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  • 251.
    Stenfelt, Stefan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Teknisk audiologi. Linköpings universitet, Hälsouniversitetet.
    Binaural hearing with bone conduction stimulation – what is possible?2013Konferensbidrag (Refereegranskat)
  • 252.
    Stenfelt, Stefan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Teknisk audiologi. Linköpings universitet, Hälsouniversitetet.
    Bone Conduction and the Middle Ear2012Ingår i: The Middle Ear: Science, Otosurgery, and Technology / [ed] Sunil Puria, Arthur N. Popper, Richard F. Fay, New York: Springer, 2012, s. 135-169Kapitel i bok, del av antologi (Refereegranskat)
    Abstract [en]

    With more than a century of research in the field of bone conduction (BC) hearing, the importance of the contributors for bone-conducted sound is not clarified and there is no consensus on the issues. However, the literature suggests that the inner ear fluid inertia is the most important mechanism for speech frequencies. But several other contributors are generally within 10 dB of the most important one, including inertial effect of the middle ear ossicles. Most pathology in the outer and middle ear that severely affects the air conduction sound transmission affects the bone conduction sensitivity only to a minor extent. So even if the changed bone conduction sensitivity in a middle ear lesion is helpful for understanding underlying bone conduction physiology, its clinical relevance is minor. Also, the use of BC thresholds for differential diagnosis of the specific middle ear lesion is risky; the Carhart notch is not always identifiable in cases of otosclerotic ears, and other lesions show BC depression similar to the Carhart notch. There are several pitfalls when conducting BC testing. The most common are occlusion of the ear canal, airborne sound radiation from the transducers, and unmasked or overmasked nontest ear.

  • 253.
    Stenfelt, Stefan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Teknisk audiologi. Linköpings universitet, Hälsouniversitetet.
    Bredbandsmätning av mellanörat2013Ingår i: Audio-Nytt, ISSN 0347-6308, Vol. 40, nr 1-2, s. 24-25Artikel i tidskrift (Övrig (populärvetenskap, debatt, mm))
  • 254.
    Stenfelt, Stefan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Teknisk audiologi. Linköpings universitet, Hälsouniversitetet.
    Skull vibration during bone conduction hearing2013Ingår i: 20th International Congress on Sound and Vibration, Bangkok, Thailand, 2013Konferensbidrag (Refereegranskat)
  • 255.
    Stenfelt, Stefan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Teknisk audiologi. Linköpings universitet, Hälsouniversitetet.
    The demands on the cognitive system – what the audiogram does not tell you2013Konferensbidrag (Refereegranskat)
  • 256.
    Stenfelt, Stefan
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Teknisk audiologi. Linköpings universitet, Hälsouniversitetet.
    Zeitooni, Mehrnaz
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Teknisk audiologi. Linköpings universitet, Hälsouniversitetet.
    Binaural Hearing Ability in Normal Hearing Subjects When Stimulation is by Bone Conduction2012Konferensbidrag (Refereegranskat)
  • 257.
    Stenfelt, Stefan
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Teknisk audiologi. Linköpings universitet, Hälsouniversitetet.
    Zeitooni, Mehrnaz
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Teknisk audiologi. Linköpings universitet, Hälsouniversitetet.
    Loudness functions with air and bone conduction stimulation in normal-hearing subjects using a categorical loudness scaling procedure2013Ingår i: Hearing Research, ISSN 0378-5955, E-ISSN 1878-5891, Vol. 301, s. 85-92Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In a previous study (Stenfelt and Håkansson, 2002) a loudness balance test between bone conducted (BC) sound and air conducted (AC) sound was performed at frequencies between 0.25 and 4 kHz and at levels corresponding to 30–80 dB HL. The main outcome of that study was that for maintaining equal loudness, the level increase of sound with BC stimulation was less than that of AC stimulation with a ratio between 0.8 and 0.93 dB/dB. However, because it was shown that AC and BC tone cancellation was independent of the stimulation level, the loudness level difference did not originate in differences in basilar membrane stimulation. Therefore, it was speculated that the result could be due to the loudness estimation procedure. To investigate this further, another loudness estimation method (adaptive categorical loudness scaling) was here employed in 20 normal-hearing subjects.

    The loudness of a low-frequency and a high-frequency noise burst was estimated using the adaptive categorical loudness scaling technique when the stimulation was bilaterally by AC or BC. The sounds where rated on an 11-point scale between inaudible and too loud. The total dynamic range for these sounds was over 80 dB when presented by AC (between inaudible and too loud) and the loudness functions were similar for the low and the high-frequency stimulation. When the stimulation was by BC the loudness functions were steeper and the ratios between the slopes of the AC and BC loudness functions were 0.88 for the low-frequency sound and 0.92 for the high-frequency sound. These results were almost equal to the previous published results using the equal loudness estimation procedure, and it was unlikely that the outcome stems from the loudness estimation procedure itself. One possible mechanism for the result was loudness integration of multi-sensory input. However, no conclusive evidence for such a mechanism could be given by the present study.

  • 258.
    Stenfelt, Stefan
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Teknisk audiologi. Linköpings universitet, Hälsouniversitetet.
    Zeitooni, Mehrnaz
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Teknisk audiologi. Linköpings universitet, Hälsouniversitetet.
    Loudness Growth with Bone Conduction Stimulation in Normal Hearing Subjects Using a Categorical Scaling Procedure2012Konferensbidrag (Refereegranskat)
  • 259.
    Stojakovic, Andrea
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Paz-Filho, Gilberto
    Australian National University, Australia.
    Arcos-Burgos, Mauricio
    Australian National University, Australia.
    Licinio, Julio
    South Australian Health and Medical Research Institute, Australia; Flinders University of South Australia, Australia.
    Wong, Ma-Li
    South Australian Health and Medical Research Institute, Australia; Flinders University of South Australia, Australia.
    Mastronardi, Claudio A.
    Australian National University, Australia; South Australian Health and Medical Research Institute, Australia; Flinders University of South Australia, Australia.
    Role of the IL-1 Pathway in Dopaminergic Neurodegeneration and Decreased Voluntary Movement2017Ingår i: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182, Vol. 54, nr 6, s. 4486-4495Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Interleukin-1 (IL-1), a proinflammatory cytokine synthesized and released by activated microglia, can cause dopaminergic neurodegeneration leading to Parkinsons disease (PD). However, it is uncertain whether IL-1 can act directly, or by exacerbating the harmful actions of other brain insults. To ascertain the role of the IL-1 pathway on dopaminergic neurodegeneration and motor skills during aging, we compared mice with impaired [caspase-1 knockout (casp1(-/-))] or overactivated IL-1 activity [IL-1 receptor antagonist knockout (IL-1ra(-/-))] to wild-type (wt) mice at young and middle age. Their motor skills were evaluated by the open-field and rotarod tests, and quantification of their dopamine neurons and activated microglia within the substantia nigra were performed by immunohistochemistry. IL-1ra(-/-) mice showed an age-related decline in motor skills, a reduced number of dopamine neurons, and an increase in activated microglia when compared to wt or casp1(-/-) mice. Casp1(-/-) mice had similar changes in motor skills and dopamine neurons, but fewer activated microglia cells than wt mice. Our results suggest that the overactivated IL-1 pathway occurring in IL-1ra(-/-) mice in the absence of inflammatory interventions (e.g., intracerebral injections performed in animal models of PD) increased activated microglia, decreased the number of dopaminergic neurons, and reduced their motor skills. Decreased IL-1 activity in casp1(-/-) mice did not yield clear protective effects when compared with wt mice. In summary, in the absence of overt brain insults, chronic activation of the IL-1 pathway may promote pathological aspects of PD per se, but its impairment does not appear to yield advantages over wt mice.

  • 260.
    Stojakovic, Andrea
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Walczak, Magdalena
    Jagiellonian Univ, Poland.
    Cieslak, Przemyslaw E.
    Polish Acad Sci, Poland.
    Trenk, Aleksandra
    Jagiellonian Univ, Poland.
    Sköld, Johan
    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.
    Mirrasekhian, Elahe
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Karlsson, Camilla
    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.
    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.
    Parkitna, Jan Rodriguez
    Polish Acad Sci, Poland.
    Blasiak, Tomasz
    Jagiellonian Univ, Poland.
    Engblom, David
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Several behavioral traits relevant for alcoholism are controlled by gamma 2 subunit containing GABA(A) receptors on dopamine neurons in mice2018Ingår i: Neuropsychopharmacology, ISSN 0893-133X, E-ISSN 1740-634X, Vol. 43, nr 7, s. 1548-1556Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The risk factors for developing alcohol addiction include impulsivity, high sensitivity to the rewarding action of ethanol, and low sensitivity to its sedative and intoxicating effects. Genetic variation in GABA(A) receptor subunits, including the gamma 2 subunit (Gabrg2), affects the risk for developing alcoholism. Alcohol directly potentiates GABA(A) receptors and activates the mesolimbic dopamine system. Here, we deleted Gabrg2 selectively in dopamine cells of adult mice. The deletion resulted in elevated firing of dopamine neurons and made them less sensitive to drugs acting at GABA(A) receptors. At the behavioral level, the deletion increased exploratory behavior and augmented both correct and incorrect responding in the go/no-go task, a test often used to assay the response inhibition component of impulsivity. In addition, conditioned place preference to alcohol, but not to cocaine or morphine, was increased. Ethanol-induced locomotor activation was enhanced in the mice lacking Gabrg2 on dopaminergic cells, whereas the sedative effect of alcohol was reduced. Finally, the alcohol drinking, but not the alcohol preference, at a high concentration was increased in the mutant mice. In summary, deletion of Gabrg2 on dopamine cells induced several behavioral traits associated with high risk of developing alcoholism. The findings suggest that mice lacking Gabrg2 on dopaminergic cells could be used as models for individuals at high risk for developing alcoholism and that GABA(A) receptors on dopamine cells are protective against the development of excessive alcohol drinking.

  • 261.
    Stokowska, Anna
    et al.
    Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
    Atkins, Alison L
    Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
    Morán, Javier
    Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
    Pekny, Tulen
    Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
    Bulmer, Linda
    Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
    Pascoe, Michaela C
    Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
    Barnum, Scott R
    University of Alabama, Birmingham, Alabama, USA.
    Wetsel, Rick A
    University of Texas-Houston, Houston, Texas, USA.
    Nilsson, Jonas A
    Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
    Dragunow, Mike
    The University of Auckland, Auckland, New Zealand.
    Pekna, Marcela
    Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden, Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia, Hunter Medical Research Institute, University of Newcastle, New South Wales, Australia.
    Complement peptide C3a stimulates neural plasticity after experimental brain ischaemia.2017Ingår i: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 140, nr 2Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Ischaemic stroke induces endogenous repair processes that include proliferation and differentiation of neural stem cells and extensive rewiring of the remaining neural connections, yet about 50% of stroke survivors live with severe long-term disability. There is an unmet need for drug therapies to improve recovery by promoting brain plasticity in the subacute to chronic phase after ischaemic stroke. We previously showed that complement-derived peptide C3a regulates neural progenitor cell migration and differentiation in vitro and that C3a receptor signalling stimulates neurogenesis in unchallenged adult mice. To determine the role of C3a-C3a receptor signalling in ischaemia-induced neural plasticity, we subjected C3a receptor-deficient mice, GFAP-C3a transgenic mice expressing biologically active C3a in the central nervous system, and their respective wild-type controls to photothrombotic stroke. We found that C3a overexpression increased, whereas C3a receptor deficiency decreased post-stroke expression of GAP43 (P < 0.01), a marker of axonal sprouting and plasticity, in the peri-infarct cortex. To verify the translational potential of these findings, we used a pharmacological approach. Daily intranasal treatment of wild-type mice with C3a beginning 7 days after stroke induction robustly increased synaptic density (P < 0.01) and expression of GAP43 in peri-infarct cortex (P < 0.05). Importantly, the C3a treatment led to faster and more complete recovery of forepaw motor function (P < 0.05). We conclude that C3a-C3a receptor signalling stimulates post-ischaemic neural plasticity and intranasal treatment with C3a receptor agonists is an attractive approach to improve functional recovery after ischaemic brain injury.media-1vid110.1093/brain/aww314_video_abstractaww314_video_abstract.

  • 262.
    Stratmann, Johannes
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten.
    Genetic Mechanisms during Terminal Cell Fate Specification in the Drosophila CNS2017Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Specification of the many unique neuronal subtypes found in the nervous system depends on spatiotemporal cues and terminal selector cascades, mostly acting in sequential combinatorial codes of transcription factors (TFs) to dictate cell fate. Out of 10,000 cells in the Drosophila embryonic ventral nerve cord (VNC), only 28 cells selectively express Nplp1. The Nplp1 neurons in the Drosophila VNC can be subdivided into the thoracic ventro-lateral Tv1 and the dorsal-medial dAp neurons. Nplp1 expression in both cell subtypes is activated by the same terminal selector cascade: col > ap/eya > dimm > Nplp1. However Tv1 and dAp neurons are generated by different neuronal progenitors (neuroblasts, NB), and depend on different upstream cues to activate the cell specification cascade. The Tv1 cells are generated by NB5-6T, and in these cells the Nplp1 terminal selector cascade is triggered by spatio-temporal input provided by Antp/hth/exd/lbe/cas. Our studies identified that NB4-3 gives rise to the dAp cells and that the Nplp1 terminal selector cascade in dAp cells is activated by Kr/pdm>grn. I demonstrated how two different spatio-temporal combinations can funnel on a shared downstream terminal selector cascade to determine a highly related cell fate, in different regions of the VNC. I tested this scenario at the molecular level, by identification of cisregulatory modules (CRMs) for the main factors involved in the Nplp1 terminal selector cascade. Intriguingly, I found that col is under control of two separate CRMs, which are controlled by either Antp/hth/exd/lbe/cas in the NB5-6T lineage, and Kr/pdm/grn in the NB4-3 lineage. In addition, CRISPR deletion of the endogenous col CRMs did not result in loss of Col and Nplp1, indicating that col might be under control of more, yet unidentified CRMs. Nplp1 is expressed in one out of four cells in the thoracic Apterous cluster (Ap cluster); the Tv1 cell. The allocation of the right cell fate to each of the four Ap cluster cells, is regulated by the sub-temporal cascade including the factors Sqz/Nab/Svp, acting downstream of the temporal factor Cas. The sub-temporal factors have a repressive action on Col and Dimm, and thus on the terminal selector cascade regulating Nplp1 expression in the Tv1  cell. We demonstrated that the late and Tv1 specific expression of the early temporal factor Kr suppresses Svp in the Tv1 cell and allows for the progression of the Nplp1 cell fate specification cascade. Hence, early temporal factors involved in temporal progression of neuronal progenitors, can be re-utilized late and postmitotically to specify cell fate. It is tempting to speculate that similar mechanisms act to generate similar cell fate in different regions of the CNS, as well as the issue of sub-temporal multitasking, are common features both in Drosophila and higher organisms.

