.

  • 52.
    Cippitelli, Andrea
    et al.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Damadzic, Ruslan
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Frankola, Kate
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Goldstein, Andrea
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Thorsell, Annika
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Singley, Erick
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Eskay, Robert L
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Heilig, Markus
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Alcohol-induced neurodegeneration, suppression of transforming growth factor-beta, and cognitive impairment in rats: prevention by group II metabotropic glutamate receptor activation2010Ingår i: Biological Psychiatry, ISSN 0006-3223, E-ISSN 1873-2402, Vol. 67, nr 9, s. 823-830Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Glutamatergic neurotransmission has been implicated in mechanisms of alcohol-induced neurodegeneration and cognitive impairment, but the underlying mechanism remains unknown. Here, we examined whether the group II metabotropic glutamate receptor agonist LY379268 prevents neuronal death and learning deficits in a rat model of binge-like exposure to alcohol.

    METHODS: Following 4-day binge alcohol exposure concurrent with LY379268 or vehicle treatment, Fluoro-Jade B and transforming growth factor-beta (TGF-beta) staining were carried out, and reversal learning in the Morris water maze was assessed.

    RESULTS: Fluoro-Jade B staining indicating neurodegeneration was most extensive in the ventral hippocampus and the entorhinal cortex (EC). LY379268 was potently neuroprotective in the EC but not in the dentate gyrus of the hippocampus. In parallel, binge alcohol exposure suppressed TGF-beta expression in both the EC and dentate gyrus, whereas LY379268 increased TGF-beta in the EC only. Finally, neuroprotective effects of LY379268 were accompanied by prevention of deficits in spatial reversal learning.

    CONCLUSIONS: Our data support a neuroprotective role for group II metabotropic glutamate receptor agonists and TGF-beta in alcohol-induced neurodegeneration.

  • 53.
    Cippitelli, Andrea
    et al.
    National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
    Damadzic, Ruslan
    National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
    Hamelink, Carol
    National Institute of Mental Health, NIH, Bethesda, MD, USA.
    Brunnquell, Michael
    National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, 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.
    Eskay, Robert L.
    National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
    Binge-like ethanol consumption increases corticosterone levels and neurodegneration whereas occupancy of type II glucocorticoid receptors with mifepristone is neuroprotective2014Ingår i: Addiction Biology, ISSN 1355-6215, E-ISSN 1369-1600, Vol. 19, nr 1, s. 27-36Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Excessive ethanol (EtOH) use leads to impaired memory and cognition. Using a rat model of binge-like intoxication, we tested whether elevated corticosterone (Cort) levels contribute to the neurotoxic consequences of EtOH exposure. Rats were adrenalectomized (Adx) and implanted with cholesterol pellets, or cholesterol pellets containing Cort in order to achieve basal, medium, or high blood concentrations of Cort. Intragastric EtOH or an isocaloric control solution was given three times daily for 4 days to achieve blood alcohol levels ranging between 200 and 350 mg/dl. Mean 24-hour plasma levels of Cort were ∼110 and ∼40 ng/ml in intact EtOH-treated and intact control animals, respectively. Basal Cort replacement concentrations in EtOH-treated Adx animals did not exacerbate alcohol-induced neurodegeneration in the hippocampal dentate gyrus (DG) or the entorhinal cortex (EC) as observed by amino-cupric silver staining. In contrast, Cort replacement pellets resulting in plasma Cort levels twofold higher (medium) than normal, or greater than twofold higher (high) in Adx-Cort-EtOH animals increased neurodegeneration. In separate experiments, pharmacological blockade of the Type II glucocorticoid (GC) receptor was initiated with mifepristone (RU38486; 0, 5, 15 mg/kg/day, i.p.). At the higher dose, mifepristone decreased the number of degenerating hippocampal DG cells in binge-EtOH-treated intact animals, whereas, only a trend for reduction was observed in 15 mg/kg/day mifepristone-treated animals in the EC, as determined by fluoro-jade B staining. These results suggest that elevated circulating Cort in part mediates EtOH-induced neurotoxicity in the brain through activation of Type II GC receptors.

  • 54.
    Cippitelli, Andrea
    et al.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Damadzic, Ruslan
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Hansson, Anita C.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Singley, Erick
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Sommer, Wolfgang H.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Eskay, Robert
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, 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.
    Neuropeptide Y (NPY) suppresses yohimbine-induced reinstatement of alcohol seeking2010Ingår i: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 208, nr 3, s. 417-426Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    INTRODUCTION: Reinstatement of responding to a previously alcohol-associated lever following extinction is an established model of relapse-like behavior and can be triggered by stress exposure. Here, we examined whether neuropeptide Y (NPY), an endogenous anti-stress mediator, blocks reinstatement of alcohol-seeking induced by the pharmacological stressor yohimbine.

    MATERIALS AND METHODS: NPY [5.0 or 10.0 mug/rat, intracerebroventricularly (ICV)] dose-dependently blocked the reinstatement of alcohol seeking induced by yohimbine (1.25 mg/kg, i.p.) but failed to significantly suppress the maintenance of alcohol self-administration. We then used c-fos expression mapping to examine neuronal activation following treatment with yohimbine or NPY alone or yohimbine following NPY pre-treatment.

    RESULTS AND DISCUSSION: The analysis was focused on a network of structures previously implicated in yohimbine-induced reinstatement, comprised of central (CeA) and basolateral (BLA) amygdala and the shell of the nucleus accumbens (Nc AccS). Within this network, both yohimbine and NPY potently induced neuronal activation, and their effects were additive, presumably indicating activation of excitatory and inhibitory neuronal populations, respectively.

    CONCLUSION: These results suggest that NPY selectively suppresses relapse to alcohol seeking induced by stressful events and support the NPY system as an attractive target for the treatment of alcohol addiction.

  • 55.
    Cippitelli, Andrea
    et al.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Damadzic, Ruslan
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Singley, Erick
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Thorsell, Annika
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Ciccocioppo, Roberto
    University of Camerino, Italy.
    Eskay, Robert L.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Heilig, Markus
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Pharmacological blockade of corticotropin-releasing hormone receptor 1 (CRH1R) reduces voluntary consumption of high alcohol concentrations in non-dependent Wistar rats2012Ingår i: Pharmacology, Biochemistry and Behavior, ISSN 0091-3057, E-ISSN 1873-5177, Vol. 100, nr 3, s. 522-529Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: A dysregulation of the corticotropin-releasing hormone (CRH) system has been implicated in the development of excessive alcohol consumption and dependence. The aim of the present study was to evaluate whether the CRH system is also recruited when non-dependent Wistar rats escalate to high alcohol intake in the intermittent (alternate days) model of drinking.

    METHODS: We compared intermittent and continuous access to 20% (v/v) alcohol in a two-bottle free choice drinking paradigm. Following a total of twenty 24-hour exposures for every experimental group, we assessed signs of alcohol withdrawal, including anxiety-like behavior and sensitivity to stress. The selective CRH1 receptor (CRH1R) antagonist antalarmin (0, 10, 20 mg/kg, i.p.) was tested on alcohol consumption.

    RESULTS: Intermittent access to 20% alcohol led non-selected Wistar rats to escalate their voluntary intake to a high and stable level, whereas continuously exposed animals maintained a lower consumption. These groups did not differ in physical withdrawal signs. In addition, no differences were found when anxiogenic-like behavior was studied, neither under basal conditions or following restraint stress. Nevertheless, sensitivity to the treatment with the CRH1R antalarmin was observed since a reduction of 20% alcohol intake was found in both groups of animals regardless of the regimen of alcohol exposure. In addition, antalarmin was effective when injected to animals exposed to intermittent 10% (v/v) alcohol whereas it failed to suppress 10% continuous alcohol intake.

    CONCLUSIONS: Pharmacological blockade of CRH1R reduced alcohol drinking when sustained high levels of intake were achieved suggesting that the CRH system plays a key role when high doses of ethanol are consumed by non-dependent subjects. This supports the notion that CRH system not only maintains the dependent state but also engages the transition to dependence.

  • 56.
    Cippitelli, Andrea
    et al.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Karlsson, Camilla
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Shaw, Janice L.
    Eli Lilly, Indianapolis, IN, USA.
    Thorsell, Annika
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Gehlert, Donald R.
    Eli Lilly, Indianapolis, IN, USA.
    Heilig, Markus
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Suppression of alcohol self-administration and reinstatement of alcohol seeking by melanin-concentrating hormone receptor 1 (MCH1-R) antagonism in Wistar rats2010Ingår i: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 211, nr 4, s. 367-375Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    RATIONALE: Melanin-concentrating hormone (MCH) is involved in regulation of appetitive behaviors as well as emotional reactivity and reward, behavioral domains relevant to alcohol addiction.

    MATERIALS AND METHODS: We evaluated the effects of the non-peptide MCH1 receptor antagonist, GW803430 [6-(4-chloro-phenyl)-3-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3H-thieno[3,2-d]pyrimidin-4-one; 3-30 mg/kg, i.p.] on alcohol-related behaviors in Wistar rats.

    RESULTS: Ex vivo binding experiments demonstrated that the GW803430 dose range used resulted in high central MCH1 receptor occupancy. Alcohol self-administration was dose-dependently and potently suppressed, by approximately 80% at the highest dose. Reinstatement of alcohol-seeking induced by alcohol-associated cues was essentially eliminated. In contrast, reinstatement induced by footshock stress was not significantly altered. Taste preference for a quinine/saccharin solution, locomotor activity, and alcohol elimination were unaffected.

    CONCLUSION: Together, these observations support a specific involvement of the MCH system in mediating alcohol reward and cue-induced relapse to alcohol seeking. MCH1-R antagonism may constitute an attractive treatment target for alcohol use disorders.

  • 57.
    Cippitelli, Andrea
    et al.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Rezvani, Amir H.
    Duke University Medical Center, Durham, NC, USA.
    Robinson, J. Elliott
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Eisenberg, Lindsay
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Levin, Edward D.
    Duke University Medical Center, Durham, NC, USA.
    Bonaventure, Pascal
    Johnson & Johnson Pharmaceutical Research and Development, San Diego, USA.
    Motley, S. Timothy
    Johnson & Johnson Pharmaceutical Research and Development, San Diego, USA.
    Lovenberg, Timothy W.
    Johnson & Johnson Pharmaceutical Research and Development, San Diego, USA.
    Heilig, Markus
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Thorsell, Annika
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    The novel, selective, brain-penetrant neuropeptide Y Y2 receptor antagonist, JNJ-31020028, tested in animal models of alcohol consumption, relapse, and anxiety2011Ingår i: Alcohol, ISSN 0741-8329, E-ISSN 1873-6823, Vol. 45, nr 6, s. 567-576Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Neuropeptide Y (NPY) signaling has been shown to modulate stress responses and to be involved in regulation of alcohol intake and dependence. The present study explores the possibility that blockade of NPY Y2 autoreceptors using a novel, blood-brain barrier penetrant NPY Y2 receptor antagonist, JNJ-31020028 (N-(4-{4-[2-(diethylamino)-2-oxo-1-phenylethyl]piperazin-1-yl}-3-fluorophenyl)-2-pyridin-3-ylbenzamide), may achieve a therapeutically useful activation of the NPY system in alcohol- and anxiety-related behavioral models. We examined JNJ-31020028 in operant alcohol self-administration, stress-induced reinstatement to alcohol seeking, and acute alcohol withdrawal (hangover)-induced anxiety. Furthermore, we tested its effects on voluntary alcohol consumption in a genetic animal model of alcohol preference, the alcohol-preferring (P) rat. Neither systemic (0, 15, 30, and 40 mg/kg, subcutaneously [s.c.]) nor intracerebroventricular (0.0, 0.3, and 1.0 nmol/rat) administration of JNJ-31020028 affected alcohol-reinforced lever pressing or relapse to alcohol seeking behavior following stress exposure. Also, when its effects were tested on unlimited access to alcohol in P rats, preference for alcohol solution was transiently suppressed but without affecting voluntary alcohol intake. JNJ-31020028 (15 mg/kg, s.c.) did reverse the anxiogenic effects of withdrawal from a single bolus dose of alcohol on the elevated plus-maze, confirming the anxiolytic-like properties of NPY Y2 antagonism. Our data do not support Y2 antagonism as a mechanism for reducing alcohol consumption or relapse-like behavior, but the observed effects on withdrawal-induced anxiety suggest that NPY Y2 receptor antagonists may be a putative treatment for the negative affective states following alcohol withdrawal.

  • 58.
    Dadi, Kamalaker Reddy
    Linköpings universitet, Institutionen för medicinsk teknik. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV. Linköpings universitet, Tekniska högskolan.
    Circadian Rhythms in the Brain - A first step2013Självständigt arbete på avancerad nivå (masterexamen), 20 poäng / 30 hpStudentuppsats (Examensarbete)
    Abstract [en]

    Circadian Rhythms (CR) are driven by a biological clock called as suprachiasmaticnucleus (SCN), located in a brain region called the hypothalamus. These rhythms are very much necessary in maintaining the sleep and wake cycle at appropriate times in a day. As a starting step towards non-invasive investigation of CR, aim is to study changes in the physiological processes of two Regions of Interest (ROI), the hypothalamus and the visual cortex. This was studied using a functional Magnetic Resonance Imaging (fMRI) technique to investigate for any changes or differences in the Blood Oxygen Level Dependent (BOLD)signals extracted from the ROI during a visual stimulation. We acquired and processed fMRI data to extract BOLD signals from ROI and the extracted signals are again further used to study the correlation with the experimental ON-OFF design paradigm.

    The extracted BOLD signals varied a lot between the two specified brain regions within the same subject and between three types of fMRI data. These variations were found in terms of number of activated voxels and also Signal to Noise ratio(SNR) level present in the signals. The number of activated voxels and SNR werehigh in visual cortex whereas low number of activated voxels and low SNR were found in hypothalamus. The correlation between BOLD responses from primaryvisual cortex were shown as positive with the experimental stimulation whereas BOLD responses extracted from hypothalamus have shown a negative correlation in time with the experimental stimulation.

    As a start up of the project, these BOLD responses can provide references for a future use in research studies, especially to further study about change in phase of the BOLD signal extracted exactly from the SCN. These phase responses can then be used to study physiological processing in subjects affected by sleep disorders.

