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  • 1. Adage, Tiziana
    et al.
    Scheurink, Anton
    de Boer, Sietse
    de Vries, Koert
    Konsman, Jan Pieter
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Kuipers, Folkert
    Adan, Roger
    Baskin, Denis
    Schwartz, Michael
    van Dijk, Gertjan
    Hypothalamic, metabolic,and behavioral responses to pharmacological inhibition of CNS melanocortin signaling in rats.2001In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 21, p. 3639-3645Article in journal (Refereed)
  • 2.
    Adage, Tiziana
    et al.
    University of Groningen.
    Scheurink, Anton J W
    University of Groningen.
    de Boer, Sietse F
    University of Groningen.
    de Vries, Koert
    University of Groningen.
    Konsman, Jan Pieter
    Linköping University, Department of Biomedicine and Surgery. Linköping University, Faculty of Health Sciences.
    Kuipers, Folkert
    University Hospital, Groningen.
    Adan, Roger A H
    University of Utrecht.
    Baskin, Denis G
    University of Washington.
    Schwartz, Michael W
    University of Washington and Harborview Medical Center.
    van Dijk, Gertjan
    University of Groningen.
    Hypothalamic, metabolic, and behavioral responses to pharmacological inhibition of CNS melanocortin signaling in rats2001In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 21, no 10, p. 3639-3645Article in journal (Refereed)
    Abstract [en]

    The CNS melanocortin (MC) system is implicated as a mediator of the central effects of leptin, and reduced activity of the CNS MC system promotes obesity in both rodents and humans. Because activation of CNS MC receptors has direct effects on autonomic outflow and metabolism, we hypothesized that food intake- independent mechanisms contribute to development of obesity induced by pharmacological blockade of MC receptors in the brain and that changes in hypothalamic neuropeptidergic systems known to regulate weight gain [i. e., corticotropin-releasing hormone (CRH), cocaine- amphetamine- related transcript (CART), proopiomelanocortin (POMC), and neuropeptide Y (NPY)] would trigger this effect. Relative to vehicle- treated controls, third intracerebroventricular (i3vt) administration of the MC receptor antagonist SHU9119 to rats for 11 d doubled food and water intake (toward the end of treatment) and increased body weight (similar to 14%) and fat content (similar to 90%), hepatic glycogen content (similar to 40%), and plasma levels of cholesterol (similar to 48%), insulin (similar to 259%), glucagon (similar to 80%), and leptin (similar to 490%), whereas spontaneous locomotor activity and body temperature were reduced. Pair- feeding of i3vt SHU9119- treated animals to i3vt vehicle- treated controls normalized plasma levels of insulin, glucagon, and hepatic glycogen content, but only partially reversed the elevations of plasma cholesterol (similar to 31%) and leptin (similar to 104%) and body fat content (similar to 27%). Reductions in body temperature and locomotor activity induced by i3vt SHU9119 were not reversed by pair feeding, but rather were more pronounced. None of the effects found can be explained by peripheral action of the compound. The obesity effects occurred despite a lack in neuropeptide expression responses in the neuroanatomical range selected across the arcuate (i. e., CART, POMC, and NPY) and paraventricular (i. e., CRH) hypothalamus. The results indicate that reduced activity of the CNS MC pathway promotes fat deposition via both food intake- dependent and -independent mechanisms.

  • 3.
    Barbier, Estelle
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Tapocik, Jenica D.
    NIAAA, MD 20892 USA.
    Juergens, Nathan
    NIAAA, MD 20892 USA.
    Pitcairn, Caleb
    NIAAA, MD 20892 USA.
    Borich, Abbey
    NIAAA, MD 20892 USA.
    Schank, Jesse R.
    NIAAA, MD 20892 USA.
    Sun, Hui
    NIAAA, MD 20892 USA.
    Schuebel, Kornel
    NIAAA, MD 20892 USA.
    Zhou, Zhifeng
    NIAAA, MD 20892 USA.
    Yuan, Qiaoping
    NIAAA, MD 20892 USA.
    Vendruscolo, Leandro F.
    NIDA, MD 21224 USA.
    Goldman, David
    NIAAA, MD 20892 USA.
    Heilig, Markus
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    DNA Methylation in the Medial Prefrontal Cortex Regulates Alcohol-Induced Behavior and Plasticity2015In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 35, no 15, p. 6153-6164Article in journal (Refereed)
    Abstract [en]

    Recent studies have suggested an association between alcoholism and DNA methylation, a mechanism that can mediate long-lasting changes in gene transcription. Here, we examined the contribution of DNA methylation to the long-term behavioral and molecular changes induced by a history of alcohol dependence. In search of mechanisms underlying persistent rather than acute dependence-induced neuroadaptations, we studied the role of DNA methylation regulating medial prefrontal cortex (mPFC) gene expression and alcohol-related behaviors in rats 3 weeks into abstinence following alcohol dependence. Postdependent rats showed escalated alcohol intake, which was associated with increased DNA methylation as well as decreased expression of genes encoding synaptic proteins involved in neurotransmitter release in the mPFC. Infusion of the DNA methyltransferase inhibitor RG108 prevented both escalation of alcohol consumption and dependence-induced downregulation of 4 of the 7 transcripts modified in postdependent rats. Specifically, RG108 treatment directly reversed both downregulation of synaptotagmin 2 (Syt2) gene expression and hypermethylation on CpG#5 of its first exon. Lentiviral inhibition of Syt2 expression in the mPFC increased aversion-resistant alcohol drinking, supporting a mechanistic role of Syt2 in compulsive-like behavior. Our findings identified a functional role of DNA methylation in alcohol dependence-like behavioral phenotypes and a candidate gene network that may mediate its effects. Together, these data provide novel evidence for DNA methyltransferases as potential therapeutic targets in alcoholism.