    Delarbeten
    1. Neuronal Cell Fate Specification by the Convergence of Different Spatiotemporal Cues on a Common Terminal Selector Cascade
    Öppna denna publikation i ny flik eller fönster >>Neuronal Cell Fate Specification by the Convergence of Different Spatiotemporal Cues on a Common Terminal Selector Cascade
    Visa övriga...
    2016 (Engelska)Ingår i: PLoS biology, ISSN 1544-9173, E-ISSN 1545-7885, Vol. 14, nr 5, s. e1002450-Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Specification of the myriad of unique neuronal subtypes found in the nervous system depends upon spatiotemporal cues and terminal selector gene cascades, often acting in sequential combinatorial codes to determine final cell fate. However, a specific neuronal cell subtype can often be generated in different parts of the nervous system and at different stages, indicating that different spatiotemporal cues can converge on the same terminal selectors to thereby generate a similar cell fate. However, the regulatory mechanisms underlying such convergence are poorly understood. The Nplp1 neuropeptide neurons in the Drosophila ventral nerve cord can be subdivided into the thoracic-ventral Tv1 neurons and the dorsal-medial dAp neurons. The activation of Nplp1 in Tv1 and dAp neurons depends upon the same terminal selector cascade: colamp;gt;ap/eyaamp;gt;dimmamp;gt;Nplp1. However, Tv1 and dAp neurons are generated by different neural progenitors (neuroblasts) with different spatiotemporal appearance. Here, we find that the same terminal selector cascade is triggered by Kr/pdmamp;gt;grn in dAp neurons, but by Antp/hth/exd/lbe/cas in Tv1 neurons. Hence, two different spatiotemporal combinations can funnel into a common downstream terminal selector cascade to determine a highly related cell fate.

    Ort, förlag, år, upplaga, sidor
    PUBLIC LIBRARY SCIENCE, 2016
    Nationell ämneskategori
    Utvecklingsbiologi
    Identifikatorer
    urn:nbn:se:liu:diva-129501 (URN)10.1371/journal.pbio.1002450 (DOI)000376906100001 ()27276273 (PubMedID)
    Anmärkning

    Funding Agencies|Swedish Research Council (VR-NT) [621-2010-5214]; Wallenberg Foundation [KAW2012.0101]; Swedish Cancer Foundation [120531]; Spanish Ministerio de Economia y Competitividad [BFU2013-43858-P]

    Tillgänglig från: 2016-06-20 Skapad: 2016-06-20 Senast uppdaterad: 2017-11-28
    2. Neuronal cell fate diversification controlled by sub-temporal action of Kruppel
    Öppna denna publikation i ny flik eller fönster >>Neuronal cell fate diversification controlled by sub-temporal action of Kruppel
    2016 (Engelska)Ingår i: eLIFE, E-ISSN 2050-084X, Vol. 5, artikel-id e19311e19311Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    During Drosophila embryonic nervous system development, neuroblasts express a programmed cascade of five temporal transcription factors that govern the identity of cells generated at different time-points. However, these five temporal genes fall short of accounting for the many distinct cell types generated in large lineages. Here, we find that the late temporal gene castor sub-divides its large window in neuroblast 5-6 by simultaneously activating two cell fate determination cascades and a sub-temporal regulatory program. The sub-temporal program acts both upon itself and upon the determination cascades to diversify the castor window. Surprisingly, the early temporal gene Kruppel acts as one of the sub-temporal genes within the late castor window. Intriguingly, while the temporal gene castor activates the two determination cascades and the sub-temporal program, spatial cues controlling cell fate in the latter part of the 5-6 lineage exclusively act upon the determination cascades.

    Ort, förlag, år, upplaga, sidor
    eLife Sciences Publications Ltd., 2016
    Nationell ämneskategori
    Immunologi inom det medicinska området
    Identifikatorer
    urn:nbn:se:liu:diva-132850 (URN)10.7554/eLife.19311 (DOI)000386456200001 ()27740908 (PubMedID)
    Anmärkning

    Funding Agencies|Svenska Forskningsradet Formas [621-2013-5258]; Cancerfonden [120531]; Knut och Alice Wallenbergs Stiftelse [KAW2011.0165]; Ministerio de Industria, Energia y Turismo [BFU2013-43858-P]

    Tillgänglig från: 2016-12-06 Skapad: 2016-11-30 Senast uppdaterad: 2018-03-19
    3. Neuronal cell fate specification by the molecular convergence of different spatio-temporal cues on a common initiator terminal selector gene
    Öppna denna publikation i ny flik eller fönster >>Neuronal cell fate specification by the molecular convergence of different spatio-temporal cues on a common initiator terminal selector gene
    2017 (Engelska)Ingår i: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, nr 4, s. 26Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The extensive genetic regulatory flows underlying specification of different neuronal subtypes are not well understood at the molecular level. The Nplp1 neuropeptide neurons in the developing Drosophila nerve cord belong to two sub-classes; Tv1 and dAp neurons, generated by two distinct progenitors. Nplp1 neurons are specified by spatial cues; the Hox homeotic network and GATA factor grn, and temporal cues; the hb -greater than Kr -greater than Pdm -greater than cas -greater than grh temporal cascade. These spatio-temporal cues combine into two distinct codes; one for Tv1 and one for dAp neurons that activate a common terminal selector feedforward cascade of col -greater than ap/eya -greater than dimm -greater than Nplp1. Here, we molecularly decode the specification of Nplp1 neurons, and find that the cis-regulatory organization of col functions as an integratory node for the different spatio-temporal combinatorial codes. These findings may provide a logical framework for addressing spatio-temporal control of neuronal sub-type specification in other systems. [ABSTRACT FROM AUTHOR]

    Ort, förlag, år, upplaga, sidor
    PLOS, 2017. s. 26
    Nyckelord
    Animal cells, Animal models, Animals, Arthropoda, Biochemistry, Biology and life sciences, Cell binding, Cell biology, Cell physiology, Cell staining, Cellular neuroscience, Cellular types, Developmental biology, DNA-binding proteins, Drosophila, Drosophila melanogaster, Embryology, Embryos, Experimental organism systems, Gene expression, Gene regulation, Genetics, Insects, Invertebrates, Model organisms, Neurons, Neuroscience, Organisms, Proteins, Regulatory proteins, Research and analysis methods, Research Article, Specimen preparation and treatment, Staining, Transcription factors
    Nationell ämneskategori
    Utvecklingsbiologi
    Identifikatorer
    urn:nbn:se:liu:diva-136555 (URN)10.1371/journal.pgen.1006729 (DOI)000402549200037 ()28414802 (PubMedID)
    Anmärkning

    Funding agencies: Cancerfonden [140780]; Vetenskapsradet [621-20135258]; Knut och Alice Wallenbergs Stiftelse [KAW2011.0165]

    Tillgänglig från: 2017-04-19 Skapad: 2017-04-19 Senast uppdaterad: 2017-06-26Bibliografiskt granskad
  • 263.
    Sundberg, Sofie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Neuromodulation, Short-Term and Long-Term Plasticity in Corticothalamic and Hippocampal Neuronal Networks2018Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Research in neuroscience relies to a large extent on the use of genetically modified animals. Extensive validation of new and existing models is a requirement for the acquisition of trustworthy data and to enable generalization to human physiology and disease. This thesis includes, as one part (project I and II), validation of a transgenic mouse model with the expression of the enzyme Cre-recombinase restricted to neurons in a band in the deepest layer of the cerebral cortex. Secondly, in project III we use this mouse model to study the process of short-term plasticity in neuronal cultures. Lastly, we investigate synaptic plasticity by studying the effect that the developmental signaling factor Hedgehog (Hh) has on mature hippocampal cultures (project IV). 

    In project I and II, we identified the transgenic mouse Neurotensin receptor 1-Cre GN220 (Ntsr1-Cre) to have Cre expression targeted to the corticothalamic (CT) pyramidal neuron population in neocortical layer 6. Further, we identified a small group of Ntsr1-Cre positive neurons present in the white matter that is distinct from the CT population. We also identified that the transcription factor Forkhead box protein 2 (FoxP2) was specifically expressed by CT neurons in neocortex. In project I, we further explored the sensitivity of CT neurons to cholinergic modulation and found that they are sensitive to even low concentrations of acetylcholine. Both nicotinic and muscarinic acetylcholine receptors depolarize the neurons. Presenting CT neurons as a potential target for cholinergic modulation in wakefulness and arousal. 

    In project III we studied Ntsr1-Cre neurons in cortical cultures and found that cultured neurons have similar properties to CT neurons in the intact nervous system. Ntsr1-Cre neurons in culture often formed synapses with itself, i. e. autapses, with short-term synaptic plasticity that was different to ordinary synapses. By expressing the light-controlled ion channel channelrhodopsin-2 (ChR2) in Ntsr1-Cre neurons we could compare paired pulse ratios with either electrical or light stimulation. Electrical stimulation typically produced paired-pulse facilitation while light stimulation produced paired pulse depression, presumably due to unphysiological Ca2+ influx in presynaptic terminals. Thus, cultured Ntsr1- Cre neurons can be used to study facilitation, and ChR2 could be used as a practical tool to further study the dependence of Ca2+ for short-term plasticity. 

    In project IV we investigated the role of Hedgehog (Hh) for hippocampal neuron plasticity. Non-canonical Hh-signaling negatively regulated NMDA- receptor function through an unknown mechanism resulting in changes in NMDA-receptor mediated currents and subsequent changes in AMPA- receptors in an LTP/LTD manner in mature neurons. Proposing Hh as a slow-acting factor with ability to scale down excitation for instances of excessive activity, e.g. during an epileptic seizure, as a mechanism to make the activity in the neuronal networks stable. 

     

    Delarbeten
    1. Cre-expressing neurons in visual cortex of Ntsr1-Cre GN220 mice are corticothalamic and are depolarized by acetylcholine
    Öppna denna publikation i ny flik eller fönster >>Cre-expressing neurons in visual cortex of Ntsr1-Cre GN220 mice are corticothalamic and are depolarized by acetylcholine
    2018 (Engelska)Ingår i: Journal of Comparative Neurology, ISSN 0021-9967, E-ISSN 1096-9861, Vol. 526, nr 1, s. 120-132Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The Ntsr1-Cre GN220 mouse expresses Cre-recombinase in corticothalamic (CT) neurons in neocortical layer 6. It is not known if the other major types of pyramidal neurons in this layer also express this enzyme. By electrophysiological recordings in slices and histological analysis of the uptake of retrogradely transported beads we show that Cre-positive neurons are CT and not corticocortical or corticoclaustral types. Furthermore, we show that Ntsr1-Cre-positive cells are immuno-positive for the nuclear transcription factor Forkhead box protein P2 (FoxP2). We conclude that Cre-expression is limited to a specific type of pyramidal neuron: CT. However, it appears as not all CT neurons are Cre-expressing; there are indications that the penetrance of the gene is about 90%. We demonstrate the utility of assigning a specific identity to individual neurons by determining that the CT neurons are potently modulated by acetylcholine acting on both nicotinic and muscarinic acetylcholine receptors. These results corroborate the suggested function of these neurons in regulating the gain of thalamocortical transfer of sensory information depending on attentional demand and state of arousal.

    Ort, förlag, år, upplaga, sidor
    WILEY, 2018
    Nyckelord
    acetylcholine; corticothalamic; claustrum; FoxP2; Ntsr1; visual cortex; RRID: MMRRC_030648-UCD; RRID: AB_10000240; RRID: AB_2313516; RRID: AB_2107107; RRID: SCR_002074
    Nationell ämneskategori
    Neurovetenskaper
    Identifikatorer
    urn:nbn:se:liu:diva-144137 (URN)10.1002/cne.24323 (DOI)000418575500008 ()28884467 (PubMedID)
    Anmärkning

    Funding Agencies|Swedish Research Council [3050, 2862]; Linkoping University

    Tillgänglig från: 2018-01-10 Skapad: 2018-01-10 Senast uppdaterad: 2018-10-12
    2. Cre-expressing neurons in the cortical white matter of Ntsr1-Cre GN220 mice
    Öppna denna publikation i ny flik eller fönster >>Cre-expressing neurons in the cortical white matter of Ntsr1-Cre GN220 mice
    2018 (Engelska)Ingår i: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 675, s. 36-40Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Genetically modified mouse strains that express Cre-recombinase in specific neuronal sub-populations have become widely used tools for investigating neuronal function. The Ntsr1-Cre GN220 mouse expresses this enzyme in corticothalamic neurons in layer 6 of cerebral cortex. We observed that about 7% of Cre-expressing cells in the primary visual cortex are found within the white matter bordering layer 6. By using the immunohistochemical marker for layer 6 neurons, Forkhead box protein 2 (FoxP2), and fluorescently conjugated latex beads injected into the dorsal lateral geniculate nucleus, we show that about half of these cells are similar to and could belong to the layer 6 corticothalamic neuron population. The other half seems to be a distinct white matter (WM) neuron sub-population that we estimate to constitute 2-4% of the total cortical Cre expressing population. Staining for the neuronal marker Neuronal nuclei (NeuN) revealed that about 15-40% of WM neurons are Cre-expressing. Thus, the potential contribution from WM neurons needs to be considered when interpreting the results from experiments using the Ntsr1-Cre GN220 mouse for investigating corticothalamic neuronal function.