  • 59.
    Dash-Wagh, Suvarna
    et al.
    Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Jacob, Stefan
    Department of Clinical Science, Intervention, and Technology, Karolinska Institutet, Stockholm, Sweden.
    Lindberg, Staffan
    Department of Neurochemistry, Stockholm University, Stockholm, Sweden.
    Fridberger, Anders
    Department of Clinical Science, Intervention, and Technology, Karolinska Institutet, Stockholm, Sweden.
    Langel, Ülo
    Department of Neurochemistry, Stockholm University, Stockholm, Sweden.
    Ulfendahl, Mats
    Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Intracellular Delivery of Short Interfering RNA in Rat Organ of Corti Using a Cell-penetrating Peptide PepFect62012Ingår i: Molecular Therapy - Nucleic Acids, ISSN 2162-2531, E-ISSN 2162-2531, Vol. 1Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    RNA interference (RNAi) using short interfering RNA (siRNA) is an attractive therapeutic approach for treatment of dominant-negative mutations. Some rare missense dominant-negative mutations lead to congenital-hearing impairments. A variety of viral vectors have been tested with variable efficacy for modulating gene expression in inner ear. However, there is concern regarding their safety for clinical use. Here, we report a novel cell-penetrating peptide (CPP)-based nonviral approach for delivering siRNA into inner ear tissue using organotypic cultures as model system. PepFect6 (PF6), a variant of stearyl-TP10, was specially designed for improved delivery of siRNA by facilitating endosomal release. We show that PF6 was internalized by all cells without inducing cytotoxicity in cochlear cultures. PF6/siRNA nanoparticles lead to knockdown of target genes, a housekeeping gene and supporting cell-specific connexin 26. Interestingly, application of PF6/connexin 26 siRNA exhibited knockdown of both connexin 26 and 30 mRNA and their absence led to impaired intercellular communication as demonstrated by reduced transfer of calcein among the PF6/connexin 26-siRNA-treated cells. Thus, we conclude that PF6 is an efficient nonviral vector for delivery of siRNA, which can be applied as a tool for the development of siRNA-based therapeutic applications for hearing impairments.Molecular Therapy - Nucleic Acids (2012) 1, e61; doi:10.1038/mtna.2012.50; published online 11 December 2012.

  • 60.
    Domert, Jakob
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Neuron-to-neuron propagation of neurodegenerative proteins; relation to degradative systems2017Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Alzheimer’s disease (AD) and Parkinson’s disease (PD) are defined by neurodegeneration and accumulations of misfolded proteins that spread through the brain in a well characterized manner. In AD these accumulations consist mainly of β-amyloid (Aβ) and tau, while in PD, α-synuclein (α-syn) make up the characteristic lewy pathology. 

       The general aim of this thesis was to investigate mechanisms associated with neurotoxic peptide activity by Aβ, tau and α-syn in relation to cellular degradation and transfer with a cell-to-cell transfer model system.

       We found that intercellular transfer of oligomeric Aβ occurs independently of isoform. However, the amount of transfer correlates with each isoforms ability to resist degradation or cellular clearance. The Aβ1-42 isoform showed particular resistance to clearance, which resulted in higher levels of cell-to-cell transfer of the isoform and lysosomal stress caused by accumulation.

       As Aβ accumulations can inhibit the proteasomal degradation we investigated how reduced proteasomal degradation affected neuron-like cells. We found increased levels of phosphorylated tau protein, disturbed microtubule stability and impaired neuritic transport after reduced proteasomal activity. These changes was partly linked to c-Jun and ERK 1/2 kinase activity.

       We could also show that α-syn transferred from cell-to-cell in our model system, with a higher degree of transfer for the larger oligomer and fibrillar species. Similar to Aβ, α-syn mainly colocalized with lysosomes, before and after transfer.

        Lastly, we have developed our cell-to-cell transfer system into a model suitable for high throughput screening (HTS). The type of cells have been upgraded from SH-SY5Y cells to induced pluripotent stem cells (iPSCs), with a differentiation profile more similar to mature neurons. The next step will be screening a small molecular library for substances with inhibitory effect on cell-to-cell transfer of Aβ peptides. 

       The importance of the degradative systems in maintaining protein homeostasis and prevent toxic accumulations in general is well known. Our findings shows the importance of these systems for neurodegenerative diseases and also highlight the link between degradation and cell-to-cell transfer. To restore or enhance the degradative systems would be an interesting avenue to treat neurodegenerative diseases. Another way would be to inhibit the transfer of misfolded protein aggregates. By using the HTS model we developed, a candidate substance with good inhibitory effect on transfer can hopefully be found.

    Delarbeten
    1. Spreading of Amyloid-β Peptides via Neuritic Cell-to-cell Transfer Is Dependent on Insufficient Cellular Clearance
    Öppna denna publikation i ny flik eller fönster >>Spreading of Amyloid-β Peptides via Neuritic Cell-to-cell Transfer Is Dependent on Insufficient Cellular Clearance
    Visa övriga...
    2014 (Engelska)Ingår i: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 65, s. 82-92Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The spreading of pathology through neuronal pathways is likely to be the cause of the progressive cognitive loss observed in Alzheimer's disease (AD) and other neurodegenerative diseases. We have recently shown the propagation of AD pathology via cell-to-cell transfer of oligomeric amyloid beta (Aβ) residues 1-42 (oAβ1-42) using our donor-acceptor 3-D co-culture model. We now show that different Aβ-isoforms (fluorescently labeled 1-42, 3(pE)-40, 1-40 and 11-42 oligomers) can transfer from one cell to another. Thus, transfer is not restricted to a specific Aβ-isoform. Although different Aβ isoforms can transfer, differences in the capacity to clear and/or degrade these aggregated isoforms result in vast differences in the net amounts ending up in the receiving cells and the net remaining Aβ can cause seeding and pathology in the receiving cells. This insufficient clearance and/or degradation by cells creates sizable intracellular accumulations of the aggregation-prone Aβ1-42 isoform, which further promotes cell-to-cell transfer; thus, oAβ1-42 is a potentially toxic isoform. Furthermore, cell-to-cell transfer is shown to be an early event that is seemingly independent of later appearances of cellular toxicity. This phenomenon could explain how seeds for the AD pathology could pass on to new brain areas and gradually induce AD pathology, even before the first cell starts to deteriorate, and how cell-to-cell transfer can act together with the factors that influence cellular clearance and/or degradation in the development of AD.

    Ort, förlag, år, upplaga, sidor
    Elsevier, 2014
    Nyckelord
    Alzheimer's disease, Amyloid-β oligomers, Cell-to-cell transfer, Intracellular accumulation, Prion-like propagation
    Nationell ämneskategori
    Cellbiologi
    Identifikatorer
    urn:nbn:se:liu:diva-103179 (URN)10.1016/j.nbd.2013.12.019 (DOI)000333546300008 ()24412310 (PubMedID)
    Tillgänglig från: 2014-01-14 Skapad: 2014-01-14 Senast uppdaterad: 2017-12-06Bibliografiskt granskad
    2. Proteasome Inhibition Induces Stress Kinase Dependent Transport Deficits – Implications for Alzheimer’s Disease
    Öppna denna publikation i ny flik eller fönster >>Proteasome Inhibition Induces Stress Kinase Dependent Transport Deficits – Implications for Alzheimer’s Disease
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    2014 (Engelska)Ingår i: Molecular and Cellular Neuroscience, ISSN 1044-7431, E-ISSN 1095-9327, Vol. 58, s. 29-39Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Alzheimer’s disease (AD) is characterized by accumulation of two misfolded and aggregated proteins, β-amyloid and hyperphosphorylated tau. Both cellular systems responsible for clearance of misfolded and aggregated proteins, the lysosomal and the proteasomal, have been shown to be malfunctioning in the aged brain and more so in AD patients. This malfunction could be the cause of β-amyloid and tau accumulation, eventually aggregating in plaques and tangles. We have investigated how decreased proteasome activity affects AD related pathophysiological changes of microtubule transport and stability, as well as tau phosphorylation. To do this, we used our recently developed neuronal model where human SH-SY5Y cells obtain neuronal morphology and function through differentiation. We found that exposure to low doses of the proteasome inhibitor MG-115 caused disturbed neuritic transport, together with microtubule destabilization and tau phosphorylation. Furthermore, reduced proteasome activity activated several kinases implicated in AD pathology, including JNK, c-Jun and ERK 1/2. Restoration of the microtubule transport was achieved by inhibiting ERK 1/2 activation, and simultaneous inhibition of both ERK 1/2 and c-Jun reversed the proteasome inhibition-induced tau phosphorylation. Taken together, this study suggests that a decrease in proteasome activity can, through activation of c-Jun and ERK 1/2, result in several events contributing to AD pathology. Restoring proteasome function or inhibiting ERK 1/2 and c-Jun could therefore be used as novel treatments against AD.

    Ort, förlag, år, upplaga, sidor
    Elsevier, 2014
    Nationell ämneskategori
    Klinisk medicin
    Identifikatorer
    urn:nbn:se:liu:diva-81339 (URN)10.1016/j.mcn.2013.11.001 (DOI)000331853600004 ()
    Tillgänglig från: 2012-09-12 Skapad: 2012-09-12 Senast uppdaterad: 2017-12-07Bibliografiskt granskad
    3. Aggregated Alpha-Synuclein Transfer Efficiently between Cultured Human Neuron-Like Cells and Localize to Lysosomes
    Öppna denna publikation i ny flik eller fönster >>Aggregated Alpha-Synuclein Transfer Efficiently between Cultured Human Neuron-Like Cells and Localize to Lysosomes
    Visa övriga...
    2016 (Engelska)Ingår i: PLOS ONE, ISSN 1932-6203, Vol. 11, nr 12, artikel-id e0168700Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Parkinsons disease and other alpha-synucleinopathies are progressive neurodegenerative diseases characterized by aggregates of misfolded alpha-synuclein spreading throughout the brain. Recent evidence suggests that the pathological progression is likely due to neuron-to-neuron transfer of these aggregates between neuroanatomically connected areas of the brain. As the impact of this pathological spreading mechanism is currently debated, we aimed to investigate the transfer and subcellular location of alpha-synuclein species in a novel 3D co-culture human cell model based on highly differentiated SH-SY5Y cells. Fluorescently-labeled monomeric, oligomeric and fibrillar species of alpha-synuclein were introduced into a donor cell population and co-cultured with an EGFP-expressing acceptor-cell population of differentiated neuron-like cells. Subsequent transfer and colocalization of the different species were determined with confocal microscopy. We could confirm cell-to-cell transfer of all three alpha-synuclein species investigated. Interestingly the level of transferred oligomers and fibrils and oligomers were significantly higher than monomers, which could affect the probability of seeding and pathology in the recipient cells. Most alpha-synuclein colocalized with the lysosomal/endosomal system, both pre- and postsynaptically, suggesting its importance in the processing and spreading of alpha-synuclein.

    Ort, förlag, år, upplaga, sidor
    PUBLIC LIBRARY SCIENCE, 2016
    Nationell ämneskategori
    Neurovetenskaper
    Identifikatorer
    urn:nbn:se:liu:diva-134306 (URN)10.1371/journal.pone.0168700 (DOI)000391222000063 ()28030591 (PubMedID)
    Anmärkning

    Funding Agencies|Swedish Research Council [MH: 523-2013-2735]; Swedish Brain Power Program; Research Foundation of the Swedish Parkinsons Disease Association; Ostergotland Research Foundation for Parkinsons Disease; Parkinson Research Foundation; Hans-Gabriel and Alice Trolle-Wachtmeister Foundation for Medical Research; Gustav V and Queen Victorias Foundation; Swedish Dementia Foundation; Linkoping University Neurobiology Centre; County Council of Ostergotland; Marianne and Marcus Wallenberg Foundation

    Tillgänglig från: 2017-02-06 Skapad: 2017-02-03 Senast uppdaterad: 2018-01-13
  • 61.
    Domert, Jakob
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Sackmann, Christopher
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Severinsson, Emelie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Agholme, Lotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. University of Gothenburg, Sweden.
    Bergstrom, Joakim
    Uppsala University, Sweden.
    Ingelsson, Martin
    Uppsala University, Sweden.
    Hallbeck, Martin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Aggregated Alpha-Synuclein Transfer Efficiently between Cultured Human Neuron-Like Cells and Localize to Lysosomes2016Ingår i: PLOS ONE, ISSN 1932-6203, Vol. 11, nr 12, artikel-id e0168700Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Parkinsons disease and other alpha-synucleinopathies are progressive neurodegenerative diseases characterized by aggregates of misfolded alpha-synuclein spreading throughout the brain. Recent evidence suggests that the pathological progression is likely due to neuron-to-neuron transfer of these aggregates between neuroanatomically connected areas of the brain. As the impact of this pathological spreading mechanism is currently debated, we aimed to investigate the transfer and subcellular location of alpha-synuclein species in a novel 3D co-culture human cell model based on highly differentiated SH-SY5Y cells. Fluorescently-labeled monomeric, oligomeric and fibrillar species of alpha-synuclein were introduced into a donor cell population and co-cultured with an EGFP-expressing acceptor-cell population of differentiated neuron-like cells. Subsequent transfer and colocalization of the different species were determined with confocal microscopy. We could confirm cell-to-cell transfer of all three alpha-synuclein species investigated. Interestingly the level of transferred oligomers and fibrils and oligomers were significantly higher than monomers, which could affect the probability of seeding and pathology in the recipient cells. Most alpha-synuclein colocalized with the lysosomal/endosomal system, both pre- and postsynaptically, suggesting its importance in the processing and spreading of alpha-synuclein.