  • 4.
    Bjartmar, Lisa
    et al.
    Cleveland Clinic Foundation.
    Huberman, Andrew
    Neurobiology, Stanford University School of Medicine, Stanford, California 94305, USA.
    Ullian, Erik
    Neurobiology, Stanford University School of Medicine, Stanford, California 94305, USA.
    Rentería, René
    8Department of Ophthalmology, University of California, San Francisco, San Francisco, California 94143, USA.
    Liu, Xiaoqin
    Neurosciences Research, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
    Xu, Weifeng
    Neurobiology and Psychiatry, Stanford University School of Medicine, Stanford, California 94305, USA.
    Prezioso, Jennifer
    Neurosciences and 2Ophthalmic Research, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
    Susman, Michael
    Neurobiology, Stanford University School of Medicine, Stanford, California 94305, USA.
    Stellwagen, David
    Neurobiology and Psychiatry, Stanford University School of Medicine, Stanford, California 94305, USA.
    Stokes, Caleb
    Neurobiology, Stanford University School of Medicine, Stanford, California 94305, USA.
    Cho, Richard
    Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
    Worley, Paul
    Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
    Malenka, Robert
    Neurobiology and Psychiatry, Stanford University School of Medicine, Stanford, California 94305, USA.
    Ball, Sherry
    Ophthalmic Research, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA/Research Service, Cleveland VA Medical Center, Cleveland, Ohio 44106, USA.
    Peachey, Neal
    Ophthalmic Research, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA/Research Service, Cleveland VA Medical Center, Cleveland, Ohio 44106, USA.
    Copenhagen, David
    Department of Ophthalmology, University of California, San Francisco, San Francisco, California 94143, USA.
    Chapman, Barbara
    Center for Neuroscience, University of California, Davis, California 95616, USA.
    Nakamoto, Masaru
    Neurosciences Research, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
    Barres, Ben
    Neurobiology, Stanford University School of Medicine, Stanford, California 94305, USA.
    Perin, Mark
    Neurosciences and 2Ophthalmic Research, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
    Neuronal pentraxins mediate synaptic refinement in the developing visual system2006In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 26, no 23, p. 6269-6281Article in journal (Refereed)
    Abstract [en]

    Neuronal pentraxins (NPs) define a family of proteins that are homologous to C-reactive and acute-phase proteins in the immune system and have been hypothesized to be involved in activity-dependent synaptic plasticity. To investigate the role of NPs in vivo, we generated mice that lack one, two, or all three NPs. NP1/2 knock-out mice exhibited defects in the segregation of eye-specific retinal ganglion cell (RGC) projections to the dorsal lateral geniculate nucleus, a process that involves activity-dependent synapse formation and elimination. Retinas from mice lacking NP1 and NP2 had cholinergically driven waves of activity that occurred at a frequency similar to that of wild-type mice, but several other parameters of retinal activity were altered. RGCs cultured from these mice exhibited a significant delay in functional maturation of glutamatergic synapses. Other developmental processes, such as pathfinding of RGCs at the optic chiasm and hippocampal long-term potentiation and long-term depression, appeared normal in NP-deficient mice. These data indicate that NPs are necessary for early synaptic refinements in the mammalian retina and dorsal lateral geniculate nucleus. We speculate that NPs exert their effects through mechanisms that parallel the known role of short pentraxins outside the CNS.

  • 5.
    Björnsdotter, Malin
    et al.
    Institute of Neuroscience and Physiology, University of Gothenburg, Göteborg, Sweden.
    Löken, Line
    Institute of Neuroscience and Physiology, University of Gothenburg, Göteborg, Sweden.
    Olausson, Håkan
    Institute of Neuroscience and Physiology, University of Gothenburg, Göteborg, Sweden.
    Vallbo, Åke
    Institute of Neuroscience and Physiology, University of Gothenburg, Göteborg, Sweden.
    Wessberg, Johan
    Institute of Neuroscience and Physiology, University of Gothenburg, Göteborg, Sweden.
    Somatotopic Organization of Gentle Touch Processing in the Posterior Insular Cortex2009In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 29, no 29, p. 9314-9320Article in journal (Refereed)
    Abstract [en]

    A network of thin (C and A delta) afferents relays various signals related to the physiological condition of the body, including sensations of gentle touch, pain, and temperature changes. Such afferents project to the insular cortex, where a somatotopic organization of responses to noxious and cooling stimuli was recently observed. To explore the possibility of a corresponding body-map topography in relation to gentle touch mediated through C tactile (CT) fibers, we applied soft brush stimuli to the right forearm and thigh of a patient (GL) lacking A beta afferents, and six healthy subjects during functional magnetic resonance imaging (fMRI). For improved fMRI analysis, we used a highly sensitive multivariate voxel clustering approach. A somatotopic organization of the left (contralateral) posterior insular cortex was consistently demonstrated in all subjects, including GL, with forearm projecting anterior to thigh stimulation. Also, despite denying any sense of touch in daily life, GL correctly localized 97% of the stimuli to the forearm or thigh in a forced-choice paradigm. The consistency in activation patterns across GL and the healthy subjects suggests that the identified organization reflects the central projection of CT fibers. Moreover, substantial similarities of the presently observed insular activation with that described for noxious and cooling stimuli solidify the hypothesized sensory-affective role of the CT system in the maintenance of physical well-being as part of a thin-afferent homeostatic network.