    Ort, förlag, år, upplaga, sidor
    ELSEVIER IRELAND LTD, 2018
    Nyckelord
    Corticothalamic; White matter; Neurotensin receptor 1; Layer 6; Visual cortex; Forkhead box protein 2
    Nationell ämneskategori
    Neurovetenskaper
    Identifikatorer
    urn:nbn:se:liu:diva-148387 (URN)10.1016/j.neulet.2018.03.053 (DOI)000432759500007 ()29580883 (PubMedID)
    Anmärkning

    Funding Agencies|Swedish Research Council [3050, 2862]; Linkoping University

    Tillgänglig från: 2018-06-15 Skapad: 2018-06-15 Senast uppdaterad: 2018-10-12
  • 264.
    Sundberg, Sofie
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Granseth, Björn
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Cre-expressing neurons in the cortical white matter of Ntsr1-Cre GN220 mice2018Ingår i: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 675, s. 36-40Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Genetically modified mouse strains that express Cre-recombinase in specific neuronal sub-populations have become widely used tools for investigating neuronal function. The Ntsr1-Cre GN220 mouse expresses this enzyme in corticothalamic neurons in layer 6 of cerebral cortex. We observed that about 7% of Cre-expressing cells in the primary visual cortex are found within the white matter bordering layer 6. By using the immunohistochemical marker for layer 6 neurons, Forkhead box protein 2 (FoxP2), and fluorescently conjugated latex beads injected into the dorsal lateral geniculate nucleus, we show that about half of these cells are similar to and could belong to the layer 6 corticothalamic neuron population. The other half seems to be a distinct white matter (WM) neuron sub-population that we estimate to constitute 2-4% of the total cortical Cre expressing population. Staining for the neuronal marker Neuronal nuclei (NeuN) revealed that about 15-40% of WM neurons are Cre-expressing. Thus, the potential contribution from WM neurons needs to be considered when interpreting the results from experiments using the Ntsr1-Cre GN220 mouse for investigating corticothalamic neuronal function.

  • 265.
    Sundberg, Sofie
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Lindström, Sarah
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten.
    Sanchez, Gonzalo Manuel
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Granseth, Björn
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Cre-expressing neurons in visual cortex of Ntsr1-Cre GN220 mice are corticothalamic and are depolarized by acetylcholine2018Ingår i: Journal of Comparative Neurology, ISSN 0021-9967, E-ISSN 1096-9861, Vol. 526, nr 1, s. 120-132Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The Ntsr1-Cre GN220 mouse expresses Cre-recombinase in corticothalamic (CT) neurons in neocortical layer 6. It is not known if the other major types of pyramidal neurons in this layer also express this enzyme. By electrophysiological recordings in slices and histological analysis of the uptake of retrogradely transported beads we show that Cre-positive neurons are CT and not corticocortical or corticoclaustral types. Furthermore, we show that Ntsr1-Cre-positive cells are immuno-positive for the nuclear transcription factor Forkhead box protein P2 (FoxP2). We conclude that Cre-expression is limited to a specific type of pyramidal neuron: CT. However, it appears as not all CT neurons are Cre-expressing; there are indications that the penetrance of the gene is about 90%. We demonstrate the utility of assigning a specific identity to individual neurons by determining that the CT neurons are potently modulated by acetylcholine acting on both nicotinic and muscarinic acetylcholine receptors. These results corroborate the suggested function of these neurons in regulating the gain of thalamocortical transfer of sensory information depending on attentional demand and state of arousal.

  • 266.
    Sörqvist, Patrik
    et al.
    Linköpings universitet, Institutionen för beteendevetenskap, Avdelningen för kognition, utveckling och handikapp, CDD. Linköpings universitet, Filosofiska fakulteten. University of Gavle, Sweden.
    Dahlström, Örjan
    Linköpings universitet, Institutionen för beteendevetenskap och lärande, Handikappvetenskap. Linköpings universitet, Filosofiska fakulteten. Linköpings universitet, Institutet för handikappvetenskap (IHV).
    Karlsson, Thomas
    Linköpings universitet, Institutionen för beteendevetenskap och lärande, Handikappvetenskap. Linköpings universitet, Filosofiska fakulteten.
    Rönnberg, Jerker
    Linköpings universitet, Institutionen för beteendevetenskap och lärande, Handikappvetenskap. Linköpings universitet, Filosofiska fakulteten. Linköpings universitet, Institutet för handikappvetenskap (IHV).
    Concentration: The Neural Underpinnings of How Cognitive Load Shields Against Distraction2016Ingår i: Frontiers in Human Neuroscience, ISSN 1662-5161, E-ISSN 1662-5161, Vol. 10, nr 221Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Whether cognitive load and other aspects of task difficulty increases or decreases distractibility is subject of much debate in contemporary psychology. One camp argues that cognitive load usurps executive resources, which otherwise could be used for attentional control, and therefore cognitive load increases distraction. The other camp argues that cognitive load demands high levels of concentration (focal task engagement), which suppresses peripheral processing and therefore decreases distraction. In this article, we employed an functional magnetic resonance imaging (fMRI) protocol to explore whether higher cognitive load in a visually-presented task suppresses task-irrelevant auditory processing in cortical and subcortical areas. The results show that selectively attending to an auditory stimulus facilitates its neural processing in the auditory cortex, and switching the locus-of-attention to the visual modality decreases the neural response in the auditory cortex. When the cognitive load of the task presented in the visual modality increases, the neural response to the auditory stimulus is further suppressed, along with increased activity in networks related to effortful attention. Taken together, the results suggest that higher cognitive load decreases peripheral processing of task-irrelevant information which decreases distractibility as a side effect of the increased activity in a focused-attention network.

  • 267.
    Taxén, Lars
    Linköpings universitet, Institutionen för datavetenskap. Linköpings universitet, Tekniska högskolan.
    The Activity Modalities: A Priori Categories of Coordination2015Ingår i: Proceedings of the Fourth International Conference on Cognitive Neurodynamics - 2013 / [ed] Hans Liljenström, Springer Publishing Company, 2015, Vol. 1, s. 21-29Konferensbidrag (Refereegranskat)
    Abstract [en]

    A conceptualization of a-priori forms of coordination as activity modalities is proposed. Sensations in various sensory modalities are integrated by our brain into a coherent, actionable percept, structured by the processes of objectivation, contextualization, spatialization, temporalization, stabilization, and transition. This conceptualization promises to bridge neuroscientific and applied research into the coordination problem. 

  • 268.
    Tegern, Gunilla
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Hälsa och samhälle. Linköpings universitet, Filosofiska fakulteten.
    Flodmark, O
    Department of Clinical Neuroscience, Karolinska Institute; Dept of Neuroradiology, Karolinska Hospital, Stockholm, Sweden.
    Psychological, social and economic consequences of incidental discovery of aneurysm2003Ingår i: Rivista di neuroradiologia, ISSN 1120-9976, Vol. 16, nr 5, s. 739-742Artikel i tidskrift (Refereegranskat)
  • 269.
    Theodorsson, Annette
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet.
    Estrogen-inducible neuropeptides in the rat brain: role in focal ischemic lesions2005Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Sex steroids in general and estrogens in particular – in addition to their effects on the reproductive organs – affect a large number of crucial bodily functions, including “higher” brain functions.

    Neuropeptides constitute the phylogenetically oldest neurotransmitter system and are currently thought to act mainly during stress, disease or injury. The concentration of galanin is i.a. up-regulated by injury to the nervous system and by estrogen.

    The main focus of the present thesis was to investigate whether the reported neuroprotective effect of 17β-estradiol in experimental animal stroke models is partially mediated through its effects on galanin and if galanin per se exerts neuroprotective effects in stroke.

    An exploratory study of the effects of sex steroid concentrations due to gender and pubertal development showed differences in concentrations of i.a. the neuropeptides galanin and neuropeptide Y also in brain regions of female rats important for higher brain functions, including hippocampus and cortex, brain regions not directly involved in reproduction. Puberty brings about changes in several hormonal mechanisms, and our studies showed that the major effect on the concentrations of galanin in various brain regions of ovariectomized (ovx) rats, was brought about by 17β-estradiol.

    The pathophysiological mechanisms involved in thrombolysis – the current treatment of choice in human stroke – attempts the re-establishment of perfusion (reperfusion) to the lesioned area of the brain. This prompted us to develop a reperfusion stroke model in rats designed to be mild, focal and transient, allowing long-term observation periods of animals thriving well postoperatively. Mortality and morbidity during and after the middle cerebral artery (MCA) occlusion are important confounding factors crucial for the results. Changing anaesthesia from intraperitoneally administered chloral hydrate to isofl urane inhalation anaesthesia using endotracheal intubation and controlled ventilation markedly reduced the mortality rate from 25% to 10.6%, which was even further reduced down to 2.7 % by successively improved surgical skills.

    Contrary to our initial hypothesis, long-term 17β-estradiol treatment resulted in larger ischemic lesions in our stroke model compared to control treatment. After 3 days the cerebral ischemic lesion area was doubled after 17β-estradiol treatment in rats subjected to 60 min microclip occlusion of the MCA followed by reperfusion. A similar, but not statistically signifi cant difference was found after 7 and 14 days. Three groups studying different types of experimental animal stroke and different doses of 17β-estradiol treatment have recently also demonstrated lack of neuroprotection by 17β-estradiol treatment. Furthermore, large epidemiological clinical studies have recently also reported an increased risk and poorer outcome in postmenopausal women subjected to hormone replacement therapy.

    The concentrations of galanin-like immunoreactivity in extracts of punch biopsies from the penumbra area after transient MCA occlusion were found unchanged, but were decreased (p=0.015) in the apparently undamaged ipsilateral hippocampus. Galanin administered by continuous intracerebroventricular infusion (2.4 nmol/day) resulted in a 30% larger ischemic lesion compared to controls, measured 7 days after the MCA occlusion. Taken together, these results indicate that galanin in the brain is primarily a factor reacting to ischemic injury rather than a neuroprotective factor in its own right.

    Very limited information is available about the steady state serum concentrations of 17β-estradiol in response to different modes of administration to rats for days and weeks. The need for this information has become especially apparent during recent years due to the observable dichotomy of estrogens effects – neuroprotective or not – in the various animal models of brain ischemia reported in the current scientific literature. The cause of this dichotomy is likely to be found in the experimental setup, including the mode of administration of 17β-estradiol. Delayed steady state of serum 17β-estradiol concentrations were found when comparing two common modes of exogenous administration of 17β-estradiol – slow-release osmotic pumps vs. daily subcutaneously injections of 17β-estradiol solved in sesame oil – to ovx rats during 2 times 6 weeks crossover treatment. Steady state was reached at week 4 in the daily injections group compared to at week 6 in the slow release osmotic pumps group. Once steady state was reached, the concentration was the same in both groups for the reminder of the experiment (in total 12 weeks).

    Delarbeten
    1. Sex differences in neuropeptide distribution in the rat brain
    Öppna denna publikation i ny flik eller fönster >>Sex differences in neuropeptide distribution in the rat brain
    Visa övriga...
    1999 (Engelska)Ingår i: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 20, nr 1, s. 81-86Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    We have investigated possible sex differences in the regional concentrations of neuropeptides in the rat brain. Immunoreactive neurotensin (NT), neurokinin A (NKA), galanin (GAL), calcitonin gene-related peptide (CGRP), substance P (SP) and neuropeptide Y (NPY) were measured by radioimmunoassay in frontal cortex, occipital cortex, hippocampus, striatum, hypothalamus and pituitary in male and female pre- and postpubertal rats. Sex differences were found for NPY (p < 0.001), NT (p < 0.01) and GAL (p < 0.05), in particular in hippocampus, striatum, hypothalamus and pituitary, but not for CGRP, SP and NKA. Results from analysis of neuropeptides in one sex may not be entirely applicable to the other.

    Nyckelord
    Sex differences, Neuropeptide Y, Neurotensin, Galanin, Hippocampus, Pituitary, Frontal cortex, Puberty
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-13441 (URN)10.1016/S0196-9781(98)00139-9 (DOI)
    Tillgänglig från: 2005-11-11 Skapad: 2005-11-11 Senast uppdaterad: 2017-12-13Bibliografiskt granskad
    2. Effects of estradiol, progesterone, and norethisterone on regional concentrations of galanin in the rat brain
    Öppna denna publikation i ny flik eller fönster >>Effects of estradiol, progesterone, and norethisterone on regional concentrations of galanin in the rat brain
    1999 (Engelska)Ingår i: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 20, nr 6, s. 743-748Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Concentrations of immunoreactive galanin were compared in eight gross brain regions of ovariectomized female rats treated with either estradiol, estradiol + progesterone, estradiol + norethisterone, or placebo. Higher concentrations with estradiol treatment compared with placebo were found in the pituitary (357%), frontal cortex (162%), occipital cortex (174%), hippocampus (170%), and median eminence (202%). A more profound difference with addition of progesterone or norethisterone was seen in the pituitary (529% and 467%, respectively). Sex steroids, particularly estradiol, modulate galanin concentrations not only in reproductive, but also in nonreproductive, brain regions.

    Nyckelord
    Galanin, Estradiol, Progesterone, Norethisterone, Hippocampus, Pituitary, Frontal cortex
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-13442 (URN)10.1016/S0196-9781(99)00057-1 (DOI)
    Tillgänglig från: 2005-11-11 Skapad: 2005-11-11 Senast uppdaterad: 2017-12-13Bibliografiskt granskad
    3. Modern anesthesia and peroperative monitoring methods reduce per- and postoperative mortality during transient occlusion of the middle cerebral artery in rats
    Öppna denna publikation i ny flik eller fönster >>Modern anesthesia and peroperative monitoring methods reduce per- and postoperative mortality during transient occlusion of the middle cerebral artery in rats
    2005 (Engelska)Ingår i: Brain Research Protocols, ISSN 1385-299X, E-ISSN 1872-809X, Vol. 14, nr 3, s. 181-190Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Mortality and morbidity during and after occlusion of the middle cerebral artery in rats are important confounding factors which may be minimized by improved anesthesia and peroperative monitoring techniques. We describe state of the art techniques for inducing anesthesia, endotracheal intubation, ventilation and monitoring peroperatively in this context.