  • 62.
    Domi, Esi
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Barbier, Estelle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Augier, Eric
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Augier, Gaëlle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Gehlert, D.
    Cerecor, MD USA; Matrix Pharmaceut Consulting, CO USA.
    Barchiesi, Riccardo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Thorsell, Annika
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Holm, Lovisa
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    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.
    Preclinical evaluation of the kappa-opioid receptor antagonist CERC-501 as a candidate therapeutic for alcohol use disorders2018Ingår i: Neuropsychopharmacology, ISSN 0893-133X, E-ISSN 1740-634X, Vol. 43, nr 9, s. 1805-1812Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Prior work suggests a role of kappa-opioid signaling in the control of alcohol drinking, in particular when drinking is escalated due to alcohol-induced long-term neuroadaptations. Here, we examined the small molecule selective kappa antagonist CERC-501 in rat models of alcohol-related behaviors, with the objective to evaluate its potential as a candidate therapeutic for alcohol use disorders. We first tested the effect of CERC-501 on acute alcohol withdrawal-induced anxiety-like behavior. CERC-501 was then tested on basal as well as escalated alcohol self-administration induced by 20% alcohol intermittent access. Finally, we determined the effects of CERC-501 on relapse to alcohol seeking triggered by both stress and alcohol-associated cues. Control experiments were performed to confirm the specificity of CERC-501 effects on alcohol-related behaviors. CERC-501 reversed anxiety-like behavior induced by alcohol withdrawal. It did not affect basal alcohol self-administration but did dose-dependently suppress self-administration that had escalated following long-term intermittent access to alcohol. CERC-501 blocked relapse to alcohol seeking induced by stress, but not when relapse-like behavior was triggered by alcohol-associated cues. The effects of CERC-501 were observed in the absence of sedative side effects and were not due to effects on alcohol metabolism. Thus, in a broad battery of preclinical alcohol models, CERC-501 has an activity profile characteristic of anti-stress compounds. Combined with its demonstrated preclinical and clinical safety profile, these data support clinical development of CERC-501 for alcohol use disorders, in particular for patients with negatively reinforced, stress-driven alcohol seeking and use.

  • 63.
    Domi, Esi
    et al.
    University of Camerino, Italy.
    Uhrig, Stefanie
    Heidelberg University, Germany.
    Soverchia, Laura
    University of Camerino, Italy.
    Spanagel, Rainer
    Heidelberg University, Germany.
    Hansson, Anita C.
    Heidelberg University, Germany.
    Barbier, Estelle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Heilig, Markus
    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.
    Ciccocioppo, Roberto
    University of Camerino, Italy.
    Ubaldi, Massimo
    University of Camerino, Italy.
    Genetic Deletion of Neuronal PPAR gamma Enhances the Emotional Response to Acute Stress and Exacerbates Anxiety: An Effect Reversed by Rescue of Amygdala PPAR gamma Function2016Ingår i: JOURNAL OF NEUROSCIENCE, ISSN 0270-6474, Vol. 36, nr 50, s. 12611-12623Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    PPAR gamma is one of the three isoforms of the Peroxisome Proliferator-Activated Receptors (PPARs). PPAR gamma is activated by thiazolidinediones such as pioglitazone and is targeted to treat insulin resistance. PPAR gamma is densely expressed in brain areas involved in regulation of motivational and emotional processes. Here, we investigated the role of PPAR gamma in the brain and explored its role in anxiety and stress responses in mice. The results show that stimulation of PPAR gamma by pioglitazone did not affect basal anxiety, but fully prevented the anxiogenic effect of acute stress. Using mice with genetic ablation of neuronal PPAR gamma (PPAR gamma(NestinCre)), we demonstrated that a lack of receptors, specifically in neurons, exacerbated basal anxiety and enhanced stress sensitivity. The administration of GW9662, a selective PPAR gamma antagonist, elicited a marked anxiogenic response in PPAR gamma wild-type (WT), but not in PPAR gamma(NestinCre) knock-out (KO) mice. Using c-Fos immunohistochemistry, we observed that acute stress exposure resulted in a different pattern of neuronal activation in the amygdala (AMY) and the hippocampus (HIPP) of PPAR gamma(NestinCre) KO mice compared with WT mice. No differences were found between WT and KO mice in hypothalamic regions responsible for hormonal response to stress or in blood corticosterone levels. Microinjection of pioglitazone into the AMY, but not into the HIPP, abolished the anxiogenic response elicited by acute stress. Results also showed that, in both regions, PPAR gamma colocalizes with GABAergic cells. These findings demonstrate that neuronal PPAR gamma is involved the regulation of the stress response and that the AMY is a key substrate for the anxiolytic effect of PPAR gamma

  • 64.
    Drissi, Natasha Morales
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    Brain Networks and Dynamics in Narcolepsy2018Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Narcolepsy is a chronic sleep disorder, characterised by excessive daytime sleepiness with frequent uncontrollable sleep attacks. In addition to sleeprelated problems, changes in cognition have also been observed in patients with narcolepsy and has been linked to the loss of Orexin-A in a number of studies. Results from previous functional and structural neuroimaging studies would suggest that the loss of Orexin-A has numerous downstream effects in terms of both resting state glucose metabolism and perfusion and reduction in cortical grey matter.

    Specifically, studies investigating narcolepsy with positron emission tomography (PET) and single photon emission computed tomography (SPECT) have observed aberrant perfusion and glucose metabolism in the hypothalamus and thalamus, as well as in prefrontal cortex. A very recent PET study in a large cohort of adolescents with type 1 narcolepsy further observed that the hypoand hypermetabolism in many of these cortico-frontal and subcortical brain regions also exhibited significant correlations with performance on a number of neurocognitive tests. These findings parallel those found in structural neuroimaging studies, where a reduction of cortical grey matter in frontotemporal areas has been observed.

    The Aim of this thesis was to investigate mechanisms and aetiology behind the symptoms in narcolepsy through the application of different neuroimaging techniques. I present in this thesis evidence supporting that the complaints about subjective memory deficits in narcolepsy are related to a misallocation of resources.

    I further describe how this has its seat in defective default mode network activation, possibly involving alterations to GABA and Glutamate signaling. In addition to this, I present our findings of a structural deviation in an area of the brainstem previously not described in the aetiology of narcolepsy.

    This finding may have implications for further understanding the aetiology of the disease and the specific neuronal populations involved.

    In addition to this, I show evidence from adipose tissue measurements in specific compartments, confirming that weight gain in narcolepsy is characterized by centrally located weight gain and may be specifically related to OX changes, but maybe not brown adipose tissue volume.

    The findings presented in this thesis provides new insights to the pathophysiology of narcolepsy beyond the well-known depletion of OX producing neurons in the hypothalamus.

    Delarbeten
    1. Altered Brain Microstate Dynamics in Adolescents with Narcolepsy
    Öppna denna publikation i ny flik eller fönster >>Altered Brain Microstate Dynamics in Adolescents with Narcolepsy
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    2016 (Engelska)Ingår i: Frontiers in Human Neuroscience, ISSN 1662-5161, E-ISSN 1662-5161, Vol. 10, nr 369Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Narcolepsy is a chronic sleep disorder caused by a loss of hypocretin-1 producing neurons in the hypothalamus. Previous neuroimaging studies have investigated brain function in narcolepsy during rest using positron emission tomography (PET) and single photon emission computed tomography (SPECT). In addition to hypothalamic and thalamic dysfunction they showed aberrant prefrontal perfusion and glucose metabolism in narcolepsy. Given these findings in brain structure and metabolism in narcolepsy, we anticipated that changes in functional magnetic resonance imaging (fMRI) resting state network (RSN) dynamics might also be apparent in patients with narcolepsy. The objective of this study was to investigate and describe brain microstate activity in adolescents with narcolepsy and correlate these to RSNs using simultaneous fMRI and electroencephalography (EEG). Sixteen adolescents (ages 13-20) with a confirmed diagnosis of narcolepsy were recruited and compared to age-matched healthy controls. Simultaneous EEG and fMRI data were collected during 10 min of wakeful rest. EEG data were analyzed for microstates, which are discrete epochs of stable global brain states obtained from topographical EEG analysis. Functional fMRI data were analyzed for RSNs. Data showed that narcolepsy patients were less likely than controls to spend time in a microstate which we found to be related to the default mode network and may suggest a disruption of this network that is disease specific. We concluded that adolescents with narcolepsy have altered resting state brain dynamics.

    Ort, förlag, år, upplaga, sidor
    FRONTIERS MEDIA SA, 2016
    Nyckelord
    narcolepsy; default mode network; functional magnetic resonance imaging (fMRI); electroencephalography (EEG); microstates; resting state networks; orexin; sleep
    Nationell ämneskategori
    Neurologi
    Identifikatorer
    urn:nbn:se:liu:diva-131167 (URN)10.3389/fnhum.2016.00369 (DOI)000380989900001 ()27536225 (PubMedID)
    Anmärkning

    Funding Agencies|Research Council of South East Sweden (FORSS); Knut and Alice Wallenberg foundation (KAW); strategic research area of systems neurobiology at Linkoping University; Country council of Ostergotland Sweden

    Tillgänglig från: 2016-09-20 Skapad: 2016-09-12 Senast uppdaterad: 2019-01-04
    2. Evidence for cognitive resource imbalance in adolescents with narcolepsy
    Öppna denna publikation i ny flik eller fönster >>Evidence for cognitive resource imbalance in adolescents with narcolepsy
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    2018 (Engelska)Ingår i: Brain Imaging and Behavior, ISSN 1931-7557, E-ISSN 1931-7565, Vol. 12, nr 2, s. 411-424Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The study investigated brain activity changes during performance of a verbal working memory task in a population of adolescents with narcolepsy. Seventeen narcolepsy patients and twenty healthy controls performed a verbal working memory task during simultaneous fMRI and EEG acquisition. All subjects also underwent MRS to measure GABA and Glutamate concentrations in the medial prefrontal cortex. Activation levels in the default mode network and left middle frontal gyrus were examined to investigate whether narcolepsy is characterized by an imbalance in cognitive resources. Significantly increased deactivation within the default mode network during task performance was observed for the narcolepsy patients for both the encoding and recognition phases of the task. No evidence for task performance deficits or reduced activation within the left middle frontal gyrus was noted for the narcolepsy patients. Correlation analyses between the spectroscopy and fMRI data indicated that deactivation of the anterior aspect of the default mode in narcolepsy patients correlated more with increased concentrations of Glutamate and decreased concentrations of GABA. In contrast, deactivation in the default mode was correlated with increased concentrations of GABA and decreased concentrations of Glutamate in controls. The results suggested that narcolepsy is not characterized by a deficit in working memory but rather an imbalance of cognitive resources in favor of monitoring and maintaining attention over actual task performance. This points towards dysregulation within the sustained attention system being the origin behind self-reported cognitive difficulties in narcolepsy.

    Ort, förlag, år, upplaga, sidor
    Springer-Verlag New York, 2018
    Nyckelord
    EEG, GABA, MRS, Narcolepsy, Working memory, fMRI
    Nationell ämneskategori
    Radiologi och bildbehandling
    Identifikatorer
    urn:nbn:se:liu:diva-145535 (URN)10.1007/s11682-017-9706-y (DOI)000429029000011 ()28321606 (PubMedID)2-s2.0-85015625386 (Scopus ID)
    Tillgänglig från: 2018-03-05 Skapad: 2018-03-05 Senast uppdaterad: 2019-05-01Bibliografiskt granskad
    3. Unexpected Fat Distribution in Adolescents With Narcolepsy
    Öppna denna publikation i ny flik eller fönster >>Unexpected Fat Distribution in Adolescents With Narcolepsy
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    2018 (Engelska)Ingår i: Frontiers in Endocrinology, ISSN 1664-2392, E-ISSN 1664-2392, Vol. 9, artikel-id 728Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Narcolepsy type 1 is a chronic sleep disorder with significantly higher BMI reported in more than 50% of adolescent patients, putting them at a higher risk for metabolic syndrome in adulthood. Although well-documented, the body fat distribution and mechanisms behind weight gain in narcolepsy are still not fully understood but may be related to the loss of orexin associated with the disease. Orexin has been linked to the regulation of brown adipose tissue (BAT), a metabolically active fat involved in energy homeostasis. Previous studies have used BMI and waist circumference to characterize adipose tissue increases in narcolepsy but none have investigated its specific distribution. Here, we examine adipose tissue distribution in 19 adolescent patients with narcolepsy type 1 and compare them to 17 of their healthy peers using full body magnetic resonance imaging (MRI). In line with previous findings we saw that the narcolepsy patients had more overall fat than the healthy controls, but contrary to our expectations there were no group differences in supraclavicular BAT, suggesting that orexin may have no effect at all on BAT, at least under thermoneutral conditions. Also, in line with previous reports, we observed that patients had more total abdominal adipose tissue (TAAT), however, we found that they had a lower ratio between visceral adipose tissue (VAT) and TAAT indicating a relative increase of subcutaneous abdominal adipose tissue (ASAT). This relationship between VAT and ASAT has been associated with a lower risk for metabolic disease. We conclude that while weight gain in adolescents with narcolepsy matches that of central obesity, the lower VAT ratio may suggest a lower risk of developing metabolic disease.

    Ort, förlag, år, upplaga, sidor
    FRONTIERS MEDIA SA, 2018
    Nyckelord
    orexin; hypocretin; brown adipose tissue; visceral adipose tissue; subcutaneous adipose tissue; BMI; magnetic resonance imaging (MRI); obesity
    Nationell ämneskategori
    Endokrinologi och diabetes
    Identifikatorer
    urn:nbn:se:liu:diva-153502 (URN)10.3389/fendo.2018.00728 (DOI)000452268600001 ()
    Anmärkning

    Funding Agencies|Research Council of South East Sweden [FORSS-480551]; Knut and Alice Wallenberg foundation [KAW 2013.0076]

    Tillgänglig från: 2019-01-02 Skapad: 2019-01-02 Senast uppdaterad: 2019-06-14
  • 65.
    Duan, Maoli
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Bjelke, Börje
    Örebro University Hospital, Sweden.
    Fridberger, Anders
    Karolinska Institutet, Stockholm, Sweden.
    Counter, Allen
    Karolinska Institutet, Stockholm, Sweden.
    Klason, Tomas
    Karolinska Institutet, Stockholm, Sweden.
    Skjönsberg, Åsa
    Karolinska Institutet, Stockholm, Sweden.
    Herrlin, Petra
    Karolinska Institutet, Stockholm, Sweden.
    Borg, Erik
    Örebro University Hospital, Sweden.
    Laurell, Göran
    Karolinska Institutet, Stockholm, Sweden.
    Imaging of the guinea pig cochlea following round window gadolinium application2004Ingår i: NeuroReport, ISSN 0959-4965, E-ISSN 1473-558X, Vol. 15, nr 12, s. 1927-1930Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Precise, non-invasive determination of the aetiology and site of pathology of inner ear disorders is difficult. The aim of this study was to describe an alternative method for inner ear visualization, based on local application of the paramagnetic contrast agent gadolinium. Using a 4.7 T MRI scanner, high contrast images of all four cochlear turns were obtained 3.5 h after placing gadolinium on the round window membrane. Gadolinium cleared from the cochlea within 96 h. Auditory brainstem response measurements performed on a separate group of animals showed no significant threshold shifts after the application, indicating that gadolinium is non-toxic to the guinea pig cochlea.