  • 6.
    Borgegard, Tomas
    et al.
    AstraZeneca, Sweden .
    Gustavsson, Susanne
    AstraZeneca, Sweden .
    Nilsson, Charlotte
    AstraZeneca, Sweden .
    Parpal, Santiago
    AstraZeneca, Sweden .
    Klintenberg, Rebecka
    AstraZeneca, Sweden .
    Berg, Anna-Lena
    AstraZeneca, Sweden .
    Rosqvist, Susanne
    AstraZeneca, Sweden .
    Serneels, Lutgarde
    University of Louvain, Belgium University of Louvain, Belgium VIB Centre Biol Disease VIB, Belgium .
    Svensson, Samuel
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Olsson, Fredrik
    AstraZeneca, Sweden .
    Jin, Shaobo
    Karolinska Institute, Sweden .
    Yan, Hongmei
    AstraZeneca, Sweden .
    Wanngren, Johanna
    Karolinska Institute, Sweden .
    Jureus, Anders
    AstraZeneca, Sweden .
    Ridderstad-Wollberg, Anna
    AstraZeneca, Sweden .
    Wollberg, Patrik
    AstraZeneca, Sweden .
    Stockling, Kenneth
    AstraZeneca, Sweden .
    Karlstrom, Helena
    Karolinska Institute, Sweden .
    Malmberg, Asa
    AstraZeneca, Sweden .
    Lund, Johan
    AstraZeneca, Sweden .
    I. Arvidsson, Per
    AstraZeneca, Sweden Uppsala University, Sweden University of KwaZulu Natal, South Africa .
    De Strooper, Bart
    University of Louvain, Belgium University of Louvain, Belgium VIB Centre Biol Disease VIB, Belgium .
    Lendahl, Urban
    Karolinska Institute, Sweden .
    Lundkvist, Johan
    Alzacure Fdn, Sweden AstraZeneca, Sweden Karolinska Institute, Sweden .
    Alzheimers Disease: Presenilin 2-Sparing gamma-Secretase Inhibition Is a Tolerable A beta Peptide-Lowering Strategy2012In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 32, no 48, p. 17297-17305Article in journal (Refereed)
    Abstract [en]

    gamma-Secretase inhibition represents a major therapeutic strategy for lowering amyloid beta (A beta) peptide production in Alzheimers disease (AD). Progress toward clinical use of gamma-secretase inhibitors has, however, been hampered due to mechanism-based adverse events, primarily related to impairment of Notch signaling. The gamma-secretase inhibitor MRK-560 represents an exception as it is largely tolerable in vivo despite displaying only a small selectivity between A beta production and Notch signaling in vitro. In exploring the molecular basis for the observed tolerability, we show that MRK-560 displays a strong preference for the presenilin 1(PS1) over PS2 subclass of gamma-secretases and is tolerable in wild-type mice but causes dose-dependent Notch-related side effect in PS2-deficient mice at drug exposure levels resulting in a substantial decrease in brain A beta levels. This demonstrates that PS2 plays an important role in mediating essential Notch signaling in several peripheral organs during pharmacological inhibition of PS1 and provide preclinical in vivo proof of concept for PS2-sparing inhibition as a novel, tolerable and efficacious gamma-secretase targeting strategy for AD.

  • 7.
    Case, Laura K.
    et al.
    NIH, MD 20892 USA.
    Laubacher, Claire M.
    NIH, MD 20892 USA.
    Olausson, Håkan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Wang, Binquan
    NIH, MD 20892 USA.
    Spagnolo, Primavera A.
    NIAAA, MD 20892 USA.
    Catherine Bushnell, M.
    NIH, MD 20892 USA.
    Encoding of Touch Intensity But Not Pleasantness in Human Primary Somatosensory Cortex2016In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 36, no 21, p. 5850-5860Article in journal (Refereed)
    Abstract [en]

    Growing interest in affective touch has delineated a neural network that bypasses primary somatosensory cortex (S1). Several recent studies, however, have cast doubt on the segregation of touch discrimination and affect, suggesting that S1 also encodes affective qualities. We used functional magnetic resonance imaging (fMRI) and repetitive transcranial magnetic stimulation (rTMS) to examine the role of S1 in processing touch intensity and pleasantness. Twenty-six healthy human adults rated brushing on the hand during fMRI. Intensity ratings significantly predicted activation in S1, whereas pleasantness ratings predicted activation only in the anterior cingulate cortex. Nineteen subjects also received inhibitory rTMS over right hemisphere S1 and the vertex (control). After S1 rTMS, but not after vertex rTMS, sensory discrimination was reduced and subjects with reduced sensory discrimination rated touch as more intense. In contrast, rTMS did not alter ratings of touch pleasantness. Our findings support divergent neural processing of touch intensity and pleasantness, with affective touch encoded outside of S1.