    Introducing the subtemporal approach of Tamura et al. in our laboratory 5 years ago, we experienced 25% peroperative and 24 h postoperative rat mortality when performing temporary clipping of the middle cerebral artery. This prompted us to abandon intraperitoneal anesthesia by chloral hydrate and ventilation by tracheotomy in favor of endotracheal intubation and isoflurane anesthesia (1% isoflurane in 30%:70% O2/N2O). These anesthetic techniques in combination with improved surgical skills have reduced our initial 25% peroperative- and 24 h postoperative mortality to 2.7% (1.8% peroperatively and 0.9% 24 h postoperatively). Furthermore, the following 14 days postoperative mortality rate was 1.8%. A total number of 203 rats have been operated with this method in different studies where a focal reperfusion stroke model combined with extended periods of observations were the cornerstone.

    Nyckelord
    Cerebral ischemia; Focal; Middle cerebral artery occlusion; Anesthetic method; Isoflurane; Rat
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-13443 (URN)10.1016/j.brainresprot.2005.01.002 (DOI)
    Tillgänglig från: 2005-11-11 Skapad: 2005-11-11 Senast uppdaterad: 2017-12-13Bibliografiskt granskad
    4. Serum concentrations of 17β-estradiol in ovariectomized rats during 2 times 6 weeks crossover treatment by daily injections in comparison with slow-release pellets
    Öppna denna publikation i ny flik eller fönster >>Serum concentrations of 17β-estradiol in ovariectomized rats during 2 times 6 weeks crossover treatment by daily injections in comparison with slow-release pellets
    Visa övriga...
    2005 (Engelska)Ingår i: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 1502-7686 (electronic) 0036-5513 (paper), Vol. 65, nr 8, s. 699-706Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Estrogens exert widespread biological functions that reach far beyond their well-known role in reproduction. Exogenous administration of 17β-estradiol to ovariectomized experimental animals is of the utmost importance in elucidating its mechanisms of action. In the present study, we compared two different modes of exogenous administration of 17β-estradiol to ovariectomized rats in relation to the serum 17β-estradiol concentrations over prolonged periods of time. 17β-estradiol was administered either by slow-release pellets (Innovative Research of America, Sarasota, Fl. 34236, USA, 90-day release, NHH-115, 1.5 mg) or by daily subcutaneous injections of 15 µg 17β-estradiol dissolved in sesame oil. After 6 weeks, the mode of administration of estradiol was changed to the opposite method and continued for a further 6 weeks. Blood samples for measurement of serum 17β-estradiol were taken every second week. After 2 weeks, the serum concentrations of 17β-estradiol in group A initially receiving the pellets were 73 % higher (p<0.001) compared to those of group B receiving daily injections. The difference was even more prominent, 580 % (p<0.001), after 4 weeks. Steady state was reached at week 6 in group A, but already by week 4 in group B. Once steady state was reached, the concentrations were the same in both groups for the remainder of the experiment (12 weeks in total). Our study indicates that steady-state concentrations of 17β-estradiol occur 5-6 weeks later than the 48 h the manufacturer of the slow-release pellets claims.

    Nyckelord
    Estrogen; 17β-estradiol; rat; slow-release pellet
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-13444 (URN)10.1080/00365510500375206 (DOI)
    Tillgänglig från: 2005-11-11 Skapad: 2005-11-11 Senast uppdaterad: 2018-01-26
    5. Estradiol increases brain lesions in the cortex and lateral striatum after transient occlusion of the middle cerebral artery in rats: No effect of ischemia on galanin in the stroke area but decreased levels in the hippocampus
    Öppna denna publikation i ny flik eller fönster >>Estradiol increases brain lesions in the cortex and lateral striatum after transient occlusion of the middle cerebral artery in rats: No effect of ischemia on galanin in the stroke area but decreased levels in the hippocampus
    2005 (Engelska)Ingår i: Peptides, ISSN 0196-9781, Vol. 26, nr 11, s. 2257-2264Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    A distinctive feature of galanin expression is that it is extensively increased by neuronal injury, estrogens, Alzheimer's disease and during development. Since stroke is amongst the clinically most important causes of neuronal injury we studied the tissue concentrations of galanin in a rat stroke model and the possibility of modulating this effect with estrogen. Transient focal middle cerebral artery ischemia was induced in rats that 2 weeks earlier underwent ovariectomy and received 1.5 mg 17β-estradiol slow-release or placebo pellets. The concentrations of galanin and neuropeptide Y were measured after observation periods of 3, 7 and 14 days in extracts of punch biopsies from both the lesioned and the contra lateral control hemisphere. The galanin levels were not changed in any of the brain regions studied except in the hippocampus where they were lower in the ischemic hemisphere in both the estrogen- and placebo-treated animals compared to the corresponding contra lateral intact hemisphere (p = 0.015). Estrogen treatment up-regulated galanin concentrations in both the ventral and dorsal hippocampus (p = 0.003). The effects on the galanin concentrations were similar after all observation periods: 3, 7 and 14 days (p = 0.144). No significant changes were observed in the concentration of neuropeptide Y in response to the lesions. The ischemic lesions were markedly larger in the estrogen-treated animals observed after 3 days compared to the corresponding control group. In the estrogen group the lesion was largest at bregma and the slice 2 mm anterior to the bregma, 82% and 435% larger than in the control group (p < 0.001). A similar, but much less pronounced (not statistically significant) difference was seen in the groups observed after 7 and 14 days. Earlier studies of lesions in the peripheral and central nervous systems have generally shown an up-regulation of galanin markers in response to but at a distance from the injury. Our results indicate that galanin is not involved in the response of the ischemic penumbra itself to stroke, whereas it may participate in the reactions of the neural stem-cell rich hippocampus to stroke.

    Nyckelord
    Galanin; Neuropeptide Y; Neuropeptides; Stroke; Cerebral ischemia; Estrogen; Neuroprotection; Middle cerebral artery occlusion; Rat
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-13445 (URN)10.1016/j.peptides.2005.04.013 (DOI)
    Tillgänglig från: 2005-11-11 Skapad: 2005-11-11 Senast uppdaterad: 2009-06-05
    6. Galanin administered intracerebroventricularly increases ischemic lesions measured 7 days after focal and transient occlusion of the middle cerebral artery in female rats
    Öppna denna publikation i ny flik eller fönster >>Galanin administered intracerebroventricularly increases ischemic lesions measured 7 days after focal and transient occlusion of the middle cerebral artery in female rats
    2005 (Engelska)Artikel i tidskrift (Refereegranskat) Submitted
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-13446 (URN)
    Tillgänglig från: 2005-11-11 Skapad: 2005-11-11
  • 270.
    Thor, Stefan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Utvecklingsbiologi. Linköpings universitet, Hälsouniversitetet.
    Neuroscience: Light moulds plastic brains2008Ingår i: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 456, nr 7219, s. 177-178Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    In tadpoles, the number of neurons expressing the neurotransmitter dopamine increases on exposure to light. Such plasticity might allow animals to physically match their brains’ activity to environmental stimuli.

  • 271.
    Thor, Stefan
    et al.
    Molecular Neurobiology Laboratory, The Salk Institute, PO Box 85800, San Diego, California 92186, USA.
    Andersson, Siv G E
    Center for Neurobiology and Behavior, Department of Genetics and Development, College of Physicians and Surgeons of Columbia University, 701 West 168th Street, New York, New York 10032, USA.
    Tomlinson, Andrew
    Center for Neurobiology and Behavior, Department of Genetics and Development, College of Physicians and Surgeons of Columbia University, 701 West 168th Street, New York, New York 10032, USA.
    Thomas, John B
    Molecular Neurobiology Laboratory, The Salk Institute, PO Box 85800, San Diego, California 92186, USA.
    A LIM-homeodomain combinatorial code for motor-neuron pathway selection.1999Ingår i: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 397, nr 6714, s. 76-80Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Different classes of vertebrate motor neuron that innervate distinct muscle targets express unique combinations of LIM-homeodomain transcription factors, suggesting that a combinatorial code of LIM-homeodomain proteins may underlie the control of motor-neuron pathway selection. Studies of LIM-homeodomain genes in mouse, Drosophila melanogaster and Caenorhabditis elegans have revealed functions of these genes in neuronal survival, axon guidance, neurotransmitter expression and neuronal function, but, to our knowledge, none of these studies have addressed the issue of a functional code. Here we study two members of this gene family in Drosophila, namely lim3, the homologue of the vertebrate Lhx3 and Lhx4 genes, and islet, the homologue of the vertebrate Isl1 and Is12 genes. We show that Drosophila lim3 is expressed by a specific subset of islet-expressing motor neurons and that mutating or misexpressing lim3 switches motor-neuron projections predictably. Our results provide evidence that lim3 and islet constitute a combinatorial code that generates distinct motor-neuron identities.

  • 272.
    Thorsell, Annika
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Brain neuropeptide Y and corticotropin-releasing hormone in mediating stress and anxiety2010Ingår i: Experimental biology and medicine (Maywood, N.J.: Print), ISSN 1535-3702, E-ISSN 1535-3699, Vol. 235, nr 10, s. 1163-1167Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Neuropeptides such as neuropeptide Y (NPY) and corticotropin-releasing hormone (CRH) have been implicated not only in acute regulation of stress/anxiety-related behaviors, but adaptations and changes in these neuropeptide systems may also participate in the regulation of behavior and endocrine responses during chronic stress. NPY is an endogenous anxiolytic neuropeptide, while CRH has anxiogenic properties upon central administration. Changes in these neuropeptide systems may contribute to disease states and give us indications for putative treatment targets for stress/anxiety disorders as well as alcohol/drug dependence. In this review, we briefly present these two systems and review their involvement in mediating the responses to acute and chronic stressors, as well as their possible roles in the development and progression of stress/anxiety disorders. We suggest that neuropeptides may be attractive in treatment development for stress/anxiety disorders, as well as for alcohol/drug dependence, based on their specificity and activity following exposure to external challenges, i.e. stressors, and their differential adaptations during transition from an acute to a chronic stress exposure state.

  • 273.
    Thorsell, Annika
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Central neuropeptide Y in anxiety- and stress-related behavior and in ethanol intake2008Ingår i: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1148, s. 136-140Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    One of the most profound properties of central neuropeptide Y (NPY) is its anxiolytic, or anti-anxiety, effect. This has been demonstrated repeatedly in a number of animal models. In addition, stressors affect NPY expression in the central nervous system, with acute and repeated (chronic) stress having differential effects. Here, a brief summary of some work performed in our laboratory is presented that supports a role for NPY in regulation of stress responses and behaviors.

  • 274.
    Thorsell, Annika
    The Scripps Research Institute, La Jolla, CA, USA.
    Neuropeptide Y (NPY) in alcohol intake and dependence2007Ingår i: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 28, nr 2, s. 480-483Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Neuropeptide Y has a role in alcohol intake and dependence. NPY's effect on alcohol intake appears to be in part dependent on the individual's history of alcohol dependence. In models of high intake such as alcohol-preferring, selectively bred rat lines (e.g., the P-line and the HAD line), as well as in ethanol-vapor-exposed subjects, NPY modulates alcohol intake while leaving it unaffected during baseline conditions. The primary receptor subtype mediating NPY's effect on ethanol intake remains in question. The Y2-antagonist BIIE0246 significantly suppresses ethanol intake in an operant paradigm with a sensitization to the effect of BIIE0246 in vapor-exposed subjects. We propose the NPY system to be one of the most interesting target systems for the development of treatments for alcohol abuse and dependence.

  • 275.
    Thorsell, Annika
    et al.
    Magnus Huss Clinic, Karolinska Hospital, S-17176 Stockholm, Sweden.
    Blomqvist, Anders G
    Department of Medical Genetics, Uppsala University, Uppsala, Sweden.
    Heilig, Markus
    Magnus Huss Clinic, Karolinska Hospital, S-17176 Stockholm, Sweden.
    Cationic lipid-mediated delivery and expression of prepro-neuropeptide Y cDNA after intraventricular administration in rat: feasibility and limitations.1996Ingår i: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 61, nr 3, s. 205-211Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The utility of in vivo lipofection for delivery and expression of a neuropeptide gene in the adult rat brain was explored. Prepro-neuropeptide Y (NPY) cDNA was cloned into the episomal eucaryotic expression vector pCEP4. This construct was complexed to lipofectamine or lipofectin. Complexed DNA was injected into the lateral ventricles of adult rats. Brains were removed for analysis following various time intervals. Polymerase chain reaction (PCR) reactions were designed for specific detection of endogenous and vector derived NPY sequence, respectively. PCR of DNA preparations from 5 major brain regions (frontal and parietal cortex, striatum, hypothalamus, brain stem) demonstrated presence of vector DNA up to 1 month (longest interval studied) in all brain regions. Reverse-transcription (RT-) PCR of DNase treated RNA-preparations from brain tissue demonstrated presence of both vector-derived and endogenous NPY mRNA in treated animals, while only endogenous mRNA was detected in controls. In situ hybridization histochemistry indicated scattered patches of vector uptake into tissue in the vicinity of the CSF compartment, but not into deeper located structures. Weight gain was not affected, indicating that the expression levels achieved may not be sufficient to play a functional role, and/or may need to be targeted to specific brain areas. These findings suggest a potential for cationic lipid mediated gene transfer in the brain as an experimental tool and as a possible future therapeutic principle, but also indicate the need for optimization of delivery strategies in order to achieve functionally relevant expression levels.