  • 66.
    Edell-Gustafsson, Ulla
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Omvårdnad. Linköpings universitet, Hälsouniversitetet.
    Swahn, Eva
    Linköpings universitet, Institutionen för medicin och hälsa, Kardiologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärtcentrum, Kardiologiska kliniken.
    Svanborg, Eva
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk neurofysiologi. Linköpings universitet, Hälsouniversitetet.
    Sleep-activity profile and quality of life in patients with stable coronary disease2003Ingår i: Sleep, ISSN 0161-8105, E-ISSN 1550-9109, Vol. 26, nr Abstract supplement, s. A357-A357Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    Introduction: Previous studies have examined the relationship between initiation sleep difficulties and quality of life. However, when reviewing the literature in this area we found no reports of a relationship between evening physical activity and health related quality of life in patients with coronary disease. This study was designed to investigate assumed sleep, circadian rhythm, evening physical activity and health related quality of life.

    Methods: Twenty-six men and 21 women, mean age 64.0 (SD 8.9) years and 63 (SD 9.3) years, respectively, with stable angina pectoris were included. For assessment of health related quality of life the patients completed the SF36 questionnaire. The data were compared with those for men and women in the general Swedish population. Physical activity was continuously recorded at home, using actigraphy with an integral light recorder (Model AW-L, Cambridge Neurotechnology Ltd, UK) in 1-minute epochs during one week. The data were downloaded by Actiwatch Reader and imported to the Actiwatch software for Windows 98.

    Results: Average time of going to bed was 22.37, sleep latency 27 minutes, assumed sleep duration 7.59 hr, time in bed 8.56 hr and sleep efficiency 79.2%. No differences were found during the seven nights. Nonparametric analysis of the circadian rhythm showed that 39 of 47 patients had the lowest 5-hour count activity onset at 00.00 p.m. and 41of 47 patients had the maximal 10 hr count onset 08.00 a.m. or later. Sleep analysis indicated reduced activity in the evening (p.m. 06.00-09.00). Some actigraphic parameters of the evening activity associated significantly with circadian rhythm parameters. Compared to the general Swedish population, the patients ́ health related quality of life waspoor. Linear stepwise regression analysis showed that reduced activity 3 evenings/week significantly explained health related quality of life in32.3% of role function outcome, due to physical causes (p=0.0001) and in 24.7% (p<0.01) of social function, whereas reduced activity 2 evenings/week explained 20% (p<0.01) of body pain.

    Conclusions: These data indicate that sleep-activity profile is associated with health related quality of life in patients with stable angina pectoris.

  • 67.
    Eeg-Olofsson, Måns
    et al.
    Göteborgs Universitet.
    Stenfelt, Stefan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Teknisk audiologi. Linköpings universitet, Hälsouniversitetet.
    Taghavi, Hamidreza
    Chalmers.
    Reinfeldt, Sabine
    Chalmers.
    Håkansson, Bo
    Chalmers.
    Finizina, Catharina
    Göteborgs Universitet.
    Transmission of bone conducted sound – correlation between hearing perception and cochlear vibration2012Konferensbidrag (Refereegranskat)
  • 68.
    Engström, Linda
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Inflammation-Induced Gene Expression in Brain and Adrenal Gland2008Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    The autonomic nervous system serves to maintain a constant inner environment, a process termed homeostasis. Thus, in response to the homeostatic challenge posed by infectious agents, the autonomic nervous system answers to signals from the immune system and elicits adaptive physiological and behavioral reactions. These so called sickness responses include fever, anorexia, hyperalgesia, social avoidance, and the release of stress hormones.

    Neuropeptides, used in the communication between neurons, are because of their release properties and sustained actions likely mediators of homeostatic responses. The enkephalinergic system constitutes one of the largest neuropeptidergic systems in the brain, but its involvement in inflammatory conditions has been little studied. We first examined the immune-induced activation of the parabrachial nucleus (paper I), an enkephalinergic autonomic relay center in the brain stem. We found that intravenous injection of bacterial endotoxin, lipopolysaccharide (LPS), activated the external lateral parabrachial subnucleus, as measured in terms of Fos expression, but that the enkephalinergic cell population in this subnucleus was largely separated from the LPS-activated neurons. Because Fos may not always be a reliable activity marker, we next examined by in situ hybridization the immune-induced expression of newly transcribed preproenkephalin (ppENK) heteronuclear RNA (hnRNA), which gives a direct indication of the utilization of enkephalin in a particular neuron (paper II). We detected induced expression of ppENK hnRNA in several autonomic structures in the brain, including the paraventricular hypothalamic nucleus (PVH) but not the parabrachial nucleus, indicating increased enkephalinergic signaling activity in the positively labeled structures during inflammatory condition. We then examined the projections of the immune-induced ppENK transcribing PVH neurons by injecting rats intraperitoneally with the retrograde tracer substance Fluoro-Gold, hence labeling neurons with axonal projections outside the blood-brain barrier, followed by systemic injection of LPS (paper III). Dual-labeling histochemical and hybridization techniques showed that the vast majority of the ppENK hnRNA expressing cells were hypophysiotropic cells, hence being involved in neuroendocrine regulation. These findings suggest that centrally produced enkephalin is involved in the coordination of the sickness responses during systemic immune challenge, including the modulation of the release of stress hormones or other hypothalamic hormones during inflammatory conditions.

    We next turned to the role of prostaglandins in the hypothalamic-pituitary-adrenal (HPA) axis response to inflammation. We injected mice deficient for the terminal prostaglandin (PG) E2 synthesizing enzyme mPGES-1 with LPS and studied their stress hormone release (paper IV). The genetically modified mice displayed attenuated plasma levels of adrenocorticotropic hormone (ACTH) and corticosterone during the later phases of the HPA-axis response compared with wild type mice, and this impairment did not depend on a changed activation pattern in the brain, but instead correlated to an early decrease in corticotropin-releasing hormone mRNA expression in the PVH, hence being the likely cause of the blunted ACTH and corticosterone responses at later time-points. Based on these findings we suggest that a neural, mPGES-1-independent pathway, and a humoral, mPGES-1-dependent pathway act in concert but in distinct temporal patterns to initiate and maintain the HPA-axis response during immune challenge.

    In addition to activating the central limb of the HPA-axis, inflammatory mediators have been suggested to act directly on the adrenal gland to induce the release of corticosterone, but little is known about the underlying mechanisms. We examined adrenal tissue isolated from rats injected with LPS or interleukin-1β (IL-1β) (paper V), and found that immune stimulation resulted in dynamic changes in the adrenal immune cell population, implying a rapid depletion of dendritic cells in the inner cortical layer and the recruitment of immature cells to the outer layers. These changes were accompanied by an induced production of IL-1β and IL-1 receptor type 1, as well as of cyclo-oxygenase-2 and mPGES-1 in these cells, implying local cytokine-mediated PGE2 production in the adrenals, which also displayed EP1 and EP3 receptors in the cortex and medulla. Additional mechanistic studies using an IL-1 receptor antagonist showed that IL-1β acts locally to affect its own synthesis, as well as that of cyclooxygenase-2. Taken together these data demonstrate a mechanism by which systemic inflammatory agents activate an intrinsically regulated local signaling circuit that may influence the adrenals’ response to immune stress and may help explain the dissociation between plasma levels of ACTH and corticosteroids during chronic immune perturbations.

    Delarbeten
    1. Preproenkephalin mRNA expression in rat parabrachial neurons: relation to cells activated by systemic immune challenge
    Öppna denna publikation i ny flik eller fönster >>Preproenkephalin mRNA expression in rat parabrachial neurons: relation to cells activated by systemic immune challenge
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    2001 (Engelska)Ingår i: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 316, nr 3, s. 165-168Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    By using a dual-labeling immunohistochemical/in situ hybridization technique we examined if enkephalin-expressing neurons in the pontine parabrachial nucleus, a major brain stem relay for ascending visceral and homeostatic information, were activated by systemic immune challenge. While rats subjected to intravenous injection of bacterial wall lipopolysaccharide expressed dense labeling for the immediate-early gene product FOS in parts of the parabrachial nucleus that also demonstrated dense preproenkephalin expression, only a small proportion of the enkephalin-positive neurons were FOS-positive. These data indicate that enkephalins, although implicated in a variety of autonomic responses, are not primarily involved in the transmission of immune-related information from the parabrachial nucleus to its different forebrain and brain stem targets.

    Ort, förlag, år, upplaga, sidor
    Elsevier Science B.V., Amsterdam., 2001
    Nyckelord
    Parabrachial nucleus, Systemic inflammation, FOS, Enkephalin, In situ hybridization, Feeding
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-12954 (URN)10.1016/S0304-3940(01)02393-X (DOI)000173268200010 ()
    Tillgänglig från: 2008-02-25 Skapad: 2008-02-25 Senast uppdaterad: 2018-03-26
    2. Systemic immune challenge induces preproenkephalin gene transcription in distinct autonomic structures of the rat brain
    Öppna denna publikation i ny flik eller fönster >>Systemic immune challenge induces preproenkephalin gene transcription in distinct autonomic structures of the rat brain
    2003 (Engelska)Ingår i: Journal of Comparative Neurology, ISSN 0021-9967, Vol. 462, nr 4, s. 450-461Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The involvement of enkephalins in the immune response was investigated in rats injected intravenously with interleukin-1 (2 g/kg). In situ hybridization with a riboprobe complementary to intron A of the preproenkephalin (ppENK) gene showed distinct transcriptional activation within several brain regions known to be activated by immune stimuli, including the nucleus of the solitary tract, the area postrema, the paraventricular hypothalamic nucleus, and the oval nucleus of the bed nucleus of the stria terminalis, and dual labeling confirmed that a large proportion of the intron expressing neurons co-expressed c-fos mRNA. Rats injected with saline (controls) showed little or no heteronuclear transcript in these structures. The induced signal was strongest after 1 hour but was present in some structures 30 minutes after interleukin-1 injection. At 3 hours, transcriptional activity returned to basal levels. High basal expression of the heteronuclear transcript that appeared unchanged by the immune stimulus was seen in regions not primarily involved in the immune response, such as the striatum, the olfactory tubercle, and the islands of Calleja and in the immune activated central nucleus of the amygdala. The heteronuclear transcript colocalized with ppENK mRNA, demonstrating that it occurred in enkephalinergic neurons and was not the result of alternative transcription from the ppENK gene in other cells. These results demonstrated that enkephalin transcription is induced in central autonomic neurons during immune challenge, suggesting that enkephalins are involved in the centrally orchestrated response to such stimuli.

    Nyckelord
    interleukin, enkephalin, heteronuclear RNA, brainstem, neuroendocrine, in situ hybridization
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-12955 (URN)10.1002/cne.10770 (DOI)
    Tillgänglig från: 2008-02-25 Skapad: 2008-02-25 Senast uppdaterad: 2009-05-12
    3. Lipopolysaccharide induces preproenkephalin transcription in hypophysiotropic neurons of the rat paraventricular hypothalamic nucleus suggesting a neuroendocrine role for enkephalins during immune stress
    Öppna denna publikation i ny flik eller fönster >>Lipopolysaccharide induces preproenkephalin transcription in hypophysiotropic neurons of the rat paraventricular hypothalamic nucleus suggesting a neuroendocrine role for enkephalins during immune stress
    2006 (Engelska)Ingår i: Neuroscience, ISSN 0306-4522, Vol. 142, nr 3, s. 781-788Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Opioids have impact on stress responses and possess immune modulatory functions. We have previously shown that immune stress elevates the levels of preproenkephalin transcript in a variety of autonomic structures in the rat brain, including the paraventricular hypothalamic nucleus. By using in situ hybridization with an intronic probe recognizing the preproenkephalin heteronuclear RNA combined with retrograde tract tracing, we examined the efferent target of the enkephalinergic neurons in the paraventricular hypothalamic nucleus that display induced transcriptional activity during immune challenge. Rats were first given i.p. injections of the tracer substance Fluoro-Gold, which following this route of administration is taken up only by nerve terminals residing outside the blood–brain barrier, and were then given an i.v. injection of lipopolysaccharide. Neuronal cell bodies retrogradely labeled with Fluoro-Gold were detected by immunohistochemistry, and—using a dual-labeling approach—the same cells were then examined for their expression of preproenkephalin heteronuclear RNA. We found that over 90% of the neurons that expressed preproenkephalin heteronuclear RNA also contained Fluoro-Gold. In addition, approximately 40% of the neurons expressing preproenkephalin heteronuclear RNA co-expressed mRNA for corticotropin-releasing hormone, the main adrenocorticotropic hormone secretagogue. These data show that the paraventricular hypothalamic neurons that display induced preproenkephalin transcription following immune challenge are almost exclusively hypophysiotropic neurons, indicating a role for enkephalin in the hypothalamic control of hormone release during infectious and inflammatory conditions.