  • 8.
    Elander, Louise
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Engström, Linda
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Ruud, Johan
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Mackerlova, Ludmila
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Jakobsson, Per-Johan
    Karolinska Institute.
    Engblom, David
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Nilsberth, Camilla
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Blomqvist, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Inducible Prostaglandin E-2 Synthesis Interacts in a Temporally Supplementary Sequence with Constitutive Prostaglandin-Synthesizing Enzymes in Creating the Hypothalamic-Pituitary-Adrenal Axis Response to Immune Challenge2009In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 29, no 5, p. 1404-1413Article in journal (Refereed)
    Abstract [en]

    Inflammation-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis has been suggested to depend on prostaglandins, but the prostaglandin species and the prostaglandin-synthesizing enzymes that are responsible have not been fully identified. Here, we examined HPA axis activation in mice after genetic deletion or pharmacological inhibition of prostaglandin E-2-synthesizing enzymes, including cyclooxygenase-1 (Cox-1), Cox-2, and microsomal prostaglandin E synthase-1 (mPGES-1). After immune challenge by intraperitoneal injection of lipopolysaccharide, the rapid stress hormone responses were intact after Cox-2 inhibition and unaffected by mPGES-1 deletion, whereas unselective Cox inhibition blunted these responses, implying the involvement of Cox-1. However, mPGES-1-deficient mice showed attenuated transcriptional activation of corticotropin-releasing hormone (CRH) that was followed by attenuated plasma concentrations of adrenocorticotropic hormone and corticosterone. Cox-2 inhibition similarly blunted the delayed corticosterone response and further attenuated corticosterone release in mPGES-1 knock-out mice. The expression of the c-fos gene, an index of synaptic activation, was maintained in the paraventricular hypothalamic nucleus and its brainstem afferents both after unselective and Cox-2 selective inhibition as well as in Cox-1, Cox-2, and mPGES-1 knock-out mice. These findings point to a mechanism by which ( 1) neuronal afferent signaling via brainstem autonomic relay nuclei and downstream Cox-1-dependent prostaglandin release and ( 2) humoral, CRH transcription-dependent signaling through induced Cox-2 and mPGES-1 elicited PGE(2) synthesis, shown to occur in brain vascular cells, play distinct, but temporally supplementary roles for the stress hormone response to inflammation.

  • 9.
    Eskilsson, Anna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Matsuwaki, Takashi
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Shionoya, Kiseko
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Mirrasekhian, Elahe
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Zajdel, Joanna
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Schwaninger, Markus
    University of Lubeck, Germany.
    Engblom, David
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Blomqvist, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Immune-Induced Fever Is Dependent on Local But Not Generalized Prostaglandin E-2 Synthesis in the Brain2017In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 37, no 19, p. 5035-5044Article in journal (Refereed)
    Abstract [en]

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

  • 10.
    Eskilsson, Anna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Mirrasekhian, Elahe
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Dufour, Sylvie
    Institute Curie, France.
    Schwaninger, Markus
    Medical University of Lubeck, Germany.
    Engblom, David
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Blomqvist, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Immune-Induced Fever Is Mediated by IL-6 Receptors on Brain Endothelial Cells Coupled to STAT3-Dependent Induction of Brain Endothelial Prostaglandin Synthesis2014In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 34, no 48, p. 15957-15961Article in journal (Refereed)
    Abstract [en]

    The cytokine IL-6, which is released upon peripheral immune challenge, is critical for the febrile response, but the mechanism by which IL-6 is pyrogenic has remained obscure. Herewegenerated mice with deletion of themembranebound IL-6 receptor alpha (IL-6R alpha) onneural cells, on peripheral nerves, on fine sensory afferent fibers, and on brain endothelial cells, respectively, and examined its role for the febrile response to peripherally injected lipopolysaccharide. We show that IL-6R alpha on neural cells, peripheral nerves, and fine sensory afferents are dispensable for the lipopolysaccharide-induced fever, whereas IL-6R alpha in the brain endothelium plays an important role. Hence deletion of IL-6R alpha on brain endothelial cells strongly attenuated the febrile response, and also led to reduced induction of the prostaglandin synthesizing enzyme Cox-2 in the hypothalamus, the temperature-regulating center in the brain, as well as reduced expression of SOCS3, suggesting involvement of the STAT signaling pathway. Furthermore, deletion of STAT3 in the brain endothelium also resulted in attenuated fever. These data show that IL-6, when endogenously released during systemic inflammation, is pyrogenic by binding to IL-6R alpha on brain endothelial cells to induce prostaglandin synthesis in these cells, probably in concerted action with other peripherally released cytokines.

  • 11. Felix, Richard A
    et al.
    Fridberger, Anders
    Karolinska Institutet / Karolinska University Hospital, Stockholm, Sweden.
    Leijon, Sara
    Berrebi, Albert S
    Magnusson, Anna K
    Sound rhythms are encoded by postinhibitory rebound spiking in the superior paraolivary nucleus2011In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 31, no 35, p. 12566-12578Article in journal (Refereed)
    Abstract [en]

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

  • 12.
    Fieblinger, Tim
    et al.
    Lund University, Sweden .
    Sebastianutto, Irene
    Lund University, Sweden .
    Alcacer, Cristina
    Lund University, Sweden .
    Bimpisidis, Zisis
    Lund University, Sweden .
    Maslava, Natallia
    Lund University, Sweden .
    Sandberg, Sabina
    Lund University, Sweden .
    Engblom, David
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Cenci, M. Angela
    Lund University, Sweden .
    Mechanisms of Dopamine D1 Receptor-Mediated ERK1/2 Activation in the Parkinsonian Striatum and Their Modulation by Metabotropic Glutamate Receptor Type 52014In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 34, no 13, p. 4728-4740Article in journal (Refereed)
    Abstract [en]