  • 276.
    Thorsell, Annika
    et al.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Johnson, Justin
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Heilig, Markus
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Effect of the adenosine A2a receptor antagonist 3,7-dimethyl-propargylxanthine on anxiety-like and depression-like behavior and alcohol consumption in Wistar Rats2007Ingår i: Alcoholism: Clinical and Experimental Research, ISSN 0145-6008, E-ISSN 1530-0277, Vol. 31, nr 8, s. 1302-1307Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: It has been suggested that the reinforcing properties of ethanol are in part mediated via an A2 activation of cAMP/PKA signaling in the nucleus accumbens, predicting that administration of an A2a antagonist might reduce ethanol reward and consumption. We therefore examined the effect of the adenosine A2a receptor antagonist 3,7-dimethylpropargylxanthine (DMPX, 3, and 10 mg/kg intraperitoneal) on alcohol reinforcement, anxiety-related, depression, and rewarding behaviors in nonselected Wistar rats.

    METHODS: Operant ethanol self-administration was used for examining alcohol intake, elevated plus-maze and Vogel conflict test for anxiety-related behavior, Porsolt swim test for depression-like behavior, and conditioned place preference for examination of the rewarding properties of the drug.

    RESULTS: 3,7-Dimethylpropargylxanthine decreased lever-pressing for ethanol in a dose-dependent manner. When analyzed as percentage of pretreatment baseline, maximum suppression was approximately 60% (39+/-7.5 vs 98+/-12%, mean+/-SEM, p=0.017). This effect was behaviorally specific, as no effect was found on the water lever. In agreement with previously published data, stimulation of locomotion was found (beam-breaks: 3590+/-540 vs 2475+/-240, 10 mg/kg vs saline, p=0.048). No anxiety-modulating effects were seen in either the elevated plus-maze or the Vogel conflict test. 3,7-Dimethylpropargylxanthine was not found to have intrinsic rewarding properties in the conditioned place preference model.

    CONCLUSIONS: In summary, DMPX produced a robust and behaviorally selective reduction of ethanol reinforcement, while anxiety-modulating effects were less consistent. These results bring further support to a role for adenosine in the regulation of ethanol consumption and possibly alcohol addiction/abuse, and the A2a receptor as a potential target for the treatment of alcoholism and alcohol abuse.

  • 277.
    Thorsell, Annika
    et al.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Karlsson, Rose-Marie
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Heilig, Markus
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    NPY in alcoholism and psychiatric disorders2006Ingår i: NPY Family of Peptides in Neurobiology, Cardiovascular and Metabolic Disorders: from Genes to Therapeutics / [ed] Zofia Zukowska, Giora Z. Feuerstein, Basel: Birkhäuser Verlag, 2006, Vol. 95, s. 183-192Kapitel i bok, del av antologi (Refereegranskat)
    Abstract [en]

    The NPY system may well be one of the most interesting target systems for development of treatments for alcohol dependence as well as mood disorders such as depression and anxiety syndromes. NPY is an endogenous anxiolytic compound, functions as an antidepressant, and is effective in modifying alcohol intake in high drinking states. Through receptor subtype specific compounds, the NPY system offers an interesting and innovative future approach for treatment designs. Selective Y2 receptor antagonists and/or Y1 agonists that are peripherally available and effectively penetrate the CNS are possible candidates. In conclusion, the NPY system offers attractive targets for development of future treatments for depression, anxiety, and alcohol dependence.

  • 278.
    Thorsell, Annika
    et al.
    The Scripps Research Institute, La Jolla, CA, USA.
    Repunte-Canonigo, Vez
    The Scripps Research Institute, La Jolla, CA, USA.
    O'Dell, Laura E.
    The Scripps Research Institute, La Jolla, CA, USA.
    Chen, Scott A.
    The Scripps Research Institute, La Jolla, CA, USA.
    King, Alvin R.
    The Scripps Research Institute, La Jolla, CA, USA.
    Lekic, Dusan
    The Scripps Research Institute, La Jolla, CA, USA.
    Koob, George F.
    The Scripps Research Institute, La Jolla, CA, USA.
    Sanna, Pietro Paolo
    The Scripps Research Institute, La Jolla, CA, USA.
    Viral vector-induced amygdala NPY overexpression reverses increased alcohol intake caused by repeated deprivations in Wistar rats2007Ingår i: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 130, nr Pt 5, s. 1330-1337Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Acute administration of neuropeptide Y (NPY) modulates alcohol intake in genetic and chemical models of high intake, while leaving intake unaffected during 'normal' or baseline conditions. In non-selected, normal rat lines, alcohol consumption can be increased by prolonged exposure to alcohol, and it is unclear what effect a constitutive increase in NPY function will have on alcohol intake. The purpose of the present study was to examine the effects on alcohol intake of an inducible, constitutive overexpression of NPY, one of the most abundant neuropeptides in the central nervous system. A liquid diet was used in combination with repeated alcohol deprivation sessions to increase alcohol intake in normal Wistar rats. We then examined the effect of NPY overexpression in the amygdala on excessive alcohol intake produced by prolonged exposure to alcohol and alcohol deprivation. Repeated withdrawal increased alcohol consumption in a 24-h continuous access two-bottle choice model. Both the number of withdrawals as well as the length of the withdrawal periods affected alcohol consumption with an increased intake resulting from multiple withdrawals and the alcohol deprivation effect being enhanced by longer periods of abstinence. The increase in intake following repeated abstinence was blunted by intra-amygdala administration of a Sindbis viral vector containing NPY cDNA. Amygdala NPY overexpression also was demonstrated to be anxiolytic in the open field test. Repeated withdrawal in combination with a history of alcohol consumption significantly elevated alcohol intake, and the amygdala may mediate the transition to high-drinking states in this model.

  • 279.
    Thorsell, Annika
    et al.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Schank, Jesse R.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Singley, Erick
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Hunt, Stephen P
    University College London, UK.
    Heilig, Markus
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Neurokinin-1 receptors (NK1Rs), alcohol consumption, and alcohol reward in mice2010Ingår i: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 209, nr 1, s. 103-111Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    RATIONALE: Reduced voluntary alcohol consumption was recently found in neurokinin-1 receptor (NK1R)-deficient (KO) mice. It remains unknown whether this reflects developmental effects or direct regulation of alcohol consumption by NK1R:s, and whether the reduced consumption reflects motivational effects.

    OBJECTIVE: The objective of this study is to obtain an expanded preclinical validation of NK1R antagonism as a candidate therapeutic mechanism in alcohol use disorders.

    METHODS: The NK1R antagonist L-703,606 and NK1R KO mice were used in models that assess alcohol-related behaviors.

    RESULTS: L-703,606 (3-10 mg/kg i.p.) dose-dependently suppressed alcohol intake in WT C57BL/6 mice under two-bottle free choice conditions but was ineffective in NK1R KO:s, demonstrating the receptor specificity of the effect. Alcohol reward, measured as conditioned place preference for alcohol, was reduced by NK1R receptor deletion in a gene dose-dependent manner. In a model where escalation of intake is induced by repeated cycles of deprivation and access, escalation was seen in WT mice, but not in KO mice. Among behavioral phenotypes previously reported for NK1R mice on a mixed background, an analgesic-like phenotype was maintained on the C57BL/6 background used here, while KO:s and WT:s did not differ in anxiety- and depression-related behaviors.

    CONCLUSIONS: Acute blockade of NK1R:s mimics the effects of NKR1 gene deletion on alcohol consumption, supporting a direct rather than developmental role of the receptor in regulation of alcohol intake. Inactivation of NK1R:s critically modulates alcohol reward and escalation, two key characteristics of addiction. These data provide critical support for NK1R antagonism as a candidate mechanism for treatment of alcoholism.

  • 280.
    Thorsell, Annika
    et al.
    The Scripps Research Institute, La Jolla, CA, USA.
    Slawecki, Craig J
    The Scripps Research Institute, La Jolla, CA, USA.
    Ehlers, Cindy L
    The Scripps Research Institute, La Jolla, CA, USA.
    Effects of neuropeptide Y and corticotropin-releasing factor on ethanol intake in Wistar rats: interaction with chronic ethanol exposure.2005Ingår i: Behavioural Brain Research, ISSN 0166-4328, E-ISSN 1872-7549, Vol. 161, nr 1, s. 133-40Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Neuropeptide Y (NPY) and corticotropin-releasing factor (CRF) have opposing effects on stress-associated and consummatory behaviors in rodents. Recent studies also suggest that both peptides influence ethanol intake. In the present study, the effects of administration of CRF and NPY into the lateral ventricle on ethanol intake in naive and ethanol-vapor-exposed Wistar rats were examined. A limited access paradigm was used to measure intake of a 10% (v/v) ethanol solution in Wistar rats trained to drink using a sucrose fading procedure. Ethanol vapor exposure for 8 weeks significantly elevated ethanol intake in this limited access paradigm relative to pre-exposure levels. The effects of icv administration of CRF (1 microg), NPY (10 microg) or NPY/CRF combined (10 and 1 microg, respectively) on ethanol intake were then assessed. In non-vapor-exposed subjects, icv infusion of NPY had no effect on ethanol intake, while a significant suppression of drinking was seen following icv administration of CRF. Administration of NPY in combination with CRF had no effect on ethanol intake in non-ethanol-vapor-exposed rats. In vapor-exposed subjects, both NPY and CRF reduced ethanol intake, but when given in combination, no difference from vehicle was detected. Locomotor activity was measured during drinking sessions and was unaffected by peptide administration. These studies underscore the importance of a history of exposure to chronic ethanol vapor in the regulation of ethanol intake by NPY. Furthermore, the results presented here suggest that a balance between the stress-related peptides NPY and CRF may be involved in the regulation of ethanol intake.

  • 281.
    Thorsell, Annika
    et al.
    The Scripps Research Institute, La Jolla, CA, USA.
    Slawecki, Craig J.
    The Scripps Research Institute, La Jolla, CA, USA.
    Ehlers, Cindy L.
    The Scripps Research Institute, La Jolla, CA, USA.
    Effects of neuropeptide Y on appetitive and consummatory behaviors associated with alcohol drinking in wistar rats with a history of ethanol exposure2005Ingår i: Alcoholism: Clinical and Experimental Research, ISSN 0145-6008, E-ISSN 1530-0277, Vol. 29, nr 4, s. 584-590Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Neuropeptide Y (NPY) reduces ethanol intake under free access conditions in Wistar rats with a history of prolonged ethanol vapor exposure. The current study was designed to determine whether NPY differentially alters ethanol-associated appetitive behavior (i.e., lever pressing) or ethanol consumption in Wistar rats with a history of ethanol vapor exposure.

    METHODS: Wistar rats were first trained to self-administer 10% ethanol in a paradigm that provided 25 min of free access to 10% ethanol after completing a 20-lever press response requirement (i.e., an RR20 schedule). After stable level lever pressing was established, operant sessions were suspended during a 9-week period of ethanol vapor exposure. Self-administration sessions were then reinstituted, and a fixed time (FT) schedule of 10% ethanol access was used to assess the effects of ethanol exposure and NPY on lever pressing and drinking behavior. Under the FT schedule, the maximum number of lever presses emitted within 10 min was assessed before providing access to 10% ethanol.

    RESULTS: Ethanol vapor exposure did not alter patterns of lever pressing under the RR20 schedule, but lever presses emitted under the FT schedule were reduced after ethanol vapor exposure. Ethanol intake was significantly increased after ethanol vapor exposure. NPY significantly reduced ethanol intake but did not significantly reduce lever pressing under the FT schedule.

    CONCLUSIONS: Taken together, these data suggest that chronic ethanol exposure increases ethanol intake without clearly enhancing its reinforcing value. Furthermore, NPY has a greater impact on the consummatory factors mediating ethanol intake than appetitive factors mediating ethanol seeking.

  • 282.
    Thorsell, Annika
    et al.
    The Scripps Research Institute, La Jolla, CA, USA.
    Slawecki, Craig J.
    The Scripps Research Institute, La Jolla, CA, USA.
    El Khoury, Aram
    Karolinska Institutet, Huddinge University Hospital, Stockholm, Sweden.
    Mathe, Aleksander A.
    Karolinska Institutet, Huddinge University Hospital, Stockholm, Sweden.
    Ehlers, Cindy L.
    The Scripps Research Institute, La Jolla, CA, USA.
    The effects of social isolation on neuropeptide Y levels, exploratory and anxiety-related behaviors in rats2006Ingår i: Pharmacology, Biochemistry and Behavior, ISSN 0091-3057, E-ISSN 1873-5177, Vol. 83, nr 1, s. 28-34Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    NPY is one of the most abundantly expressed peptides within the CNS, and has been previously demonstrated to be altered in several animal models of depression, as well as to be differentially regulated by acute and repeated stress. The effect of social deprivation, through isolation housing, on brain NPY concentrations in adult rats has not been previously investigated. The effects of 12 weeks of social isolation, in adult rats, on anxiety-related behaviors and central concentrations of NPY in: hypothalamus, amygdala, caudate-putamen, hippocampus, and frontal cortex were evaluated. Single housed animals spent significantly more time on the open arms of the elevated plus maze and in the central area of the open field as compared to pair housed controls. These data are most likely indicative of enhanced exploration and novelty seeking. Concentrations of neuropeptide Y were increased in the caudate-putamen of the single housed subjects. NPY levels in caudate/putamen and hypothalamus were also significantly correlated with time spent in the open arms of the elevated plus maze. These data suggest that chronic social isolation, in these adult Wistar rats, did not increase anxiety but produced enhanced exploration in tests of anxiety, an effect that was associated with NPY concentrations in the striatum and hypothalamus.