    Nyckelord
    opioid; corticotropin-releasing hormone; in situ hybridization; intron; gene expression; retrograde tract tracing
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-12956 (URN)10.1016/j.neuroscience.2006.06.062 (DOI)
    Tillgänglig från: 2008-02-25 Skapad: 2008-02-25
    4. Impaired hypothalamic-pituitary-adrenal axis response to bacterial endotoxin in mice lacking inducible prostaglandin E synthase-1
    Öppna denna publikation i ny flik eller fönster >>Impaired hypothalamic-pituitary-adrenal axis response to bacterial endotoxin in mice lacking inducible prostaglandin E synthase-1
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    Manuskript (Övrigt vetenskapligt)
    Identifikatorer
    urn:nbn:se:liu:diva-12957 (URN)
    Tillgänglig från: 2008-02-25 Skapad: 2008-02-25 Senast uppdaterad: 2010-01-13
    5. Systemic immune challenge activates an intrinsically regulated local inflammatory circuit in the adrenal gland
    Öppna denna publikation i ny flik eller fönster >>Systemic immune challenge activates an intrinsically regulated local inflammatory circuit in the adrenal gland
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    2008 (Engelska)Ingår i: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 149, nr 4, s. 1436-1450Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    There is evidence from in vitro studies that inflammatory messengers influence the release of stress hormone via direct effects on the adrenal gland; however, the mechanisms underlying these effects in the intact organism are unknown. Here we demonstrate that systemic inflammation in rats elicited by iv injection of lipopolysaccharide results in dynamic changes in the adrenal immune cell population, implying a rapid depletion of dendritic cells in the inner cortical layer and the recruitment of immature cells to the outer layers. These changes are accompanied by an induced production of IL-1β and IL-1 receptor type 1 as well as cyclooxygenase-2 and microsomal prostaglandin E synthase-1 in these cells, implying local cytokine-mediated prostaglandin E2 production in the adrenals, which also displayed prostaglandin E2 receptors of subtypes 1 and 3 in the cortex and medulla. The IL-1β expression was also induced by systemically administrated IL-1β and was in both cases attenuated by IL-1 receptor antagonist, consistent with an autocrine signaling loop. IL-1β similarly induced expression of cyclooxygenase-2, but the cyclooxygenase-2 expression was, in contrast, further enhanced by IL-1 receptor antagonist. These data demonstrate a mechanism by which systemic inflammatory agents activate an intrinsically regulated local signaling circuit that may influence the adrenals’ response to immune stress and may help explain the dissociation between plasma levels of ACTH and corticosteroids during chronic immune perturbations.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-12958 (URN)10.1210/en.2007-1456 (DOI)
    Tillgänglig från: 2008-02-25 Skapad: 2008-02-25 Senast uppdaterad: 2017-12-13
  • 69.
    Engström, Maria
    et al.
    Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV. Linköpings universitet, Institutionen för medicin och hälsa, Medicinsk radiologi. Linköpings universitet, Hälsouniversitetet.
    Karlsson, Thomas
    Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV. Linköpings universitet, Institutionen för beteendevetenskap och lärande, Handikappvetenskap. Linköpings universitet, Filosofiska fakulteten.
    Landtblom, Anne-Marie
    Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Neurologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Närsjukvården i centrala Östergötland, Neurologiska kliniken.
    Craig, A. D. (Bud)
    Atkinson Research Laboratory, Barrow Neurological Institute, Phoenix, AZ.
    Mental energy – an fMRI investigation of the anterior insular and the anterior cingulate network2012Konferensbidrag (Övrigt vetenskapligt)
  • 70.
    Engström, Maria
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Medicinsk radiologi.
    Karlsson, Thomas
    Linköpings universitet, Institutionen för beteendevetenskap och lärande, Handikappvetenskap.
    Landtblom, Anne-Marie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Neurologi.
    Craig, A. D. (Bud)
    Atkinson Research Laboratory, Barrow Neurological Institute, Phoenix, AZ.
    Mental energy: graded co-activation of the anterior insular and anterior cingulate cortices during challenging working memory,  visual perception and motor speed tasks.Manuskript (preprint) (Övrigt vetenskapligt)
  • 71.
    Eskilsson, Anna
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Matsuwaki, Takashi
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    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.
    Zajdel, Joanna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Schwaninger, Markus
    University of Lubeck, Germany.
    Engblom, David
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Blomqvist, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Immune-Induced Fever Is Dependent on Local But Not Generalized Prostaglandin E-2 Synthesis in the Brain2017Ingår i: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 37, nr 19, s. 5035-5044Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Fever occurs upon binding of prostaglandin E-2 (PGE(2)) to EP3 receptors in the median preoptic nucleus of the hypothalamus, but the origin of the pyrogenic PGE(2) has not been clearly determined. Here, using mice of both sexes, we examined the role of local versus generalized PGE(2) production in the brain for the febrile response. In wild-type mice and in mice with genetic deletion of the prostaglandin synthesizing enzyme cyclooxygenase-2 in the brain endothelium, generated with an inducible CreER(T2) under the Slco1c1 promoter, PGE(2) levels in the CSF were only weakly related to the magnitude of the febrile response, whereas the PGE(2) synthesizing capacity in the hypothalamus, as reflected in the levels of cyclooxygenase-2 mRNA, showed strong correlation with the immune-induced fever. Histological analysis showed that the deletion of cyclooxygenase-2 in brain endothelial cells occurred preferentially in small-and medium-sized vessels deep in the brain parenchyma, such as in the hypothalamus, whereas larger vessels, and particularly those close to the neocortical surface and in the meninges, were left unaffected, hence leaving PGE(2) synthesis largely intact in major parts of the brain while significantly reducing it in the region critical for the febrile response. Furthermore, injection of a virus vector expressing microsomal prostaglandin E synthase-1 (mPGES-1) into the median preoptic nucleus of fever-refractive mPGES-1 knock-out mice, resulted in a temperature elevation in response to LPS. We conclude that the febrile response is dependent on local release of PGE(2) onto its target neurons and not on the overall PGE(2) production in the brain.

  • 72.
    Falci, S
    et al.
    Department of Neurosurgery, Craig Hospital, Denver, Colorado.
    Holtz, A
    Department of Neurosurgery, Academic Hospital, University of Uppsala, Sweden.
    Akesson, E
    department of Clinical Neuroscience and Family Medicine, Karolinska Institute, Stockholm, Sweden.
    Azizi, M
    Department of Neurosurgery, Academic Hospital, University of Uppsala, Sweden.
    Ertzgaard, Per
    Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Rehabiliteringsmedicin. Linköpings universitet, Medicinska fakulteten.
    Hultling, C
    The Spinalis SCI Research Unit, Karolinska Institute, Stockholm, Sweden.
    Kjaeldgaard, A
    Department of Clinical Science, Huddinge University Hospital, Karolinska Institute, Stockholm, Sweden.
    Levi, Richard
    department of Clinical Neuroscience and Family Medicine, Karolinska Institute, Stockholm, Sweden.
    Ringden, O
    Department of Transplantation Immunology, Huddinge University Hospital, Karolinska Institute, Stockholm, Sweden.
    Westgren, M
    Department of Clinical Science, Huddinge University Hospital, Karolinska Institute, Stockholm, Sweden.
    Lammertse, D
    department of Physical Medicine and Rehabilitation, Craig Hospital, Denver, Colorado.
    Seiger, A
    department of Clinical Neuroscience and Family Medicine, Karolinska Institute, Stockholm, Sweden.
    Obliteration of a posttraumatic spinal cord cyst with solid human embryonic spinal cord grafts: first clinical attempt.1997Ingår i: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 14, nr 11, s. 875-884Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cystic lesions of the spinal cord (syringomyelia) may occur after spinal cord injury. Posttraumatic syringomyelia may result in a myelopathy causing symptoms of sensory and motor loss, as well as worsening spasticity, pain, hyperhidrosis, and autonomic dysreflexia. Shunting of the cyst cavity along with untethering of the scarred spinal cord is widely accepted as the treatment of choice. However, the long-term stabilization of the progressive myelopathy caused by a posttraumatic cyst is suboptimal because of arachnoidal rescarring, shunt tube blockage, and cyst reexpansion. A new neurosurgical strategy to overcome the complication of cyst reexpansion was designed. Experimental studies have shown the successful use of embryonic spinal cord grafts, including human grafts, to obliterate induced spinal cord cavities in rats. The authors report the first use of solid human embryonic spinal cord grafts to successfully obliterate 6 cm of a large cyst cavity in a patient becoming myelopathic from a posttraumatic cyst. The grafts are well visualized by MRI to the 7-month postoperative follow-up and cyst obliteration is seen in the region where the grafts were placed.

  • 73. Felix, Richard A
    et al.
    Fridberger, Anders
    Karolinska Institutet / Karolinska University Hospital, Stockholm, Sweden.
    Leijon, Sara
    Berrebi, Albert S
    Magnusson, Anna K
    Sound rhythms are encoded by postinhibitory rebound spiking in the superior paraolivary nucleus2011Ingår i: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 31, nr 35, s. 12566-12578Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The superior paraolivary nucleus (SPON) is a prominent structure in the auditory brainstem. In contrast to the principal superior olivary nuclei with identified roles in processing binaural sound localization cues, the role of the SPON in hearing is not well understood. A combined in vitro and in vivo approach was used to investigate the cellular properties of SPON neurons in the mouse. Patch-clamp recordings in brain slices revealed that brief and well timed postinhibitory rebound spiking, generated by the interaction of two subthreshold-activated ion currents, is a hallmark of SPON neurons. The I(h) current determines the timing of the rebound, whereas the T-type Ca(2+) current boosts the rebound to spike threshold. This precisely timed rebound spiking provides a physiological explanation for the sensitivity of SPON neurons to sinusoidally amplitude-modulated (SAM) tones in vivo, where peaks in the sound envelope drive inhibitory inputs and SPON neurons fire action potentials during the waveform troughs. Consistent with this notion, SPON neurons display intrinsic tuning to frequency-modulated sinusoidal currents (1-15Hz) in vitro and discharge with strong synchrony to SAMs with modulation frequencies between 1 and 20 Hz in vivo. The results of this study suggest that the SPON is particularly well suited to encode rhythmic sound patterns. Such temporal periodicity information is likely important for detection of communication cues, such as the acoustic envelopes of animal vocalizations and speech signals.

  • 74.
    Flock, Å.
    et al.
    Karolinska Institute, Stockholm, Sweden.
    Flock, B.
    Karolinska Institute, Stockholm, Sweden.
    Fridberger, Anders
    Karolinska Institute, Stockholm, Sweden.
    Jäger, W.
    Huddinge Hospital, Sweden.
    Methods for integrating fluorimetry in the study of hearing organ structure and function1997Ingår i: Hearing Research, ISSN 0378-5955, E-ISSN 1878-5891, Vol. 106, nr 1-2, s. 29-38Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The measurement of function in the intact organ of Corti has up to now been achieved by three methods: electrophysiology, mechanical measurement and biochemical analysis. The two former methods have supplied information at the level of single identified cells. We have used a fourth method, optical fluorimetry, to measure hair cell function at the cellular level in the intact organ of Corti. Here we describe the methods involved in fluorescence labelling and video-enhanced microscopy in combination with electrophysiological recording of cochlear microphonic (CM) and summating potentials (SP). The guinea pig temporal bone containing an intact ear drum, ossicular chain and cochlea can be maintained in the isolated state by perfusion of the scala tympani with oxygenated tissue culture medium. Substances added to the perfusate readily diffuse through the basilar membrane into the organ of Corti. In this way cells in the organ can be stained by a number of fluorescent probes which label different structures and functions. Here we have used two dyes which label mitochondria and fluoresce with an intensity proportional to metabolic activity. By simultaneous measurement of CM and SP the functional state of the organ can be monitored.

  • 75.
    Flock, Å.
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Flock, B.
    Karolinska Institutet, Stockholm, Sweden.
    Fridberger, Anders
    Karolinska Institutet, Stockholm, Sweden.
    Scarfone, E.
    Université Montpellier II, France.
    Ulfendahl, M.
    Karolinska Sjukhuset, Stockholm, Sweden .
    Supporting cells contribute to control of hearing sensitivity1999Ingår i: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 19, nr 11, s. 4498-4507Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The mammalian hearing organ, the organ of Corti, was studied in an in vitro preparation of the guinea pig temporal bone. As in vivo, the hearing organ responded with an electrical potential, the cochlear microphonic potential, when stimulated with a test tone. After exposure to intense sound, the response to the test tone was reduced. The electrical response either recovered within 10-20 min or remained permanently reduced, thus corresponding to a temporary or sustained loss of sensitivity. Using laser scanning confocal microscopy, stimulus-induced changes of the cellular structure of the hearing organ were simultaneously studied. The cells in the organ were labeled with two fluorescent probes, a membrane dye and a cytoplasm dye, showing enzymatic activity in living cells. Confocal microscopy images were collected and compared before and after intense sound exposure. The results were as follows. (1) The organ of Corti could be divided into two different structural entities in terms of their susceptibility to damage: an inner, structurally stable region comprised of the inner hair cell with its supporting cells and the inner and outer pillar cells; and an outer region that exhibited dynamic structural changes and consisted of the outer hair cells and the third Deiters' cell with its attached Hensen's cells. (2) Exposure to intense sound caused the Deiters' cells and Hensen's cells to move in toward the center of the cochlear turn. (3) This event coincided with a reduced sensitivity to the test tone (i.e., reduced cochlear microphonic potential). (4) The displacement and sensitivity loss could be reversible. It is concluded that these observations have relevance for understanding the mechanisms behind hearing loss after noise exposure and that the supporting cells take an active part in protection against trauma during high-intensity sound exposure.

  • 76.
    Fornander, Lotta
    et al.
    Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Ortopedkliniken i Norrköping. Karolinska Institute, Sweden.
    Brismar, Tom
    Karolinska Institute, Sweden.
    Hansson, Thomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Region Östergötland, Sinnescentrum, Hand- och plastikkirurgiska kliniken US. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV. Linköpings universitet, Medicinska fakulteten.
    Wikstroem, Heidi
    Helsinki University Hospital, Finland.
    Cortical plasticity in patients with median nerve lesions studied with MEG2016Ingår i: Somatosensory & motor research, ISSN 0899-0220, E-ISSN 1369-1651, Vol. 33, nr 3-4, s. 178-185Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We have previously shown age- and time-dependent effects on brain activity in the primary somatosensory cortex (SI), in a functional magnetic resonance imaging (fMRI) study of patients with median nerve injury. Whereas fMRI measures the hemodynamic changes in response to increased neural activity, magnetoencephalography (MEG) offers a more concise way of examining the evoked response, with superior temporal resolution. We therefore wanted to combine these imaging techniques to gain additional knowledge of the plasticity processes in response to median nerve injury. Nine patients with median nerve trauma at the wrist were examined with MEG. The N1 and P1 responses at stimulation of the injured median nerve at the wrist were lower in amplitude compared to the healthy side (pamp;lt;.04). Ulnar nerve stimulation of the injured hand resulted in larger N1 amplitude (pamp;lt;.04). The amplitude and latency of the response did not correlate with the sensory discrimination ability. There was no correlation between N1 amplitude and size of cortical activation in fMRI. There was no significant difference in N1 latency between the injured and healthy median nerve. N1 latency correlated positively with age in both the median and ulnar nerve, and in both the injured and the healthy hand (pamp;lt;.02 or pamp;lt;.001). It is concluded that conduction failure in the injured segment of the median nerve decreases the amplitude of the MEG response. Disinhibition of neighboring cortical areas may explain the increased MEG response amplitude to ulnar nerve stimulation. This can be interpreted as a sign of brain plasticity.