    In animal models of Parkinsons disease, striatal overactivation of ERK1/2 via dopamine (DA) D1 receptors is the hallmark of a supersensitive molecular response associated with dyskinetic behaviors. Here we investigate the pathways involved in D1 receptor-dependent ERK1/2 activation using acute striatal slices from rodents with unilateral 6-hydroxydopamine (6-OHDA) lesions. Application of the dopamine D1-like receptor agonist SKF38393 induced ERK1/2 phosphorylation and downstream signaling in the DA-denervated but not the intact striatum. This response was mediated through a canonical D1R/PKA/MEK1/2 pathway and independent of ionotropic glutamate receptors but blocked by antagonists of L-type calcium channels. Coapplication of an antagonist of metabotropic glutamate receptor type 5 (mGluR5) or its downstream signaling molecules (PLC, PKC, IP3 receptors) markedly attenuated SKF38393-induced ERK1/2 activation. The role of striatal mGluR5 in D1-dependent ERK1/2 activation was confirmed in vivo in 6-OHDA-lesioned animals treated systemically with SKF38393. In one experiment, local infusion of the mGluR5 antagonistMTEPin the DA-denervated rat striatum attenuated the activation of ERK1/2 signaling by SKF38393. In another experiment, 6-OHDA lesions were applied to transgenic mice with a cell-specific knockdown of mGluR5 in D1 receptor-expressing neurons. These mice showed a blunted striatal ERK1/2 activation in response to SFK38393 treatment. Our results reveal that D1-dependent ERK1/2 activation in the DA-denervated striatum depends on a complex interaction between PKA-and Ca2+ -dependent signaling pathways that is critically modulated by striatal mGluR5.

  • 13.
    Flock, Å.
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Flock, B.
    Karolinska Institutet, Stockholm, Sweden.
    Fridberger, Anders
    Karolinska Institutet, Stockholm, Sweden.
    Scarfone, E.
    Université Montpellier II, France.
    Ulfendahl, M.
    Karolinska Sjukhuset, Stockholm, Sweden .
    Supporting cells contribute to control of hearing sensitivity1999In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 19, no 11, p. 4498-4507Article in journal (Refereed)
    Abstract [en]

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

  • 14.
    Fridberger, Anders
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Boutet de Monvel, Jacques
    Karolinska Institutet, Stockholm, Sweden.
    Ulfendahl, Mats
    Karolinska Institutet, Stockholm, Sweden.
    Internal shearing within the hearing organ evoked by basilar membrane motion2002In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 22, no 22, p. 9850-9857Article in journal (Refereed)
    Abstract [en]

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

  • 15.
    Fridberger, Anders
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Boutet de Monvel, Jacques
    Karolinska Institutet, Stockholm, Sweden.
    Zheng, Jiefu
    Karolinska Institutet, Stockholm, Sweden.
    Hu, Ning
    Oregon Health and Science University, Oregon Hearing Research Center, Portland, USA.
    Zou, Yuan
    Oregon Health and Science University, Oregon Hearing Research Center, Portland, USA.
    Ren, Tianying
    Oregon Health and Science University, Oregon Hearing Research Center, Portland, USA.
    Nuttall, Alfred
    Oregon Health and Science University, Oregon Hearing Research Center, Portland, USA.
    Organ of Corti potentials and the motion of the basilar membrane2004In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 24, no 45, p. 10057-10063Article in journal (Refereed)
    Abstract [en]

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

  • 16.
    Gehlert, Donald R.
    et al.
    Eli Lilly and Company, Indianapolis, IN, USA.
    Cippitelli, Andrea
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Thorsell, Annika
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Lê, Anh Dzung
    University of Toronto, Canada.
    Hipskind, Philip A
    Eli Lilly and Company, Indianapolis, IN, USA.
    Hamdouchi, Chafiq
    Eli Lilly and Company, Indianapolis, IN, USA.
    Lu, Jianliang
    Eli Lilly and Company, Indianapolis, IN, USA.
    Hembre, Erik J.
    Eli Lilly and Company, Indianapolis, IN, USA.
    Cramer, Jeffrey
    Eli Lilly and Company, Indianapolis, IN, USA.
    Song, Min
    Eli Lilly and Company, Indianapolis, IN, USA.
    McKinzie, David
    Eli Lilly and Company, Indianapolis, IN, USA.
    Morin, Michelle
    Eli Lilly and Company, Indianapolis, IN, USA.
    Ciccocioppo, Roberto
    University of Camerino, Italy.
    Heilig, Markus
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    3-(4-Chloro-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethylpropyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine: a novel brain-penetrant, orally available corticotropin-releasing factor receptor 1 antagonist with efficacy in animal models of alcoholism2007In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 27, no 10, p. 2718-2726Article in journal (Refereed)
    Abstract [en]

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

  • 17.
    Genevsky, Alexander
    et al.
    Stanford University, CA USA .
    Västfjäll, Daniel
    Linköping University, Department of Behavioural Sciences and Learning, Psychology. Linköping University, Faculty of Arts and Sciences.
    Slovic, Paul
    Decis Research, OR USA .
    Knutson, Brian
    Stanford University, CA USA .
    Neural Underpinnings of the Identifiable Victim Effect: Affect Shifts Preferences for Giving2013In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 33, no 43, p. 17188-17196Article in journal (Refereed)
    Abstract [en]

    The "identifiable victim effect" refers to peoples tendency to preferentially give to identified versus anonymous victims of misfortune, and has been proposed to partly depend on affect. By soliciting charitable donations from human subjects during behavioral and neural (i.e., functional magnetic resonance imaging) experiments, we sought to determine whether and how affect might promote the identifiable victim effect. Behaviorally, subjects gave more to orphans depicted by photographs versus silhouettes, and their shift in preferences was mediated by photograph-induced feelings of positive arousal, but not negative arousal. Neurally, while photographs versus silhouettes elicited activity in widespread circuits associated with facial and affective processing, only nucleus accumbens activity predicted and could statistically account for increased donations. Together, these findings suggest that presenting evaluable identifiable information can recruit positive arousal, which then promotes giving. We propose that affect elicited by identifiable stimuli can compel people to give more to strangers, even despite costs to the self.