  • 283.
    Thorsell, Annika
    et al.
    The Scripps Research Institute, La Jolla, CA, USA.
    Slawecki, Craig J.
    The Scripps Research Institute, La Jolla, CA, USA.
    Khoury, Aram
    Karolinska Institutet, Huddinge University Hospital, Stockholm, Sweden.
    Mathe, Aleksander A.
    Karolinska Institutet, Huddinge University Hospital, Stockholm, Sweden.
    Ehlers, Cindy L.
    The Scripps Research Institute, La Jolla, CA, USA.
    Effect of social isolation on ethanol consumption and substance P/neurokinin expression in Wistar rats2005Ingår i: Alcohol, ISSN 0741-8329, E-ISSN 1873-6823, Vol. 36, nr 2, s. 91-97Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Environmental factors, such as adverse life experiences and family/peer influences have a substantial influence on the development of disorders related to alcohol use. In animals, maternal or peer separation/isolation has been used as an environmental intervention that has been shown to alter neurodevelopment and influence drinking behaviors in rodents and primates. In this study, the effects of adult peer isolation on subsequent ethanol intake were investigated in Wistar rats. Because central tachykinin levels have been reported to differ between rats selected for enhanced ethanol preference, neuropeptide [neurokinin A (NKA), substance P (SP)] concentrations were also estimated. Lower levels of ethanol intake, in a two-bottle free-choice model, were observed on the first day of forced ethanol drinking in the single-housed animals. However, overall ethanol consumption was unaffected by peer isolation. Peer isolation significantly lowered SP and NKA levels in the hypothalamus, but this effect was not related to ethanol consumption or body weight. These data indicate that endogenous SP and neurokinin levels are reduced by isolation housing, but this was not associated with alterations in drinking levels using a two-bottle choice procedure.

  • 284.
    Thorsell, Annika
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Tapocik, Jenica D
    Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA.
    Liu, Ke
    National Center for Advancing Translational Sciences, Bethesda, Maryland, USA.
    Zook, Michelle
    Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA.
    Bell, Lauren
    Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA.
    Flanigan, Meghan
    Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA.
    Patnaik, Samarjit
    National Center for Advancing Translational Sciences, Bethesda, Maryland, USA.
    Marugan, Juan
    National Center for Advancing Translational Sciences, Bethesda, Maryland, USA.
    Damadzic, Ruslan
    Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA.
    Dehdashti, Seameen J
    National Center for Advancing Translational Sciences, Bethesda, Maryland, USA.
    Schwandt, Melanie L
    Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA.
    Southall, Noel
    National Center for Advancing Translational Sciences, Bethesda, Maryland, USA.
    Austin, Christopher P
    National Center for Advancing Translational Sciences, Bethesda, Maryland, USA.
    Eskay, Robert
    Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA.
    Ciccocioppo, Roberto
    University of Camerino, Italy.
    Zheng, Wei
    National Center for Advancing Translational Sciences, Bethesda, Maryland, USA.
    Heilig, Markus
    Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA.
    A Novel Brain Penetrant NPS Receptor Antagonist, NCGC00185684, Blocks Alcohol-Induced ERK-Phosphorylation in the Central Amygdala and Decreases Operant Alcohol Self-Administration in Rats2013Ingår i: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 33, nr 24, s. 10132-10142Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The Neuropeptide S receptor, a Gs/Gq-coupled GPCR expressed in brain regions involved in mediating drug reward, has recently emerged as a candidate therapeutic target in addictive disorders. Here, we describe the in vitro and in vivo pharmacology of a novel, selective and brain penetrant NPSR antagonist with nanomolar affinity for the NPSR, NCGC00185684. In vitro, NCGC00185684 shows biased antagonist properties, and preferentially blocks ERK-phosphorylation over intracellular cAMP or calcium responses to NPS. In vivo, systemic NCGC00185684 blocks alcohol-induced ERK-phosphorylation in the rat central amygdala, a region involved in regulation of alcohol intake. NCGC00185684 also decreases operant alcohol self-administration, and lowers motivation for alcohol reward as measured using progressive ratio responding. These effects are behaviorally specific, in that they are observed at doses that do not influence locomotor activity or reinstatement responding following extinction. Together, these data provide an initial validation of the NPSR as a therapeutic target in alcoholism.

  • 285.
    Tomo, Igor
    et al.
    Karolinska Institutet / Karolinska University Hospital, Stockholm, Sweden.
    Boutet de Monvel, Jacques
    Karolinska Institutet / Karolinska University Hospital, Stockholm, Sweden.
    Fridberger, Anders
    Karolinska Institutet / Karolinska University Hospital, Stockholm, Sweden.
    Sound-evoked radial strain in the hearing organ2007Ingår i: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 93, nr 9, s. 3279-3284Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The hearing organ contains sensory hair cells, which convert sound-evoked vibration into action potentials in the auditory nerve. This process is greatly enhanced by molecular motors that reside within the outer hair cells, but the performance also depends on passive mechanical properties, such as the stiffness, mass, and friction of the structures within the organ of Corti. We used resampled confocal imaging to study the mechanical properties of the low-frequency regions of the cochlea. The data allowed us to estimate an important mechanical parameter, the radial strain, which was found to be 0.1% near the inner hair cells and 0.3% near the third row of outer hair cells during moderate-level sound stimulation. The strain was caused by differences in the motion trajectories of inner and outer hair cells. Motion perpendicular to the reticular lamina was greater at the outer hair cells, but inner hair cells showed greater radial vibration. These differences led to deformation of the reticular lamina, which connects the apex of the outer and inner hair cells. These results are important for understanding how the molecular motors of the outer hair cells can so profoundly affect auditory sensitivity.

  • 286.
    Tomo, Igor
    et al.
    arolinska Institutet and Karolinska University Hospital-Solna, Stockholm, Sweden.
    Le Calvez, Sophie
    arolinska Institutet and Karolinska University Hospital-Solna, Stockholm, Sweden.
    Maier, Hannes
    University of Hamburg, Germany.
    Boutet de Monvel, Jacques
    arolinska Institutet and Karolinska University Hospital-Solna, Stockholm, Sweden.
    Fridberger, Anders
    Karolinska Institutet and Karolinska University Hospital-Solna, Stockholm, Sweden.
    Ulfendahl, Mats
    arolinska Institutet and Karolinska University Hospital-Solna, Stockholm, Sweden.
    Imaging the living inner ear using intravital confocal microscopy2007Ingår i: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 35, nr 4, s. 1393-1400Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Confocal laser scanning microscopy permits detailed visualization of structures deep within thick fluorescently labeled specimen. This makes it possible to investigate living cells inside intact tissue without prior chemical sample fixation and sectioning. Isolated guinea pig temporal bones have previously been used for confocal experiments in vitro, but tissue deterioration limits their use to a few hours after the death of the animal. In order to preserve the cochlea in an optimal functional and physiological condition, we have developed an in vivo model based on a confocal microscopy approach. Using a ventral surgical approach, the inner ear is exposed in deeply anaesthetized, tracheotomized, living guinea pigs. To label the inner ear structures, scala tympani is perfused via an opening in the basal turn, delivering tissue culture medium with fluorescent vital dyes (RH 795 and calcein AM). An apical opening is made in the bony shell of cochlea to enable visualization using a custom-built objective lens. Intravital confocal microscopy, with preserved blood and nerve supply, may offer an important tool for studying auditory physiology and the pathology of hearing loss. After acoustic overstimulation, shortening and swelling of the sensory hair cells were observed.

  • 287.
    Tubert, Cecilia
    et al.
    University of Buenos Aires, Argentina.
    Taravini, Irene R. E.
    University of Entre Rios, Argentina.
    Flores-Barrera, Eden
    Rosalind Franklin University, IL 60064 USA.
    Sanchez, Gonzalo Manuel
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. University of Buenos Aires, Argentina.
    Prost, Maria Alejandra
    University of Buenos Aires, Argentina.
    Elena Avale, Maria
    Consejo Nacl Invest Cient and Tecn, Argentina.
    Tseng, Kuei Y.
    Rosalind Franklin University, IL 60064 USA.
    Rela, Lorena
    University of Buenos Aires, Argentina.
    Gustavo Murer, Mario
    University of Buenos Aires, Argentina.
    Decrease of a Current Mediated by K(v)1.3 Channels Causes Striatal Cholinergic Interneuron Hyperexcitability in Experimental Parkinsonism2016Ingår i: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 16, nr 10, s. 2749-2762Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The mechanism underlying a hypercholinergic state in Parkinsons disease (PD) remains uncertain. Here, we show that disruption of the K(v)1 channel-mediated function causes hyperexcitability of striatal cholinergic interneurons in a mouse model of PD. Specifically, our data reveal that Kv1 channels containing K(v)1.3 subunits contribute significantly to the orphan potassium current known as I-sAHP in striatal cholinergic interneurons. Typically, this Kv1 current provides negative feedback to depolarization that limits burst firing and slows the tonic activity of cholinergic interneurons. However, such inhibitory control of cholinergic interneuron excitability by K(v)1.3-mediated current is markedly diminished in the parkinsonian striatum, suggesting that targeting Kv1.3 subunits and their regulatory pathways may have therapeutic potential in PD therapy. These studies reveal unexpected roles of Kv1.3 subunit-containing channels in the regulation of firing patterns of striatal cholinergic interneurons, which were thought to be largely dependent on K-Ca channels.

  • 288.
    Turina, Dean
    Linköpings universitet, Institutionen för medicin och hälsa, Anestesiologi med intensivvård. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Anestesi- och operationkliniken US.
    Propofol changes the cytoskeletal function in neurons: An experimental study in cortical cultures2012Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Every day, general anaesthetics are given to a large number of patients around the world but the cellular mechanisms of how anaesthetics act are still not clear. General anaesthetics cause the intended unconsciousness, amnesia and immobility in patients, but also side effects such as a decrease in mean arterial pressure and arrhythmia, both of which contribute to complications such as heart damage and stroke. With more knowledge of the mechanism of anaesthetic drugs, these complications could be reduced.

    It has been shown that anaesthetics cause a disruption of the thalamocortical connectivity and brain network connectivity. How the network communication is disrupted however is not known. Propofol and thiopental are both intravenous anaesthetic drugs used widely in clinical anaesthesia. They bind to the GABAA receptor and enhance its function.

    The cytoskeleton helps the cell to maintain its shape and participate in cellular movement and transport. Cellular transport to and from a neuron’s cell body and periphery is performed by motor proteins that move vesicles, organelles and proteins along cytoskeletal tracks. We have previously shown that propofol causes a reorganisation of the cytoskeleton protein actin in neurons, but we were further interested to study the effects of propofol and thiopental on the cytoskeletal function of cultured cortical rat neurons.

    Our results show that propofol and thiopental cause neurite (axon and dendrite) retraction. Propofol’s effects were time- and dose-dependent, and can be reversed when propofol is removed. We were able to inhibit propofolinduced neurite retraction if we stabilised actin by blocking either the motor protein myosin II or the GABAA receptor. We have previously shown that a small GTP-binding protein, RhoA, inhibits propofol-caused actin reorganisation. Propofol-induced neurite retraction was mediated via a downstream effector of RhoA, ROK, which induces phosphorylation of the myosin light chain and increases contractility. Furthermore, we have shown that propofol causes a switch from anterograde to retrograde transport and increases the average velocity of the moving vesicles in neurites. The propofol induced retrograde vesicle transport was GABAA receptor-mediated.

    Orexin A is a neuropeptide which regulates the sleep/awake cycle and has also been shown to reduce anaesthesia in animals when given intracerebroventricularly. We found that orexin A reverses propofol and thiopental-induced neurite retraction and actin reorganisation. Moreover, we have shown that the orexin A inhibition of propofol-induced neurite retraction is mediated via the PLD/PKC intracellular signalling pathway. Propofol and thiopental decreased the tyrosine phosphorilation of the intermediate cytoskeletal protein vimentin which is reversed by orexin A.

    Taken together, these results suggest that propofol causes a time- and dose-dependent, reversible and GABAAreceptor-mediated neurite retraction in cultured cortical rat neurons. Propofol also causes a switch from anterograde to retrograde vesicle transport in neurites. Orexin A reverses propofol and thiopental-induced neurite retraction and cytoskeletal reorganisation. Orexin A inhibits propofol-induced neurite retraction via the PLD/PKC intracellular signalling pathway.

    Delarbeten
    1. Propofol causes neurite retraction in neurons
    Öppna denna publikation i ny flik eller fönster >>Propofol causes neurite retraction in neurons
    Visa övriga...
    2008 (Engelska)Ingår i: British Journal of Anaesthesia, ISSN 0007-0912, E-ISSN 1471-6771, Vol. 101, nr 3, s. 374-379Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Background The mechanism by which anaesthetic agents produce general anaesthesia is not yet fully understood. Retraction of neurites is an important function of individual neurones and neural plexuses during normal and pathological conditions, and it has been shown that such a retraction pathway exists in developing and mature neurones. We hypothesized that propofol decreases neuronal activity by causing retraction of neuronal neurites.

    Methods Primary cultures of rat cortical neurones were exposed in concentration– and time–response experiments to 0.02, 0.2, 2, and 20 µM propofol or lipid vehicle. Neurones were pretreated with the GABAA receptor (GABAAR) antagonist, bicuculline, the myosin II ATPase activity inhibitor, blebbistatin, and the F-actin stabilizing agent, phalloidin, followed by administration of propofol (20 µM). Changes in neurite retraction were evaluated using time-lapse light microscopy.

    Results Propofol caused a concentration- and time-dependent reversible retraction of cultured cortical neurone neurites. Bicuculline, blebbistatin, and phalloidin completely inhibited propofol-induced neurite retraction. Images of retracted neurites were characterized by a retraction bulb and a thin trailing membrane remnant.

    Conclusions Cultured cortical rat neurones retract their neurites after exposure to propofol in a concentration- and time-dependent manner. This retraction is GABAAR mediated, reversible, and dependent on actin and myosin II. Furthermore, the concentrations and times to full retraction and recovery correspond to those observed during propofol anaesthesia.