  • 77.
    Fotouhi, Omid
    et al.
    German Cancer Consortium (DKTK) partner site Freiburg, German Cancer Research Center (DKFZ) and Department of Urology, Medical Center-University of Freiburg, Germany.
    Zedenius, Jan
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Department of Breast and Endocrine Surgery, Karolinska University Hospital, Stockholm, Sweden.
    Höög, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi. Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden; Department of Pathology and Cytology, Karolinska University Hospital, Stockholm, Sweden.
    Juhlin, Carl Christofer
    Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden; Department of Pathology and Cytology, Karolinska University Hospital, Stockholm, Sweden.
    Regional differences in somatostatin receptor 2 (SSTR2) immunoreactivity is coupled to level of bowel invasion in small intestinal neuroendocrine tumors2018Ingår i: Neuro - endocrinology letters, ISSN 0172-780X, Vol. 39, nr 4, s. 305-309Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE: Somatostatin receptor (SSTR) expression constitutes a pivotal cornerstone for accurate radiological detection and medical treatment of small intestinal neuroendocrine tumors (SI-NETs), and the development of somatostatin analogues for these purposes have revolutionized the clinical work-up. Previous assessments of SSTR isoform expression in SI-NETs have found correlations to overall prognosis and treatment response, however these analyses usually report overall tumoral immunoreactivity, and little is reported regarding histo-regional differences in expressional patterns.

    METHODS: Thirty-seven primary SI-NETs (WHO grade I, n=32 and WHO grade II, n=5) were collected and assessed for SSTR2 immunohistochemistry. Samples were stratified with regards to histological level of bowel infiltration and spread (mucosal region, muscularis propria region, subserosal region) and each of these tumoral regions was separately scored by SSTR2 staining localization (membrane, cytoplasmic), overall staining intensity and local staining differences within each region.

    RESULTS: SSTR2 immunoreactivity was progressively weaker as the tumor cells advanced through the small intestinal layers. This was exemplified by a reduction in the amount of tumor samples with strong SSTR2 expression in the deeper histological levels of the section; 56% of tumors displayed strong SSTR2 expression in the mucosal region, as compared to 29% and 30% of tumors within muscularis propria and subserosal layers, respectively.

    CONCLUSIONS: This observation indicates a down-regulation of SSTR2 expression as the tumors progress through the intestinal wall, which might signify underlying biological processes of importance for SI-NET invasion behavior.

  • 78.
    Fredlund, Cecilia
    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, Barn- och ungdomspsykiatriska kliniken.
    Svedin, Carl Göran
    Region Östergötland, Närsjukvården i centrala Östergötland, Barn- och ungdomspsykiatriska kliniken. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Barnafrid. Linköpings universitet, Medicinska fakulteten.
    Pribe, Gisela
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Barnafrid. Linköpings universitet, Medicinska fakulteten.
    Jonsson, Linda
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Barnafrid. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Närsjukvården i centrala Östergötland, Barn- och ungdomspsykiatriska kliniken.
    Wadsby, Marie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Närsjukvården i centrala Östergötland, Barn- och ungdomspsykiatriska kliniken.
    Self-reported frequency of sex as self-injury (SASI) in a national study of Swedish adolescents and association to sociodemographic factors, sexual behaviors, abuse and mental health2017Ingår i: Child and Adolescent Psychiatry and Mental Health, ISSN 1753-2000, E-ISSN 1753-2000, Vol. 11, nr 1Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Sex as self-injury has become a concept in Swedish society; however it is a largely unexplored area of research, not yet conceptualized and far from accepted in the research field. The use of sex as a way of affect regulation is known in the literature and has, in interviews with young women who sell sex, been compared to direct self-injury, such as cutting or burning the skin. The aim of this study was to investigate the self-reported frequency of sex as self-injury and the association to sociodemographic factors, sexual orientation, voluntary sexual experiences, sexual risk-taking behaviors, sexual, physical and mental abuse, trauma symptoms, healthcare for psychiatric disorders and non-suicidal self-injury.

  • 79.
    Frias-Lasserre, Daniel
    et al.
    Univ Metropolitana Ciencias Educ, Chile.
    Villagra, Cristian A.
    Univ Metropolitana Ciencias Educ, Chile.
    Guerrero Bosagna, Carlos
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    Stress in the Educational System as a Potential Source of Epigenetic Influences on Childrens Development and Behavior2018Ingår i: Frontiers in Behavioral Neuroscience, ISSN 1662-5153, E-ISSN 1662-5153, Vol. 12, artikel-id 143Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Despite current advances on the relevance of environmental cues and epigenetic mechanisms in biological processes, including behavior, little attention has been paid to the potential link between epigenetic influences and educational sciences. For instance, could the learning environment and stress determine epigenetic marking, affecting students behavior development? Could this have consequences on educational outcomes? So far, it has been shown that environmental stress influences neurological processes and behavior both in humans and rats. Through epigenetic mechanisms, offspring from stressed individuals develop altered behavior without any exposure to traumatizing experiences. Methylated DNA and noncoding RNAs regulate neurological processes such as synaptic plasticity and brain cortex development in children. The malfunctioning of these processes is associated with several neurological disorders, and these findings open up new avenues for the design of enriched environments for education and therapy. In this article, we discuss current cases of stress and behavioral disorders found in youngsters, and highlight the importance of considering epigenetic processes affecting the development of cognitive abilities and learning within the educational environment and for the development of teaching methodologies.

  • 80.
    Fridberger, Anders
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Boutet de Monvel, Jacques
    Karolinska Institutet, Stockholm, Sweden.
    Sound-induced differential motion within the hearing organ2003Ingår i: Nature Neuroscience, ISSN 1097-6256, E-ISSN 1546-1726, Vol. 6, nr 5, s. 446-448Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Hearing depends on the transformation of sound-induced basilar membrane vibration into deflection of stereocilia1 on the sensory hair cells, but the nature of these mechanical transformations is unclear. Using new techniques to visualize and measure sound-induced vibration deep inside the moving organ of Corti, we found that two functionally crucial structures, the basilar membrane and the reticular lamina, have different centers of rotation, leading to shearing motion and rapid deformation for the mechanoreceptive outer hair cells. Structural relations within the organ of Corti are much more dynamic than previously thought, which clarifies how outer hair cell molecular motors can have such a powerful effect.

  • 81.
    Fridberger, Anders
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Boutet de Monvel, Jacques
    Karolinska Institutet, Stockholm, Sweden.
    Ulfendahl, Mats
    Karolinska Institutet, Stockholm, Sweden.
    Internal shearing within the hearing organ evoked by basilar membrane motion2002Ingår i: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 22, nr 22, s. 9850-9857Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The vibration of the hearing organ that occurs during sound stimulation is based on mechanical interactions between different cellular structures inside the organ of Corti. The exact nature of these interactions is unclear and subject to debate. In this study, dynamic structural changes were produced by stepwise alterations of scala tympani pressure in an in vitro preparation of the guinea pig temporal bone. Confocal images were acquired at each level of pressure. In this way, the motion of several structures could be observed simultaneously with high resolution in a nearly intact system. Images were analyzed using a novel wavelet-based optical flow estimation algorithm. Under these conditions, the reticular lamina moved as a stiff plate with a center of rotation in the region of the inner hair cells. Despite being enclosed in several types of supporting cells, the inner hair cells, together with the adjacent inner pillar cells, moved in a manner signifying high compliance. The outer hair cells displayed radial motion indicative of cellular bending. Together, these results show that shearing motion occurs between several parts of the organ, and that structural relationships within the organ change dynamically during displacement of the basilar membrane.

  • 82.
    Fridberger, Anders
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Boutet de Monvel, Jacques
    Karolinska Institutet, Stockholm, Sweden.
    Zheng, Jiefu
    Karolinska Institutet, Stockholm, Sweden.
    Hu, Ning
    Oregon Health and Science University, Oregon Hearing Research Center, Portland, USA.
    Zou, Yuan
    Oregon Health and Science University, Oregon Hearing Research Center, Portland, USA.
    Ren, Tianying
    Oregon Health and Science University, Oregon Hearing Research Center, Portland, USA.
    Nuttall, Alfred
    Oregon Health and Science University, Oregon Hearing Research Center, Portland, USA.
    Organ of Corti potentials and the motion of the basilar membrane2004Ingår i: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 24, nr 45, s. 10057-10063Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    During sound stimulation, receptor potentials are generated within the sensory hair cells of the cochlea. Prevailing theory states that outer hair cells use the potential-sensitive motor protein prestin to convert receptor potentials into fast alterations of cellular length or stiffness that boost hearing sensitivity almost 1000-fold. However, receptor potentials are attenuated by the filter formed by the capacitance and resistance of the membrane of the cell. This attenuation would limit cellular motility at high stimulus frequencies, rendering the above scheme ineffective. Therefore, Dallos and Evans (1995a) proposed that extracellular potential changes within the organ of Corti could drive cellular motor proteins. These extracellular potentials are not filtered by the membrane. To test this theory, both electric potentials inside the organ of Corti and basilar membrane vibration were measured in response to acoustic stimulation. Vibrations were measured at sites very close to those interrogated by the recording electrode using laser interferometry. Close comparison of the measured electrical and mechanical tuning curves and time waveforms and their phase relationships revealed that those extracellular potentials indeed could drive outer hair cell motors. However, to achieve the sharp frequency tuning that characterizes the basilar membrane, additional mechanical processing must occur inside the organ of Corti.

  • 83.
    Fridberger, Anders
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Flock, Å.
    Karolinska Institutet, Stockholm, Sweden.
    Ulfendahl, M.
    Karolinska Hospital, Stockholm, Sweden.
    Flock, B.
    Karolinska Institutet, Stockholm, Sweden.
    Acoustic overstimulation increases outer hair cell Ca2+ concentrations and causes dynamic contractions of the hearing organ1998Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 95, nr 12, s. 7127-7132Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The dynamic responses of the hearing organ to acoustic overstimulation were investigated using the guinea pig isolated temporal bone preparation. The organ was loaded with the fluorescent Ca2+ indicator Fluo-3, and the cochlear electric responses to low-level tones were recorded through a microelectrode in the scala media. After overstimulation, the amplitude of the cochlear potentials decreased significantly. In some cases, rapid recovery was seen with the potentials returning to their initial amplitude. In 12 of 14 cases in which overstimulation gave a decrease in the cochlear responses, significant elevations of the cytoplasmic [Ca2+] in the outer hair cells were seen. [Ca2+] increases appeared immediately after terminating the overstimulation, with partial recovery taking place in the ensuing 30 min in some preparations. Such [Ca2+] changes were not seen in preparations that were stimulated at levels that did not cause an amplitude change in the cochlear potentials. The overstimulation also gave rise to a contraction, evident as a decrease of the width of the organ of Corti. The average contraction in 10 preparations was 9 microm (SE 2 microm). Partial or complete recovery was seen within 30-45 min after the overstimulation. The [Ca2+] changes and the contraction are likely to produce major functional alterations and consequently are suggested to be a factor contributing strongly to the loss of function seen after exposure to loud sounds.

  • 84.
    Fridberger, Anders
    et al.
    Karolinska Institutet/Karolinska University Hospital, Stockholm, Sweden.
    Ren, Tianying
    Oregon Hearing Research Center, Oregon Health & Science University, Portland, USA.
    Local mechanical stimulation of the hearing organ by laser irradiation2006Ingår i: NeuroReport, ISSN 0959-4965, E-ISSN 1473-558X, Vol. 17, nr 1, s. 33-37Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Light produces force when interacting with matter. Such radiation pressure may be used to accelerate small objects along the beam path of a laser. Here, we demonstrate that a moderately powerful laser can deliver enough force to locally stimulate the hearing organ, in the absence of conventional sound. Damped mechanical oscillations are observed following brief laser pulses, implying that the organ of Corti is locally resonant. This new method will be helpful for probing the mechanical properties of the hearing organ, which have crucial importance for the ear's ability to detect sound.

  • 85.
    Fridberger, Anders
    et al.
    Karolinska Institutet, M1 Karolinska Universitetssjukhuset, Stockholm, Sweden .
    Tomo, Igor
    Karolinska Institutet, M1 Karolinska Universitetssjukhuset, Stockholm, Sweden.
    Ulfendahl, Mats
    Karolinska Institutet, M1 Karolinska Universitetssjukhuset, Stockholm, Sweden.
    Boutet de Monvel, Jacques
    Karolinska Institutet, M1 Karolinska Universitetssjukhuset, Stockholm, Sweden.
    Imaging hair cell transduction at the speed of sound: dynamic behavior of mammalian stereocilia2006Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 103, nr 6, s. 1918-1923Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The cochlea contains two types of sensory cells, the inner and outer hair cells. Sound-evoked deflection of outer hair cell stereocilia leads to fast force production that will enhance auditory sensitivity up to 1,000-fold. In contrast, inner hair cells are thought to have a purely receptive function. Deflection of their stereocilia produces receptor potentials, transmitter release, and action potentials in the auditory nerve. Here, we describe a method for rapid confocal imaging. The method was used to image stereocilia during simultaneous sound stimulation in an in vitro preparation of the guinea pig cochlea. We show that inner hair cell stereocilia move because they interact with the fluid surrounding the hair bundles, but stereocilia deflection occurs at a different phase of the stimulus than is generally expected. In outer hair cells, stereocilia deflections were approximately 1/3 of the reticular lamina displacement. Smaller deflections were found in inner hair cells. The ratio between stereocilia deflection and reticular lamina displacement is important for auditory function, because it determines the stimulus applied to transduction channels. The low ratio measured here suggests that amplification of hair-bundle movements may be necessary in vivo to preserve transduction fidelity at low stimulus levels. In the case of the inner hair cells, this finding would represent a departure from traditional views on their function.

  • 86.
    Fridberger, Anders
    et al.
    Karolinska Institute, Stockholm, Sweden.
    Ulfendahl, M.
    Karolinska Institute, Stockholm, Sweden.
    Acute mechanical overstimulation of isolated outer hair cells causes changes in intracellular calcium levels without shape changes1996Ingår i: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 116, nr 1, s. 17-24Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Impaired auditory function following acoustic overstimulation, or noise, is mainly reported to be accompanied by cellular changes such as damage to the sensory hair bundles, but changes in the cell bodies of the outer hair cells have also been described. To investigate more closely the immediate cellular responses to overstimulation, isolated guinea pig outer hair cells were subjected to a 200 Hz oscillating water jet producing intense mechanical stimulation. The water jet was aimed at the cell body of the isolated outer hair cell. Cell shape changes were studied using video microscopy, and intracellular calcium concentration changes were monitored by means of the fluorescent calcium indicator Fluo-3. Cells exposed to a high-intensity stimulus showed surprisingly small light-microscopical alterations. The cytoplasmic calcium concentration increased in most cells, although some cells appeared very resistant to the mechanical stress. No correlation could be found be tween the calcium concentration changes and the cell length. The changes in calcium concentration reported here are suggested to be involved in the long-term pathogenesis of noise-induced hair cell damage.