  • 18.
    Larsson, Max
    et al.
    Department of Experimental Medical Science, Division of Neuroscience, and Lund University Pain Research Center, Lund University, Lund, Sweden.
    Broman, Jonas
    Department of Experimental Medical Science, Division of Neuroscience, and Lund University Pain Research Center, Lund University, Lund, Sweden.
    Pathway-specific bidirectional regulation of Ca2+/calmodulin-dependent protein kinase II at spinal nociceptive synapses after acute noxious stimulation.2006In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 26, no 16, p. 4198-4205Article in journal (Refereed)
    Abstract [en]

    An intensely painful stimulus may lead to hyperalgesia, the enhanced sensation of subsequent painful stimuli. This is commonly believed to involve facilitated transmission of sensory signals in the spinal cord, possibly by a long-term potentiation-like mechanism. However, plasticity of identified synapses in intact hyperalgesic animals has not been reported. Here, we show, using neuronal tracing and postembedding immunogold labeling, that after acute noxious stimulation (hindpaw capsaicin injections), immunolabeling of Ca2+/calmodulin-dependent protein kinase II (CaMKII) and of CaMKII phosphorylated at Thr(286/287) (pCaMKII) are upregulated postsynaptically at synapses established by peptidergic primary afferent fibers in the superficial dorsal horn of intact rats. In contrast, postsynaptic pCaMKII immunoreactivity was instead downregulated at synapses of nonpeptidergic primary afferent C-fibers; this loss of pCaMKII immunolabel occurred selectively at distances greater than approximately 20 nm from the postsynaptic membrane and was accompanied by a smaller reduction in total CaMKII contents of these synapses. Both pCaMKII and CaMKII immunogold labeling were unaffected at synapses formed by presumed low-threshold mechanosensitive afferent fibers. Thus, distinct molecular modifications, likely indicative of plasticity of synaptic strength, are induced at different populations of presumed nociceptive primary afferent synapse by intense noxious stimulation, suggesting a complex modulation of parallel nociceptive pathways in inflammatory hyperalgesia. Furthermore, the activity-induced loss of certain postsynaptic pools of autophosphorylated CaMKII at previously unmanipulated synapses supports a role for the kinase in basal postsynaptic function.

  • 19.
    Larsson, Max
    et al.
    Department of Experimental Medical Science, Division of Neuroscience, Pain Research Center, Lund University, Lund, Sweden; Department of Anatomy and Centre for Molecular Biology and Neuroscience, University of Oslo, Oslo, Norway.
    Broman, Jonas
    Department of Experimental Medical Science, Division of Neuroscience, Pain Research Center, Lund University, Lund, Sweden; Department of Neuroscience, Karolinska Institute, Stockholm, Sweden.
    Translocation of GluR1-containing AMPA receptors to a spinal nociceptive synapse during acute noxious stimulation.2008In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 28, no 28, p. 7084-7090Article in journal (Refereed)
    Abstract [en]

    Potentiation of spinal nociceptive transmission by synaptic delivery of AMPA receptors, via an NMDA receptor- and Ca(2+)/calmodulin-dependent protein kinase II (CaMKII)-dependent pathway, has been proposed to underlie certain forms of hyperalgesia, the enhanced pain sensitivity that may accompany inflammation or tissue injury. However, the specific synaptic populations that may be subject to such plasticity have not been identified. Using neuronal tracing and postembedding immunogold labeling, we show that a model of acute inflammatory hyperalgesia is associated with an elevated density of GluR1-containing AMPA receptors, as well as an increased synaptic ratio of GluR1 to GluR2/3 subunits, at synapses established by C-fibers that lack the neuropeptide substance P. A more subtle increase in GluR1 immunolabeling was noted at synapses formed by substance P-containing nociceptors. No changes in either GluR1 or GluR2/3 contents were observed at synapses formed by low-threshold mechanosensitive primary afferent fibers. These results contrast with our previous observations in the same pain model of increased and decreased levels of activated CaMKII at synapses formed by peptidergic and nonpeptidergic nociceptive fibers, respectively, suggesting that the observed redistribution of AMPA receptor subunits does not depend on postsynaptic CaMKII activity. The present ultrastructural evidence of topographically specific, activity-dependent insertion of GluR1-containing AMPA receptors at a central synapse suggests that potentiation of nonpeptidergic C-fiber synapses by this mechanism contributes to inflammatory pain.

  • 20.
    Moriceau, Stephanie
    et al.
    Emotional Brain Institute, Nathan Kline Institute, Orangeburg, New York, USA, / Child and Adolescent Psychiatry, Child Study Center, New York University Langone Medical Center, New York, New York, USA, Department of Zoology, University of Oklahoma, Norman, Oklahoma, USA.
    Shionoya, Kiseko
    Department of Zoology, University of Oklahoma, Norman, Oklahoma, USA / Laboratory Neurosciences Sensorielles, Centre National de la Recherche Scientifique, Universite Lyon, 69007 Lyon, France.
    Jakubs, Katherine
    Department of Zoology, University of Oklahoma, Norman, Oklahoma, USA / National Institutes of Health, Bethesda, Maryland, USA.
    Sullivan, Regina M.
    Emotional Brain Institute, Nathan Kline Institute, Orangeburg, New York, USA / Child and Adolescent Psychiatry, Child Study Center, New York University Langone Medical Center, New York, New York, USA / New York University Center for Neural Science, New York, New York, USA / Department of Zoology, University of Oklahoma, Norman, Oklahoma, USA.
    Early-Life Stress Disrupts Attachment Learning: The Role of Amygdala Corticosterone, Locus Ceruleus Corticotropin Releasing Hormone, and Olfactory Bulb Norepinephrine2009In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 29, no 50, p. 15745-15755Article in journal (Refereed)
    Abstract [en]