    Ort, förlag, år, upplaga, sidor
    Oxford, UK: Oxford University Press, 2008
    Nyckelord
    Anaesthetics i.v., propofol; brain, GABA rat; theories of anaesthetic action, cellular mechanisms
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-78010 (URN)10.1093/bja/aen185 (DOI)000259093300014 ()
    Tillgänglig från: 2012-06-04 Skapad: 2012-06-04 Senast uppdaterad: 2017-12-07Bibliografiskt granskad
    2. Propofol alters vesicular transport in rat cortical neuronalcultures
    Öppna denna publikation i ny flik eller fönster >>Propofol alters vesicular transport in rat cortical neuronalcultures
    2011 (Engelska)Ingår i: Journal of Physiology and Pharmacology, ISSN 0867-5910, E-ISSN 1899-1505, Vol. 62, nr 1, s. 119-124Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Neuronal intracellular transport is performed by motor proteins, which deliver vesicles, organelles and proteins along cytoskeletal tracks inside the neuron. We have previously shown that the anesthetic propofol causes dose- and time-dependent, reversible retraction of neuronal neurites. We hypothesize that propofol alters the vesicular transport of cortical neurons due to this neurite retraction. Primary cultures of co-cultivated rat cortical neurons and glial cells were exposed to either 2 mu M propofol, control medium or the lipid vehicle, in time-response experiments. Reversibility was tested by washing propofol off the cells. The role of the GABA(A) receptor (GABA(A)R) was assessed with the GABA(A)R antagonist gabazine. Vesicles were tracked using differential interference contrast video microscopy. Propofol caused a retrograde movement in 83.4 +/- 5.2% (mean +/- S.E.M.) of vesicles, which accelerated over the observed time course (0.025 +/- 0.012 mu m.s(-1)). In control medium, vesicles moved predominantly anterograde (84.6 +/- 11.1%) with lower velocity (0.011 +/- 0.004 mu m.s(-1)). Cells exposed to the lipid vehicle showed the same dynamic characteristics as cells in control medium. The propofol-induced effect on vesicle transport was reversible and blocked by the GABA(A)R antagonist gabazine in low concentration. Our results show that propofol causes a reversible, accelerating vesicle movement toward the neuronal cell body that is mediated via synaptic GABA(A)R. We have previously reported that propofol initiates neurite retraction, and we propose that propofol causes vesicle movement by retrograde flow of cytoplasm from the narrowed neurite.

    Ort, förlag, år, upplaga, sidor
    Polish Physiological Society, 2011
    Nyckelord
    anesthetics intravenously, brain, cellular mechanism, cerebral cortex, neurotransmission effects, pharmacology, propofol, theories of anesthetic action, vesicular transport
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-67967 (URN)000289542300014 ()
    Tillgänglig från: 2011-05-04 Skapad: 2011-05-04 Senast uppdaterad: 2017-12-11Bibliografiskt granskad
    3. Orexin A reverses propofol and thiopental induced cytoskeletal rearrangement in primary cortical neuronal culture
    Öppna denna publikation i ny flik eller fönster >>Orexin A reverses propofol and thiopental induced cytoskeletal rearrangement in primary cortical neuronal culture
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Background: Orexin A (OA) is an endogenous peptide regulating awakeness. It is a potential reversing agent of anaesthetics, shown to reduce anaesthesia in animals, but on cellular level its mechanisms are unknown.

    Methods: Primary cortical cell cultures from newborn rat brains are used, and live cell light microscopy is performed to measure 1) neurite retraction after propofol, thiopental, barbituric acid and ketamine exposure and 2) the effect of OA application either before or after anaesthetics. Cytoskeletal reorganization of vimentin and actin is evaluated with fluorescence microscopy, protein changes detected with Western blot and proteins identified with mass spectrometry after treatment with anaesthetics and/or OA.

    Results: Orexin A reverses and inhibits neurite retraction and the actin ring formation induced by propofol and thiopental. No effect on retraction or actin rings was seen for ketamine (not active on GABAA receptors), the non-anaesthetic barbituric acid, OA or solvents used. OA increases tyrosine phosphorylation of a 50 kDa protein, identified as vimentin. Propofol treatment induces a granular appearance of vimentin, which OA reverses to a smooth distribution throughout the cell.

    Conclusions: OA reverses cellular effects known to be mediated via the GABAA receptor of both propofol and thiopental in cultured rat brain cells. The morphologic changes of actin and vimentin caused by propofol and thiopental, and the subsequent reversal by OA, deepens our understanding of the mechanisms of anaesthesia. In the future, an OA agonist could be used to reverse the effects of GABAA receptor dependent anaesthetic drugs.

    Nyckelord
    orexin A, propofol, thiopental
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-77167 (URN)
    Tillgänglig från: 2012-05-07 Skapad: 2012-05-07 Senast uppdaterad: 2012-06-04Bibliografiskt granskad
    4. Orexin A inhibits propofol-induced neurite retraction by a PLD-dependent mechanism in neurons
    Öppna denna publikation i ny flik eller fönster >>Orexin A inhibits propofol-induced neurite retraction by a PLD-dependent mechanism in neurons
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Background: Propofol retracts neurites and reverses the transport of vesicles in rat cortical neurons in a γ-aminobutyric acid type A (GABAA) receptor dependent manner. Orexin A (OA) is an endogenous peptide regulating wakefulness, and is known to interact with anaesthetics. We aim to investigate whether OA inhibits propofol-induced neurite retraction and elucidate the intracellular signalling involved.

    Methods: In primary cortical cell cultures from newborn rat brains, live cell light microscopy was used to measure neurite retraction after propofol (2 μM) with or without OA (10 nM) application after preincubation with the Rhokinase inhibitor (HA-1077), phospholipase D (PLD) inhibitor [5-fluoro-2- indolyl des-chlorohalopemide (FIPI)], protein kinase C (PKC) inhibitor (staurosporine) or PKC activator phorbol 12-myristate 13-acetate (PMA).

    Results: The neurite retraction induced by propofol is blocked by HA-1077 and PMA. OA blocks neurite retraction induced by propofol, and this inhibitory effect could be prevented by FIPI, as well as staurosporine.

    Conclusions: Rho-kinase is essential for propofol-induced neurite retraction in cortical neuronal cells. Activation of PKC plays an inhibitive role during neurite retraction caused by propofol. OA blocks propofol-induced neurite retraction by a PLD/PKC-mediated pathway.

    Nyckelord
    Orexin A, propofol, PLD
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-77168 (URN)
    Tillgänglig från: 2012-05-07 Skapad: 2012-05-07 Senast uppdaterad: 2012-06-04Bibliografiskt granskad
  • 289.
    Ulfendahl, M.
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Khanna, S. M.
    Karolinska Institutet, Stockholm, Sweden.
    Fridberger, Anders
    Karolinska Institutet, Stockholm, Sweden.
    Flock, Å.
    Karolinska Institutet, Stockholm, Sweden.
    Flock, B.
    Karolinska Institutet, Stockholm, Sweden.
    Jäger, W.
    Karolinska Institutet, Stockholm, Sweden.
    Mechanical response characteristics of the hearing organ in the low-frequency regions of the cochlea1996Ingår i: Journal of Neurophysiology, ISSN 0022-3077, E-ISSN 1522-1598, Vol. 76, nr 6, s. 3850-3862Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    1. With the use of an in vitro preparation of the guinea pig temporal bone, in which the apical turns of the cochlea are exposed, the mechanical and electrical responses of the cochlea in the low-frequency regions were studied during sound stimulation. 2. The mechanical characteristics were investigated in the fourth and third turns of the cochlea with the use of laser heterodyne interferometry, which allows the vibratory responses of both sensory and supporting cells to be recorded. The electrical responses, which can be maintained for several hours, were recorded only in the most apical turn. 3. In the most apical turn, the frequency locations and shapes of the mechanical and electrical responses were very similar. 4. The shapes of the tuning curves and the spatial locations of the frequency maxima in the temporal bone preparation compared very favorably with published results from in vivo recordings of hair cell receptor potentials and sound-induced vibrations of the Reissner's membrane. 5. Compressive nonlinearities were present in both the mechanical and the electrical responses at moderate sound pressure levels. 6. The mechanical tuning changed along the length of the cochlea, the center frequencies in the fourth and third turns being approximately 280 and 570 Hz, respectively. 7. The mechanical responses of sensory and supporting cells were almost identical in shape but differed significantly in amplitude radially across the reticular lamina.

  • 290.
    Von Tiedemann, M.
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Fridberger, Anders
    Karolinska Institutet, Stockholm, Sweden.
    Ulfendahl, M.
    Karolinska Institutet, Stockholm, Sweden.
    Boutet de Monvel, J.
    Karolinska Institutet, Stockholm, Sweden.
    Image adaptive point-spread function estimation and deconvolution for in vivo confocal microscopy2006Ingår i: Microscopy research and technique (Print), ISSN 1059-910X, E-ISSN 1097-0029, Vol. 69, nr 1, s. 10-20Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Visualizing deep inside the tissue of a thick biological sample often poses severe constraints on image conditions. Standard restoration techniques (denoising and deconvolution) can then be very useful, allowing one to increase the signal-to-noise ratio and the resolution of the images. In this paper, we consider the problem of obtaining a good determination of the point-spread function (PSF) of a confocal microscope, a prerequisite for applying deconvolution to three-dimensional image stacks acquired with this system. Because of scattering and optical distortion induced by the sample, the PSF has to be acquired anew for each experiment. To tackle this problem, we used a screening approach to estimate the PSF adaptively and automatically from the images. Small PSF-like structures were detected in the images, and a theoretical PSF model reshaped to match the geometric characteristics of these structures. We used numerical experiments to quantify the sensitivity of our detection method, and we demonstrated its usefulness by deconvolving images of the hearing organ acquired in vitro and in vivo.

  • 291. von Tiedemann, Miriam
    et al.
    Fridberger, Anders
    Karolinska Institutet / Karolinska University Hospital, Stockholm, Sweden.
    Ulfendahl, Mats
    Boutet de Monvel, Jacques
    Brightness-compensated 3-D optical flow algorithm for monitoring cochlear motion patterns2010Ingår i: Journal of biomedical optics, ISSN 1560-2281, Vol. 15, nr 5, s. 056012-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A method for three-dimensional motion analysis designed for live cell imaging by fluorescence confocal microscopy is described. The approach is based on optical flow computation and takes into account brightness variations in the image scene that are not due to motion, such as photobleaching or fluorescence variations that may reflect changes in cellular physiology. The 3-D optical flow algorithm allowed almost perfect motion estimation on noise-free artificial sequences, and performed with a relative error of <10% on noisy images typical of real experiments. The method was applied to a series of 3-D confocal image stacks from an in vitro preparation of the guinea pig cochlea. The complex motions caused by slow pressure changes in the cochlear compartments were quantified. At the surface of the hearing organ, the largest motion component was the transverse one (normal to the surface), but significant radial and longitudinal displacements were also present. The outer hair cell displayed larger radial motion at their basolateral membrane than at their apical surface. These movements reflect mechanical interactions between different cellular structures, which may be important for communicating sound-evoked vibrations to the sensory cells. A better understanding of these interactions is important for testing realistic models of cochlear mechanics.

  • 292.
    Walter, Susanna A
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV. Region Östergötland, Hjärt- och Medicincentrum, Magtarmmedicinska kliniken.
    Forsgren, Mikael
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Radiofysikavdelningen US.
    Lundengård, Karin
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    Simon, Rozalyn
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    Torkildsen Nilsson, Maritha
    The National Board of Forensic Medicine and Linköping University, Linköping, Sweden.
    Söderfeldt, Birgitta
    Department of Clinical Science and Education, Karolinska Institutet, Stockholm, Sweden.
    Lundberg, Peter
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Radiofysikavdelningen 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.
    Positive Allosteric Modulator of GABA Lowers BOLD Responses in the Cingulate Cortex2016Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, nr 3Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Knowledge about the neural underpinnings of the negative blood oxygen level dependent (BOLD) responses in functional magnetic resonance imaging (fMRI) is still limited. We hypothesized that pharmacological GABAergic modulation attenuates BOLD responses, and that blood concentrations of a positive allosteric modulator of GABA correlate inversely with BOLD responses in the cingulate cortex. We investigated whether or not pure task-related negative BOLD responses were co-localized with pharmacologically modulated BOLD responses. Twenty healthy adults received either 5 mg diazepam or placebo in a double blind, randomized design. During fMRI the subjects performed a working memory task. Results showed that BOLD responses in the cingulate cortex were inversely correlated with diazepam blood concentrations; that is, the higher the blood diazepam concentration, the lower the BOLD response. This inverse correlation was most pronounced in the pregenual anterior cingulate cortex and the anterior mid-cingulate cortex. For subjects with diazepam plasma concentration > 0.1 mg/L we observed negative BOLD responses with respect to fixation baseline. There was minor overlap between cingulate regions with task-related negative BOLD responses and regions where the BOLD responses were inversely correlated with diazepam concentration. We interpret that the inverse correlation between the BOLD response and diazepam was caused by GABA-related neural inhibition. Thus, this study supports the hypothesis that GABA attenuates BOLD responses in fMRI. The minimal overlap between task-related negative BOLD responses and responses attenuated by diazepam suggests that these responses might be caused by different mechanisms.