  • 87.
    Fridberger, Anders
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    van Maarseveen, J.
    Rijksuniversiteit Groningen, the Netherlands.
    Scarfone, E.
    Université de Montpellier II, France.
    Ulfendahl, M.
    Karolinska Institutet, Stockholm, Sweden.
    Flock, B.
    Karolinska Institutet, Stockholm, Sweden.
    Flock, A.
    Karolinska Institutet, Stockholm, Sweden.
    Pressure-induced basilar membrane position shifts and the stimulus-evoked potentials in the low-frequency region of the guinea pig cochlea1997Ingår i: Acta Physiologica Scandinavica, ISSN 0001-6772, E-ISSN 1365-201X, Vol. 161, nr 2, s. 239-252Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We have used the guinea pig isolated temporal bone preparation to investigate changes in the non-linear properties of the tone-evoked cochlear potentials during reversible step displacements of the basilar membrane towards either the scala tympani or the scala vestibuli. The position shifts were produced by changing the hydrostatic pressure in the scala tympani. The pressures involved were calculated from measurements of the fluid flow through the system, and the cochlear DC impedance calculated (1.5 x 10(11) kg m-4 s-1, n = 10). Confocal microscopic visualization of the organ of Corti showed that pressure increases in the scala tympani caused alterations of the position of the reticular lamina and stereocilia bundles. For low pressures, there was a sigmoidal relation between the DC pressure applied to the scala tympani (and thus the position shift of the organ of Corti) and the amplitude of the summating potential. The cochlear microphonic potential also showed a pronounced dependence on the applied pressure: pressure changes altered the amplitude of the fundamental as well as its harmonics. In addition, the sound pressure level at which the responses began to saturate was increased, implying a transition towards a linear behaviour. An increase of the phase lag of the cochlear microphonic potential was seen when the basilar membrane was shifted towards the scala vestibuli. We have also measured the intracochlear DC pressure using piezoresistive pressure transducers. The results are discussed in terms of changes in the non-linear properties of cochlear transduction. In addition, the implications of these results for the pathophysiology and diagnosis of Meniérè's disease are discussed.

  • 88.
    Fridberger, Anders
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    van Maarseveen, J.
    Rijksuniversiteit Groningen, The Netherlands.
    Ulfendahl, M.
    Karolinska Institutet, Stockholm, Sweden.
    An in vitro model for acoustic overstimulation1998Ingår i: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 118, nr 3, s. 352-361Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Although many studies have been performed on the effects of acoustic overstimulation on the inner ear, our knowledge about the cellular processes underlying reduced hearing sensitivity and auditory cell death is still limited. In order to further our understanding of cellular processes occurring in conjunction with acoustic trauma, we designed an in vitro model to study the effects of overstimulation directly on sensory hair cells isolated from the low-frequency part of the guinea pig cochlea. The isolated outer hair cells were subjected to pressure jets delivered by a glass micropipette positioned close to the cell, in order to mimic the pressure changes occurring in the intact inner ear during sound stimulation. A second micropipette coupled to a piezoresistive pressure transducer was used as a probe measuring the pressure at precise locations at and around the cell. In a previous study, we found that such stimulation gave rise to increases in the intracellular calcium concentration. The present study characterizes the stimulus, describes the computer-controlled setup used for calibration, and gives examples of different modes of overstimulation at the cellular level. The peak pressure that could be generated using the pressure jet was around 325 Pa, or 144 dB (re 20 microPa) at 140 Hz. The pressure jet elicited large mechanical vibrations of the cell bodies of isolated cells. The vibration mode of the cells often changed over time, implying that the stimulation caused changes of the cellular stiffness. However, most cells appeared quite resistant to the high intensity mechanical stimulation.

  • 89.
    Fridberger, Anders
    et al.
    Karolinska Institutet / Karolinska University Hospital, Stockholm, Sweden.
    Von Tiedemann, Miriam
    Karolinska Institutet, Stockholm.
    Flock, Åke
    Karolinska Institutet, Stockholm.
    Flock, Britta
    Karolinska Institutet, Stockholm.
    Öfverstedt, Lars-Göran
    Karolinska Institutet, Stockholm.
    Skoglund, Ulf
    Karolinska Institutet, Stockholm.
    Three-dimensional structure of outer hair cell pillars2009Ingår i: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 129, nr 9, s. 940-945Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Conclusions. Electron tomography was used to generate three-dimensional reconstructions of the pillars that connect the cell membrane with the cytoskeleton of the outer hair cell. Results are consistent with the hypothesis that pillars are important for mechanically linking the membrane with the cytoskeleton.

    Objective: To make a qualitative assessment of the morphology of the sub-membrane pillars of cochlear outer hair cells.

    Materials and methods. Guinea pig cochleae were fixed and prepared for electron microscopy using protocols described previously. Sections were imaged on an electron microscope equipped with a goniometer. The specimens were tilted through a range of 120°, and an image was acquired at each tilt angle. Filtered back-projection was used to generate three-dimensional reconstructions.

    Results. Twelve individual pillars were successfully reconstructed. Pillars often connect to the cell membrane through a thin segment, and to the cytoskeleton through a forking structure that may form a central cavity.

  • 90.
    Fridberger, Anders
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Widengren, Jerker
    Karolinska Institutet, Stockholm, Sweden.
    Boutet de Monvel, Jacques
    Karolinska Institutet, Stockholm, Sweden.
    Measuring hearing organ vibration patterns with confocal microscopy and optical flow2004Ingår i: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 86, nr 1 Pt 1, s. 535-543Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A new method for visualizing vibrating structures is described. The system provides a means to capture very fast repeating events by relatively minor modifications to a standard confocal microscope. An acousto-optic modulator was inserted in the beam path, generating brief pulses of laser light. Images were formed by summing consecutive frames until every pixel of the resulting image had been exposed to a laser pulse. Images were analyzed using a new method for optical flow computation; it was validated through introducing artificial displacements in confocal images. Displacements in the range of 0.8 to 4 pixels were measured with 5% error or better. The lower limit for reliable motion detection was 20% of the pixel size. These methods were used for investigating the motion pattern of the vibrating hearing organ. In contrast to standard theory, we show that the organ of Corti possesses several degrees of freedom during sound-evoked vibration. Outer hair cells showed motion indicative of deformation. After acoustic overstimulation, supporting cells contracted. This slowly developing structural change was visualized during simultaneous intense sound stimulation and its speed measured with the optical flow technique.

  • 91.
    Fridberger, Anders
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Zheng, Jiefu
    Oregon Health Sciences University, Portland, USA.
    Nuttall, Alfred
    University of Michigan, Ann Arbor, USA.
    Alterations of basilar membrane response phase and velocity after acoustic overstimulation2002Ingår i: Hearing Research, ISSN 0378-5955, E-ISSN 1878-5891, Vol. 167, nr 1-2, s. 214-222Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    To investigate the physiology of noise-induced hearing loss, the sound-induced vibrations of the basilar membrane (BM) of the inner ear were measured in living anesthetized guinea pigs before and after intense sound exposure. The vibrations were measured using a laser Doppler velocimeter after placing reflective glass beads on the BM. Pseudo-random noise waveforms containing frequencies between 4 and 24 kHz were used to generate velocity tuning curves. Before overstimulation, sharp response peaks were seen at stimulus frequencies between 15 and 17 kHz, consistent with the expected best frequency of the recording location. The response to low level stimuli lagged the high level ones by up to 90 degrees at the characteristic frequency. Following exposure to loud sound, the BM vibrations showed a pronounced reduction in amplitude, primarily at low stimulus levels, and the best frequency moved to approximately 12 kHz. At higher levels, the reduction was either absent or much smaller. In addition to the amplitude changes, increased phase lags were seen at frequencies near the characteristic frequency. In animals with more severe exposures, response phases were altered also at frequencies showing no change of the amplitude. The phase was independent of stimulus level after severe exposures.

  • 92.
    Fridberger, Anders
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Zheng, Jiefu
    Oregon Health & Science University, Portland, USA.
    Parthasarathi, Anand
    Bose Corporation, Framingham, Massachusetts, USA.
    Ren, Tianying
    Oregon Health & Science University, Portland, USA.
    Nuttall, Alfred
    Oregon Health & Science University, Portland, USA.
    Loud sound-induced changes in cochlear mechanics2002Ingår i: Journal of Neurophysiology, ISSN 0022-3077, E-ISSN 1522-1598, Vol. 88, nr 5, s. 2341-2348Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    To investigate the inner ear response to intense sound and the mechanisms behind temporary threshold shifts, anesthetized guinea pigs were exposed to tones at 100-112 dB SPL. Basilar membrane vibration was measured using laser velocimetry, and the cochlear microphonic potential, compound action potential of the auditory nerve, and local electric AC potentials in the organ of Corti were used as additional indicators of cochlear function. After exposure to a 12-kHz intense tone, basilar membrane vibrations in response to probe tones at the characteristic frequency of the recording location (17 kHz) were transiently reduced. This reduction recovered over the course of 50 ms in most cases. Organ of Corti AC potentials were also reduced and recovered with a time course similar to the basilar membrane. When using a probe tone at either 1 or 4 kHz, organ of Corti AC potentials were unaffected by loud sound, indicating that transducer channels remained intact. In most experiments, both the basilar membrane and the cochlear microphonic response to the 12-kHz overstimulation was constant throughout the duration of the intense stimulus, despite a large loss of cochlear sensitivity. It is concluded that the reduction of basilar membrane velocity that followed loud sound was caused by changes in cochlear amplification and that the cochlear response to intense stimulation is determined by the passive mechanical properties of the inner ear structures.

  • 93.
    Fritz, Michael
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Klawonn, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Jaarola, Maarit
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Engblom, David
    Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap.
    Interferon-ɣ mediated signaling in the brain endothelium is critical for inflammation-induced aversion2018Ingår i: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 67, s. 54-58Artikel i tidskrift (Refereegranskat)
    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.

  • 94.
    Fritzell, Peter
    et al.
    Department of Orthopedic Surgery, Falun Hospital, Falun, Sweden.
    Hägg, Olle
    Department of Orthopedic Surgery, Sahlgrenska University Hospital, Göteborg, Sweden.
    Jonsson, Dick
    Linköpings universitet, Institutionen för medicin och hälsa, Medicinsk teknologiutvärdering. Linköpings universitet, Hälsouniversitetet.
    Nordwall, Anders
    Department of Orthopedic Surgery, Sahlgrenska University Hospital, Göteborg, Sweden.
    Appelgren, G. (Medarbetare/bidragsgivare)
    Halmstad.
    Berg, S. (Medarbetare/bidragsgivare)
    Uppsala.
    B. Branth, B. (Medarbetare/bidragsgivare)
    Stockholm.
    Cederlund, C. G. (Medarbetare/bidragsgivare)
    Göteborg.
    Elkan, P. (Medarbetare/bidragsgivare)
    Stockholm.
    Hedlund, R. (Medarbetare/bidragsgivare)
    Stockholm.
    Kogler, H. (Medarbetare/bidragsgivare)
    Örebro.
    Leufvén, C. (Medarbetare/bidragsgivare)
    Eskilstuna.
    Németh, G. (Medarbetare/bidragsgivare)
    Stockholm.
    Neumann, P. (Medarbetare/bidragsgivare)
    Göteborg.
    Nilsson, M. (Medarbetare/bidragsgivare)
    Stockholm.
    Nordenström, K. (Medarbetare/bidragsgivare)
    Karlstad.
    Ohlin, A. (Medarbetare/bidragsgivare)
    Malmö.
    Ordeberg, G. (Medarbetare/bidragsgivare)
    Uppsala.
    Reigo, Tomas (Medarbetare/bidragsgivare)
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi och idrottsmedicin. Linköpings universitet, Hälsouniversitetet.
    Sahlstrand, T. (Medarbetare/bidragsgivare)
    Helsingborg.
    Sandberg, R. (Medarbetare/bidragsgivare)
    Karlstad.
    Skogland, L. (Medarbetare/bidragsgivare)
    Oslo.
    Strömqvist, B. (Medarbetare/bidragsgivare)
    Lund.
    Tropp, Hans (Medarbetare/bidragsgivare)
    Östergötlands Läns Landsting, Ortopedicentrum, Ortopedkliniken Norrköping.
    Tullberg, T. (Medarbetare/bidragsgivare)
    Stockholm.
    Wikström, T. (Medarbetare/bidragsgivare)
    Sundsvall.
    Willén, J. (Medarbetare/bidragsgivare)
    Göteborg.
    Cost-effectiveness of lumbar fusion and nonsurgical treatment for chronic low back pain in the Swedish lumbar spine study: A multicenter, randomized, controlled trial from the Swedish Lumbar Spine Study Group2004Ingår i: Spine, ISSN 0362-2436, E-ISSN 1528-1159, Vol. 29, nr 4, s. 421-434Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Study Design. A cost-effectiveness study was performed from the societal and health care perspectives. Objective. To evaluate the costs-effectiveness of lumbar fusion for chronic low back pain (CLBP) during a 2-year follow-up. Summary of Background Data. A full economic evaluation comparing costs related to treatment effects in patients with CLBP is lacking. Patients and Methods. A total of 284 of 294 patients with CLBP for at least 2 years were randomized to either lumbar fusion or a nonsurgical control group. Costs for the health care sector ( direct costs), and costs associated with production losses ( indirect costs) were calculated. Societal total costs were identified as the sum of direct and indirect costs. Treatment effects were measured using patient global assessment of improvement, back pain ( VAS), functional disability (Owestry), and return to work. Results. The societal total cost per patient ( standard deviations) in the surgical group was significantly higher than in the nonsurgical group: Swedish kroner (SEK) 704,000 ( 254,000) vs. SEK 636,000 ( 208,000). The cost per patient for the health care sector was significantly higher for the surgical group, SEK 123,000 ( 60,100) vs. 65,200 ( 38,400) for the control group. All treatment effects were significantly better after surgery. The incremental cost-effectiveness ratio ( ICER), illustrating the extra cost per extra effect unit gained by using fusion instead of nonsurgical treatment, were for improvement: SEK 2,600 ( 600 - 5,900), for back pain: SEK 5,200 ( 1,100 - 11,500), for Oswestry: SEK 11,300 ( 1,200 - 48,000), and for return to work: SEK 4,100 ( 100 21,400). Conclusion. For both the society and the health care sectors, the 2-year costs for lumbar fusion was significantly higher compared with nonsurgical treatment but all treatment effects were significantly in favor of surgery. The probability of lumbar fusion being cost-effective increased with the value put on extra effect units gained by using surgery.