    Infant rats require maternal odor learning to guide pups’ proximity-seeking of the mother and nursing. Maternal odor learning occurs using a simple learning circuit including robust olfactory bulb norepinephrine (NE), release from the locus ceruleus (LC), and amygdala suppression by low corticosterone (CORT). Early-life stress increases NE but also CORT, and we questioned whether early-life stress disrupted attachment learning and its neural correlates [2-deoxyglucose (2-DG) autoradiography]. Neonatal rats were normally reared or stressed-reared during the first 6 d of life by providing the mother with insufficient bedding for nest building and were odor–0.5 mA shock conditioned at 7 d old. Normally reared paired pups exhibited typical odor approach learning and associated olfactory bulb enhanced 2-DG uptake. However, stressed-reared pups showed odor avoidance learning and both olfactory bulb and amygdala 2-DG uptake enhancement. Furthermore, stressed-reared pups had elevated CORT levels, and systemic CORT antagonist injection reestablished the age-appropriate odor-preference learning, enhanced olfactory bulb, and attenuated amygdala 2-DG. We also assessed the neural mechanism for stressed-reared pups’ abnormal behavior in a more controlled environment by injecting normally reared pups with CORT. This was sufficient to produce odor aversion, as well as dual amygdala and olfactory bulb enhanced 2-DG uptake. Moreover, we assessed a unique cascade of neural events for the aberrant effects of stress rearing: the amygdala–LC–olfactory bulb pathway. Intra-amygdala CORT or intra-LC corticotropin releasing hormone (CRH) infusion supported aversion learning with intra-LC CRH infusion associated with increased olfactory bulb NE (microdialysis). These results suggest that early-life stress disturbs attachment behavior via a unique cascade of events (amygdala–LC–olfactory bulb).

  • 21.
    Morrison, India
    et al.
    Department of Clinical Neurophysiology, Sahlgrenska University Hospital, Gothenburg, Sweden; Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
    Björnsdotter, Malin
    Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
    Olausson, Håkan
    Department of Clinical Neurophysiology, Sahlgrenska University Hospital, Gothenburg, Sweden; Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
    Vicarious responses to social touch in posterior insular cortex are tuned to pleasant caressing speeds.2011In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 31, no 26, p. 9554-9562Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Affective touch carries strong significance for social mammals, including humans. Gentle, dynamic touch of a kind that occurs during social interactions is preferentially encoded by a distinct neural pathway involving tactile C (CT) afferents, a type of unmyelinated afferent nerve found exclusively in hairy skin. CT afferents increase firing when the skin is stroked at a pleasant, caress-like speed of ∼3 cm/s, and their discharge frequency correlates with the subjective hedonic experience of the caress. In humans, the posterior insula is a cortical target for CT afferents. Since the potential social relevance of affective touch extends to the touch interactions of others, we postulated that information from CT afferents in posterior insular cortex provides a basis for encoding observed caresses.

    RESULTS: In two experiments, we exploited CT afferents' functionally unique tuning curve for stroking speed, demonstrating that a speed optimal for eliciting CT discharge (3 cm/s) also gives rise to higher BOLD responses in posterior insula than a nonoptimal speed (30 cm/s). When participants viewed videos of others' arms being stroked at CT-optimal versus -nonoptimal speeds, the posterior insula showed a similar response as to directly felt touch. Further, this region's response was specific for social interactions, showing no CT-related modulation for nonsocial dynamic-touch videos.

    CONCLUSIONS: These findings provide direct evidence for a functional relationship between CT signaling and processing in posterior insular cortex. Such selective tuning for CT-optimal signals in insula may allow recognition of the hedonic relevance of a merely observed caress.

  • 22.
    Nath, Sangeeta
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Agholme, Lotta
    Linköping University, Department of Clinical and Experimental Medicine, Geriatric. Linköping University, Faculty of Health Sciences.
    Roshan, Firoz
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Granseth, Björn
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Marcusson, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Geriatric. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Geriatric Medicine.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Spreading of Neurodegenerative Pathology via Neuron-to-Neuron Transmission of beta-Amyloid2012In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 32, no 26, p. 8767-8777Article in journal (Refereed)
    Abstract [en]

    Alzheimers disease (AD) is the major cause of dementia. During the development of AD, neurofibrillary tangles progress in a fixed pattern, starting in the transentorhinal cortex followed by the hippocampus and cortical areas. In contrast, the deposition of beta-amyloid (A beta) plaques, which are the other histological hallmark of AD, does not follow the same strict spatiotemporal pattern, and it correlates poorly with cognitive decline. Instead, soluble A beta oligomers have received increasing attention as probable inducers of pathogenesis. In this study, we use microinjections into electrophysiologically defined primary hippocampal rat neurons to demonstrate the direct neuron-to-neuron transfer of soluble oligomeric A beta. Additional studies conducted in a human donor-acceptor cell model show that this A beta transfer depends on direct cellular connections. As the transferred oligomers accumulate, acceptor cells gradually show beading of tubulin, a sign of neurite damage, and gradual endosomal leakage, a sign of cytotoxicity. These observations support that intracellular A beta oligomers play a role in neurodegeneration, and they explain the manner in which A beta can drive disease progression, even if the extracellular plaque load is poorly correlated with the degree of cognitive decline. Understanding this phenomenon sheds light on the pathophysiological mechanism of AD progression. Additional elucidation will help uncover the detailed mechanisms responsible for the manner in which AD progresses via anatomical connections and will facilitate the development of new strategies for stopping the progression of this incapacitating disease.