  • 293.
    Wang, Chao
    et al.
    Umeå Univ, Sweden.
    Iashchishyn, Igor A.
    Umeå Univ, Sweden; Sumy State Univ, Ukraine.
    Pansieri, Jonathan
    Umeå Univ, Sweden.
    Nyström, Sofie
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Klementieva, Oxana
    Lund Univ, Sweden.
    Kara, John
    Umea Univ, Sweden.
    Horvath, Istvan
    Umea Univ, Sweden.
    Moskalenko, Roman
    Umea Univ, Sweden; Sumy State Univ, Ukraine.
    Rofougaran, Reza
    Umea Univ, Sweden.
    Gouras, Gunnar
    Lund Univ, Sweden.
    Kovacs, Gabor G.
    Med Univ Vienna, Austria.
    Shankar, S. K.
    Natl Inst Mental Hlth and Neurosci, India.
    Morozova-Roche, Ludmilla A.
    Umea Univ, Sweden.
    S100A9-Driven Amyloid-Neuroinflammatory Cascade in Traumatic Brain Injury as a Precursor State for Alzheimers Disease2018Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, artikel-id 12836Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Pro-inflammatory and amyloidogenic S100A9 protein is an important contributor to Alzheimers disease (AD) pathology. Traumatic brain injury (TBI) is viewed as a precursor state for AD. Here we have shown that S100A9-driven amyloid-neuroinflammatory cascade was initiated in TBI and may serve as a mechanistic link between TBI and AD. By analyzing the TBI and AD human brain tissues, we demonstrated that in post-TBI tissues S100A9, produced by neurons and microglia, becomes drastically abundant compared to A beta and contributes to both precursor-plaque formation and intracellular amyloid oligomerization. Conditions implicated in TBI, such as elevated S100A9 concentration, acidification and fever, provide strong positive feedback for S100A9 nucleation-dependent amyloid formation and delay in its proteinase clearance. Consequently, both intracellular and extracellular S100A9 oligomerization correlated with TBI secondary neuronal loss. Common morphology of TBI and AD plaques indicated their similar initiation around multiple aggregation centers. Importantly, in AD and TBI we found S100A9 plaques without A beta. S100A9 and A beta plaque pathology was significantly advanced in AD cases with TBI history at earlier age, signifying TBI as a risk factor. These new findings highlight the detrimental consequences of prolonged post-TBI neuroinflammation, which can sustain S100A9-driven amyloid-neurodegenerative cascade as a specific mechanism leading to AD development.

  • 294.
    Wang, Peng
    et al.
    Capital Medical University, Peoples R China; Logist University of Peoples Armed Police Force, Peoples R China.
    Li, Hui
    Capital Medical University, Peoples R China.
    Barde, Swapnali
    Karolinska Institute, Sweden.
    Zhang, Ming-Dong
    Karolinska Institute, Sweden; Karolinska Institute, Sweden.
    Sun, Jing
    Capital Medical University, Peoples R China.
    Wang, Tong
    Capital Medical University, Peoples R China.
    Zhang, Pan
    Capital Medical University, Peoples R China.
    Luo, Hanjiang
    Capital Medical University, Peoples R China.
    Wang, Yongjun
    Capital Medical University, Peoples R China.
    Yang, Yutao
    Capital Medical University, Peoples R China.
    Wang, Chuanyue
    Capital Medical University, Peoples R China.
    Svenningsson, Per
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Theodorsson, Elvar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Hokfelt, Tomas G. M.
    Karolinska Institute, Sweden.
    David Xu, Zhi-Qing
    Capital Medical University, Peoples R China.
    Depression-like behavior in rat: Involvement of galanin receptor subtype 1 in the ventral periaqueductal gray2016Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 113, nr 32, s. E4726-E4735Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The neuropeptide galanin coexists in rat brain with serotonin in the dorsal raphe nucleus and with noradrenaline in the locus coeruleus (LC), and it has been suggested to be involved in depression. We studied rats exposed to chronic mild stress (CMS), a rodent model of depression. As expected, these rats showed several endophenotypes relevant to depression-like behavior compared with controls. All these endophenotypes were normalized after administration of a selective serotonin reuptake inhibitor. The transcripts for galanin and two of its receptors, galanin receptor 1 (GALR1) and GALR2, were analyzed with quantitative real-time PCR using laser capture microdissection in the following brain regions: the hippocampal formation, LC, and ventral periaqueductal gray (vPAG). Only Galr1 mRNA levels were significantly increased, and only in the latter region. After knocking down Galr1 in the vPAG with an siRNA technique, all parameters of the depressive behavioral phenotype were similar to controls. Thus, the depression-like behavior in rats exposed to CMS is likely related to an elevated expression of Galr1 in the vPAG, suggesting that a GALR1 antagonist could have antidepressant effects.

  • 295. Watanabe, Futoshi
    et al.
    Kirkegaard, Mette
    Matsumoto, Suguru
    Gont, Cecilia
    Mannström, Paula
    Ulfendahl, Mats
    Fridberger, Anders
    Karolinska Institutet, Stockholm, Sweden.
    Signaling through erbB receptors is a critical functional regulator in the mature cochlea2010Ingår i: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 32, nr 5, s. 717-724Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Noise, ototoxic substances and various genetic factors are common causes of profound hearing loss. Cochlear implants can often restore hearing in these cases, but only if a sufficient number of responsive auditory nerve fibers remain. Over time, these nerve fibers degenerate in the damaged ear, and it is therefore important to establish factors that control neuronal survival and maintain neural excitability. Recent studies show that neuregulins and their receptors are important for survival and proper targeting of neurons in the developing inner ear. A role for neuregulins as maintainers of the neuronal population in the mature inner ear was therefore hypothesized. Here, this hypothesis was directly tested by chronic local application of substances that block neuregulin receptors. Using auditory brainstem response measurements, we demonstrate that such receptor block leads to a progressive hearing impairment that develops over the course of weeks. This impairment occurs despite a normal number of auditory neurons and preserved outer hair cell function. Real-time quantitative reverse transcriptase-polymerase chain reaction shows alterations in neurotrophin-3 expression, suggesting that this growth factor participates in regulating cochlear sensitivity. The present work demonstrates the critical importance of neuregulin/erbB signaling in long-term functional regulation in the mature guinea pig hearing organ.

  • 296.
    Watkins, Roger H.
    et al.
    University of Gothenburg, Sweden; University of Bristol, England.
    Wessberg, Johan
    University of Gothenburg, Sweden.
    Backlund Wasling, Helena
    University of Gothenburg, Sweden.
    Dunham, James P.
    Cambridge University Hospital, England.
    Olausson, Håkan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten. University of Gothenburg, Sweden.
    Johnson, Richard D.
    University of Gothenburg, Sweden; University of Florida, FL 32610 USA.
    Ackerley, Rochelle
    University of Gothenburg, Sweden; Aix Marseille University, France.
    Optimal delineation of single C-tactile and C-nociceptive afferents in humans by latency slowing2017Ingår i: Journal of Neurophysiology, ISSN 0022-3077, E-ISSN 1522-1598, Vol. 117, nr 4, s. 1608-1614Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    C-mechanoreceptors in humans comprise a population of unmyelinated afferents exhibiting a wide range of mechanical sensitivities. C-mechanoreceptors are putatively divided into those signaling gentle touch (C-tactile afferents, CTs) and nociception (C-mechanosensitive nociceptors, CMs), giving rise to positive and negative affect, respectively. We sought to distinguish, compare, and contrast the properties of a population of human C-mechanoreceptors to see how fundamental the divisions between these putative subpopulations are. We used microneurography to record from individual afferents in humans and applied electrical and mechanical stimulation to their receptive fields. We show that C-mechanoreceptors can be distinguished unequivocally into two putative populations, comprising CTs and CMs, by electrically evoked spike latency changes (slowing). After both natural mechanical stimulation and repetitive electrical stimulation there was markedly less latency slowing in CTs compared with CMs. Electrical receptive field stimulation, which bypasses the receptor end organ, was most effective in classifying C-mechanoreceptors, as responses to mechanical receptive field stimulation overlapped somewhat, which may lead to misclassification. Furthermore, we report a subclass of low-threshold CM responding to gentle mechanical stimulation and a potential subclass of CT afferent displaying burst firing. We show that substantial differences exist in the mechanisms governing axonal conduction between CTs and CMs. We provide clear electrophysiological "signatures" (extent of latency slowing) that can be used in unequivocally identifying populations of C-mechanoreceptors in single-unit and multiunit microneurography studies and in translational animal research into affective touch. Additionally, these differential mechanisms may be pharmacologically targetable for separate modulation of positive and negative affective touch information. NEW amp; NOTEWORTHY Human skin encodes a plethora of touch interactions, and affective tactile information is primarily signaled by slowly conducting C-mechanoreceptive afferents. We show that electrical stimulation of low-threshold C-tactile afferents produces markedly different patterns of activity compared with high-threshold C-mechanoreceptive nociceptors, although the populations overlap in their responses to mechanical stimulation. This fundamental distinction demonstrates a divergence in affective touch signaling from the first stage of sensory processing, having implications for the processing of interpersonal touch.

  • 297.
    Westergren, Samuel
    Linköpings universitet, Hälsouniversitetet.
    Nivåer av det lysosomala systemets proteiner i hjärnvävnad från Alzheimerpatienter2014Självständigt arbete på grundnivå (kandidatexamen), 10 poäng / 15 hpStudentuppsats (Examensarbete)
    Abstract [sv]

    Alzheimers sjukdom är den vanligaste orsaken till demens och i samband med att befolkningen blir större och allt äldre ökar även antalet patienter. Vid sjukdomen sker en hjärnatrofi och de mikroskopiska fynd man ser är extracellulära plack av β-amyloid, intracellulära neurofibriller av fosforylerat tau och förlust av nervcellsutskott, axoner, synapser och dendriter. Några av de tidiga patologiska förändringarna man kan se är störningar i nervcellernas lysosomala system som fyller en viktig roll vid nedbrytning av makromolekyler. I en tidigare studie har man påvisat förhöjda nivåer av proteiner från det lysosomala systemet i cerebrospinalvätska. Syftet med den här studien var att mäta nivåer av det lysosomala systemets proteiner i human hjärnvävnad från patienter med Alzheimer och jämföra dessa med kontrollprover. De sex proteiner som analyserades med Western blot var EEA1, PICALM, LAMP-1, LAMP-2, LC3 och TFEB. Resultaten visar på signifikant ökning i temporala cortex av LAMP-1 och LAMP-2 och en signifikant minskning av LC3 och EEA1 hos patienter med Alzheimers sjukdom. För att kunna dra riktiga slutsatser kring hur de ökade nivåerna i cerebrospinalvätska speglar de olika sjukdomsmekanismerna i hjärnan krävs vidare analyser av fler patientprover samt prover från andra områden i hjärnan.

  • 298.
    Westermark, Gunilla
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Westermark, P.
    Uppsala University.
    Serum amyloid A and protein AA: Molecular mechanisms of a transmissible amyloidosis2009Ingår i: FEBS Letters, ISSN 0014-5793, Vol. 583, nr 16, s. 2685-2690Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Systemic AA-amyloidosis is a complication of chronic inflammatory diseases and the fibril protein AA derives from the acute phase reactant serum AA. AA-amyloidosis can be induced in mice by an inflammatory challenge. The lag phase before amyloid develops can be dramatically shortened by administration of a small amount of amyloid fibrils. Systemic AA-amyloidosis is transmissible in mice and may be so in humans. Since transmission can cross species barriers it is possible that AA-amyloidosis can be induced by amyloid in food, e.g. foie gras. In mice, development of AA-amyloidosis can also be accelerated by other components with amyloid-like properties. A new possible risk factor may appear with synthetically made fibrils from short peptides, constructed for tissue repair.

  • 299.
    Wikgren, Mikael
    et al.
    Umeå University, Sweden.
    Karlsson, Thomas
    Linköpings universitet, Institutionen för beteendevetenskap och lärande, Handikappvetenskap. Linköpings universitet, Filosofiska fakulteten.
    Söderlund, Hedvig
    Uppsala University, Sweden.
    Nordin, Annelie
    Umeå University, Sweden.
    Roos, Göran
    Umeå University, Sweden.
    Nilsson, Lars-Göran
    Stockholm University, Sweden.
    Adolfsson, Rolf
    Umeå University, Sweden.
    Norrback, Karl-Fredrik
    Umeå University, Sweden.
    Shorter telomere length is linked to brain atrophy and white matter hyperintensities.2014Ingår i: Age and Ageing, ISSN 0002-0729, E-ISSN 1468-2834, Vol. 43, nr 2, s. 212-217Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: leukocyte telomere length (TL) is considered a marker of biological aging. Several studies have investigated the link between leukocyte TL and aging-associated functional attributes of the brain, but no prior study has investigated whether TL can be linked to brain atrophy and white matter hyperintensities (WMHs); two prominent structural manifestations of brain aging.

    Methods: we investigated whether leukocyte TL was related to brain atrophy and WMHs in a sample of 102 non-demented individuals aged 64–75 years.

    Results: shorter TL was related to greater degree of subcortical atrophy (β = −0.217, P = 0.034), but not to cortical atrophy. Furthermore, TL was 371 bp shorter (P = 0.041) in participants exhibiting subcortical WMHs, and 552 bp shorter (P = 0.009) in older participants exhibiting periventricular WMHs.

    Conclusion: this study provides the first evidence of leukocyte TL being associated with cerebral subcortical atrophy and WMHs, lending further support to the concept of TL as a marker of biological aging, and in particular that of the aging brain.

  • 300.
    Wilhelms, Daniel Björk
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Närsjukvården i centrala Östergötland, Akutkliniken.
    Kirilov, Milen
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Mirrasekhian, Elahe
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Eskilsson, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Örtegren Kugelberg, Unn
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Klar, Christine
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Ridder, Dirk A.
    Medical University of Lubeck, Germany.
    Herschman, Harvey R.
    University of Calif Los Angeles, CA 90095 USA.
    Schwaninger, Markus
    Medical University of Lubeck, Germany.
    Blomqvist, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Engblom, David
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Deletion of Prostaglandin E-2 Synthesizing Enzymes in Brain Endothelial Cells Attenuates Inflammatory Fever2014Ingår i: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 34, nr 35, s. 11684-11690Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Fever is a hallmark of inflammatory and infectious diseases. The febrile response is triggered by prostaglandin E-2 synthesis mediated by induced expression of the enzymes cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase 1 (mPGES-1). The cellular source for pyrogenic PGE(2) remains a subject of debate; several hypotheses have been forwarded, including immune cells in the periphery and in the brain, as well as the brain endothelium. Here we generated mice with selective deletion of COX-2 and mPGES1 in brain endothelial cells. These mice displayed strongly attenuated febrile responses to peripheral immune challenge. In contrast, inflammation-induced hypoactivity was unaffected, demonstrating the physiological selectivity of the response to the targeted gene deletions. These findings demonstrate that PGE(2) synthesis in brain endothelial cells is critical for inflammation-induced fever.

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