  • 95.
    Fändrich, M.
    et al.
    Ulm Univ, Germany.
    Nyström, Sofie
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Nilsson, Peter
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Bockmann, A.
    Univ Lyon, France.
    LeVine, H. III
    Univ Kentucky, KY 40536 USA; Univ Kentucky, KY USA.
    Hammarström, Per
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Amyloid fibril polymorphism: a challenge for molecular imaging and therapy2018Ingår i: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 283, nr 3, s. 218-237Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The accumulation of misfolded proteins (MPs), both unique and common, for different diseases is central for many chronic degenerative diseases. In certain patients, MP accumulation is systemic (e.g. TTR amyloid), and in others, this is localized to a specific cell type (e.g. Alzheimers disease). In neurodegenerative diseases, NDs, it is noticeable that the accumulation of MP progressively spreads throughout the nervous system. Our main hypothesis of this article is that MPs are not only markers but also active carriers of pathogenicity. Here, we discuss studies from comprehensive molecular approaches aimed at understanding MP conformational variations (polymorphism) and their bearing on spreading of MPs, MP toxicity, as well as MP targeting in imaging and therapy. Neurodegenerative disease (ND) represents a major and growing societal challenge, with millions of people worldwide suffering from Alzheimers or Parkinsons diseases alone. For all NDs, current treatment is palliative without addressing the primary cause and is not curative. Over recent years, particularly the shape-shifting properties of misfolded proteins and their spreading pathways have been intensively researched. The difficulty in addressing ND has prompted most major pharma companies to severely downsize their nervous system disorder research. Increased academic research is pivotal for filling this void and to translate basic research into tools for medical professionals. Recent discoveries of targeting drug design against MPs and improved model systems to study structure, pathology spreading and toxicity strongly encourage future studies along these lines to provide an opportunity for selective imaging, prognostic diagnosis and therapy.

  • 96.
    Gehlert, Donald R.
    et al.
    Eli Lilly and Company, Indianapolis, IN, USA.
    Cippitelli, Andrea
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Thorsell, Annika
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Lê, Anh Dzung
    University of Toronto, Canada.
    Hipskind, Philip A
    Eli Lilly and Company, Indianapolis, IN, USA.
    Hamdouchi, Chafiq
    Eli Lilly and Company, Indianapolis, IN, USA.
    Lu, Jianliang
    Eli Lilly and Company, Indianapolis, IN, USA.
    Hembre, Erik J.
    Eli Lilly and Company, Indianapolis, IN, USA.
    Cramer, Jeffrey
    Eli Lilly and Company, Indianapolis, IN, USA.
    Song, Min
    Eli Lilly and Company, Indianapolis, IN, USA.
    McKinzie, David
    Eli Lilly and Company, Indianapolis, IN, USA.
    Morin, Michelle
    Eli Lilly and Company, Indianapolis, IN, USA.
    Ciccocioppo, Roberto
    University of Camerino, Italy.
    Heilig, Markus
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    3-(4-Chloro-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethylpropyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine: a novel brain-penetrant, orally available corticotropin-releasing factor receptor 1 antagonist with efficacy in animal models of alcoholism2007Ingår i: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 27, nr 10, s. 2718-2726Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We describe a novel corticotropin-releasing factor receptor 1 (CRF1) antagonist with advantageous properties for clinical development, and its in vivo activity in preclinical alcoholism models. 3-(4-Chloro-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethylpropyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (MTIP) inhibited 125I-sauvagine binding to rat pituitary membranes and cloned human CRF1 with subnanomolar affinities, with no detectable activity at the CRF2 receptor or other common drug targets. After oral administration to rats, MTIP inhibited 125I-sauvagine binding to rat cerebellar membranes ex vivo with an ED50 of approximately 1.3 mg/kg and an oral bioavailability of 91.1%. Compared with R121919 (2,5-dimethyl-3-(6-dimethyl-4-methylpyridin-3-yl)-7-dipropylamino-pyrazolo[1,5-a]pyrimidine) and CP154526 (N-butyl-N-ethyl-4,9-dimethyl-7-(2,4,6-trimethylphenyl)-3,5,7-triazabicyclo[4.3.0]nona-2,4,8,10-tetraen-2-amine), MTIP had a markedly reduced volume of distribution and clearance. Neither open-field activity nor baseline exploration of an elevated plus-maze was affected by MTIP (1-10 mg/kg). In contrast, MTIP dose-dependently reversed anxiogenic effects of withdrawal from a 3 g/kg alcohol dose. Similarly, MTIP blocked excessive alcohol self-administration in Wistar rats with a history of dependence, and in a genetic model of high alcohol preference, the msP rat, at doses that had no effect in nondependent Wistar rats. Also, MTIP blocked reinstatement of stress-induced alcohol seeking both in postdependent and in genetically selected msP animals, again at doses that were ineffective in nondependent Wistar rats. Based on these findings, MTIP is a promising candidate for treatment of alcohol dependence.

  • 97.
    George, David T.
    et al.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Gilman, Jodi
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Hersh, Jacqueline
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Thorsell, Annika
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Herion, David
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Geyer, Christopher
    National Institutes of Health, Bethesda, NIH; Bethesda, MD, USA.
    Peng, Xiaomei
    Lilly Research Laboratories, Indianapolis, IN, USA.
    Kielbasa, William
    Lilly Research Laboratories, Indianapolis, IN, USA.
    Rawlings, Robert
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Brandt, John E.
    Lilly Research Laboratories, Indianapolis, IN, USA.
    Gehlert, Donald R.
    Lilly Research Laboratories, Indianapolis, IN, USA.
    Tauscher, Johannes T.
    Lilly Research Laboratories, Indianapolis, IN, USA.
    Hunt, Stephen P.
    University College London, UK.
    Hommer, Daniel
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Heilig, Markus
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Neurokinin 1 receptor antagonism as a possible therapy for alcoholism2008Ingår i: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 319, nr 5869, s. 1536-1539Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Alcohol dependence is a major public health challenge in need of new treatments. As alcoholism evolves, stress systems in the brain play an increasing role in motivating continued alcohol use and relapse. We investigated the role of the neurokinin 1 receptor (NK1R), a mediator of behavioral stress responses, in alcohol dependence and treatment. In preclinical studies, mice genetically deficient in NK1R showed a marked decrease in voluntary alcohol consumption and had an increased sensitivity to the sedative effects of alcohol. In a randomized controlled experimental study, we treated recently detoxified alcoholic inpatients with an NK1R antagonist (LY686017; n = 25) or placebo (n = 25). LY686017 suppressed spontaneous alcohol cravings, improved overall well-being, blunted cravings induced by a challenge procedure, and attenuated concomitant cortisol responses. Brain functional magnetic resonance imaging responses to affective stimuli likewise suggested beneficial LY686017 effects. Thus, as assessed by these surrogate markers of efficacy, NK1R antagonism warrants further investigation as a treatment in alcoholism.

  • 98.
    Georgiopoulos, Charalampos
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Röntgenkliniken i Linköping. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    Witt, Suzanne Tyson
    Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    Haller, Sven
    Affidea CDRC Ctr Diagnost Radiol Carouge SA, Switzerland; Uppsala Univ, Sweden.
    Dizdar Segrell, Nil
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Närsjukvården i centrala Östergötland, Neurologiska kliniken.
    Zachrisson, Helene
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Fysiologiska kliniken US.
    Engström, Maria
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    Larsson, Elna-Marie
    Uppsala Univ, Sweden.
    Olfactory fMRI: Implications of Stimulation Length and Repetition Time2018Ingår i: Chemical Senses, ISSN 0379-864X, E-ISSN 1464-3553, Vol. 43, nr 6, s. 389-398Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Studying olfaction with functional magnetic resonance imaging (fMRI) poses various methodological challenges. This study aimed to investigate the effects of stimulation length and repetition time (TR) on the activation pattern of 4 olfactory brain regions: the anterior and the posterior piriform cortex, the orbitofrontal cortex, and the insula. Twenty-two healthy participants with normal olfaction were examined with fMRI, with 2 stimulation lengths (6 s and 15 s) and 2 TRs (0.901 s and 1.34 s). Data were analyzed using General Linear Model (GLM), Tensorial Independent Component Analysis (TICA), and by plotting the event-related time course of brain activation in the 4 olfactory regions of interest. The statistical analysis of the time courses revealed that short TR was associated with more pronounced signal increase and short stimulation was associated with shorter time to peak signal. Additionally, both long stimulation and short TR were associated with oscillatory time courses, whereas both short stimulation and short TR resulted in more typical time courses. GLM analysis showed that the combination of short stimulation and short TR could result in visually larger activation within these olfactory areas. TICA validated that the tested paradigm was spatially and temporally associated with a functionally connected network that included all 4 olfactory regions. In conclusion, the combination of short stimulation and short TR is associated with higher signal increase and shorter time to peak, making it more amenable to standard GLM-type analyses than long stimulation and long TR, and it should, thus, be preferable for olfactory fMRI.

  • 99.
    Ghofrani, Saeed
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten. Cellular and Molecular Research Center and Department of Neuroscience, School of Advanced Technology, Iran University of Medical Sciences, Tehran, Iran.
    Joghataei, Mohammad-Taghi
    Cellular and Molecular Research Center and Department of Neuroscience, School of Advanced Technology, Iran University of Medical Sciences, Tehran, Iran.
    Mohseni, Simin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Baluchnejadmojarad, Tourandokht
    Department of Physiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
    Bagheri, Maryam
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Department of Physiology, School of Medicine, Ilam University of Medical Sciences, Ilam, Iran.
    Khamse, Safoura
    Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
    Roghani, Mehrdad
    Neurophysiology Research Center, Shahed University, Tehran, Iran.
    Naringenin improves learning and memory in an Alzheimer's disease rat model: Insights into the underlying mechanisms2015Ingår i: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 764, s. 195-201Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Alzheimer's disease (AD) is one of the prevalent neurological disorders of the central nervous system hallmarked by increased beta-amyloid (Aβ) deposition and ensuing learning and memory deficit. In the present study, the beneficial effect of naringenin on improvement of learning and memory was evaluated in an Alzheimer's disease rat model. The Aβ-injected rats showed a lower alternation score in Y-maze task, impairment of retention and recall capability in passive avoidance test, and lower correct choices and higher errors in radial arm maze (RAM) task as compared to sham group in addition to enhanced oxidative stress and apoptosis. Naringenin, but not a combination of naringenin and fulvestrant (an estrogenic receptor antagonist) significantly improved the performance of Aβ-injected rats in passive avoidance and RAM tasks. Naringenin pretreatment of Aβ-injected rats also lowered hippocampal malondialdehyde (MDA) with no significant effect on nitrite and superoxide dismutase (SOD) activity in addition to lowering apoptosis. These results suggest naringenin pretreatment attenuates Aβ-induced impairment of learning and memory through mitigation of lipid peroxidation and apoptosis and its beneficial effect is somewhat mediated via estrogenic pathway.

  • 100.
    Goncalves, Nadia P.
    et al.
    Aarhus Univ, Denmark; Aarhus Univ Hosp, Denmark.
    Mohseni, Simin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    El Soury, Marwa
    Univ Turin, Italy.
    Ulrichsen, Maj
    Aarhus Univ, Denmark.
    Richner, Mette
    Aarhus Univ, Denmark.
    Xiao, Junhua
    Univ Melbourne, Australia.
    Wood, Rhiannon J.
    Univ Melbourne, Australia.
    Andersen, Olav M.
    Aarhus Univ, Denmark.
    Coulson, Elizabeth J.
    Univ Queensland, Australia.
    Raimondo, Stefania
    Univ Melbourne, Australia.
    Murray, Simon S.
    Univ Melbourne, Australia.
    Vaegter, Christian B.
    Aarhus Univ, Denmark; Aarhus Univ Hosp, Denmark.
    Peripheral Nerve Regeneration Is Independent From Schwann Cell p75(NTR) Expression2019Ingår i: Frontiers in Cellular Neuroscience, ISSN 1662-5102, E-ISSN 1662-5102, Vol. 13, artikel-id 235Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Schwann cell reprogramming and differentiation are crucial prerequisites for neuronal regeneration and re-myelination to occur following injury to peripheral nerves. The neurotrophin receptor p75(NTR) has been identified as a positive modulator for Schwann cell myelination during development and implicated in promoting nerve regeneration after injury. However, most studies base this conclusion on results obtained from complete p75(NTR) knockout mouse models and cannot dissect the specific role of p75(NTR) expressed by Schwann cells. In this present study, a conditional knockout model selectively deleting p75(NTR) expression in Schwann cells was generated, where p75(NTR) expression is replaced with that of an mCherry reporter. Silencing of Schwann cell p75(NTR) expression was confirmed in the sciatic nerve in vivo and in vitro, without altering axonal expression of p75(NTR). No difference in sciatic nerve myelination during development or following sciatic nerve crush injury was observed, as determined by quantification of both myelinated and unmyelinated nerve fiber densities, myelinated axonal diameter and myelin thickness. However, the absence of Schwann cell p75(NTR) reduced motor nerve conduction velocity after crush injury. Our data indicate that the absence of Schwann cell p75(NTR) expression in vivo is not critical for axonal regrowth or remyelination following sciatic nerve crush injury, but does play a key role in functional recovery. Overall, this represents the first step in redefining the role of p75(NTR) in the peripheral nervous system, suggesting that the Schwann cell-axon unit functions as a syncytium, with the previous published involvement of p75(NTR) in remyelination most likely depending on axonal/neuronal p75(NTR) and/or mutual glial-axonal interactions.

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