  • 23.
    Novotny, Renata
    et al.
    University of Tubingen, Germany; German Centre Neurodegenerat Disease, Germany; University of Tubingen, Germany.
    Langer, Franziska
    University of Tubingen, Germany; German Centre Neurodegenerat Disease, Germany.
    Mahler, Jasmin
    University of Tubingen, Germany; German Centre Neurodegenerat Disease, Germany; University of Tubingen, Germany.
    Skodras, Angelos
    University of Tubingen, Germany; German Centre Neurodegenerat Disease, Germany.
    Vlachos, Andreas
    Goethe University of Frankfurt, Germany.
    Wegenast-Braun, Bettina M.
    University of Tubingen, Germany; German Centre Neurodegenerat Disease, Germany.
    Kaeser, Stephan A.
    University of Tubingen, Germany; German Centre Neurodegenerat Disease, Germany.
    Neher, Jonas J.
    University of Tubingen, Germany; German Centre Neurodegenerat Disease, Germany.
    Eisele, Yvonne S.
    University of Tubingen, Germany; German Centre Neurodegenerat Disease, Germany.
    Pietrowski, Marie J.
    University of Freiburg, Germany.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Deller, Thomas
    Goethe University of Frankfurt, Germany.
    Staufenbiel, Matthias
    University of Tubingen, Germany; German Centre Neurodegenerat Disease, Germany.
    Heimrich, Bernd
    University of Freiburg, Germany.
    Jucker, Mathias
    University of Tubingen, Germany; German Centre Neurodegenerat Disease, Germany.
    Conversion of Synthetic A beta to In Vivo Active Seeds and Amyloid Plaque Formation in a Hippocampal Slice Culture Model2016In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 36, no 18, p. 5084-5093Article in journal (Refereed)
    Abstract [en]

    The aggregation of amyloid-beta peptide (A beta) inbrain is an early event and hallmark of Alzheimers disease (AD). We combined the advantages of in vitro and in vivo approaches to study cerebral beta-amyloidosis by establishing a long-term hippocampal slice culture(HSC) model. While no A beta deposition was noted in untreated HSCs of postnatal A beta precursor protein transgenic (APP tg) mice, A beta deposition emerged in HSCs when cultures were treated once with brain extract from aged APP tg mice and the culture medium was continuously supplemented with synthetic A beta. Seeded A beta deposition was also observed under the same conditions in HSCs derived from wild-type or App-null mice but in no comparable way when HSCs were fixed before cultivation. Both the nature of the brain extract and the synthetic A beta species determined the conformational characteristics of HSCA beta deposition. HSCA beta deposits induced a microglia response, spine loss, and neuritic dystrophy but no obvious neuron loss. Remarkably, in contrast to in vitro aggregated synthetic A beta, homogenates of A beta deposits containing HSCs induced cerebral beta-amyloidosis upon intracerebral inoculation into young APP tg mice. Our results demonstrate that a living cellular environment promotes the seeded conversion of synthetic A beta into a potent in vivo seeding-active form.

  • 24.
    Pantazis, Antonios
    et al.
    Department of Physiology, Development, and Neuroscience, University of Cambridge, Cambridge CB2 3DY, United Kingdom.
    Segaran, Ashvina
    Department of Physiology, Development, and Neuroscience, University of Cambridge, Cambridge CB2 3DY, United Kingdom.
    Liu, Che-Hsiung
    Department of Physiology, Development, and Neuroscience, University of Cambridge, Cambridge CB2 3DY, United Kingdom.
    Nikolaev, Anton
    Department of Biomedical Science, University of Sheffield, Sheffield S10 2TN, United Kingdom.
    Rister, Jens
    Lehrstuhl für Genetik und Neurobiologie, Universität Würzburg, 97074 Würzburg, Germany.
    Thum, Andreas S.
    Lehrstuhl für Genetik und Neurobiologie, Universität Würzburg, 97074 Würzburg, Germany.
    Roeder, Thomas
    Zoologisches Institut, Abteilung Zoophysiologie, Christian-Albrechts-Universität, D-24098 Kiel, Germany.
    Semenov, Eugene
    Department of Molecular Neurobiology, Drosophila Neurogenetics Laboratory, Institute of Molecular Biology, Bulgarian Academy of Sciences, Sofia 1113, Bulgaria.
    Juusola, Mikko
    Department of Biomedical Science, University of Sheffield, Sheffield S10 2TN, United Kingdom.
    Hardie, Roger C.
    Department of Physiology, Development, and Neuroscience, University of Cambridge, Cambridge CB2 3DY, United Kingdom.
    Distinct Roles for Two Histamine Receptors (hclA and hclB) at the Drosophila Photoreceptor Synapse2008In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 28, no 29, p. 7250-7259Article in journal (Refereed)
    Abstract [en]

    Histamine (HA) is the photoreceptor neurotransmitter in arthropods, directly gating chloride channels on large monopolar cells (LMCs), postsynaptic to photoreceptors in the lamina. Two histamine-gated channel genes that could contribute to this channel in Drosophila are hclA (also known as ort) and hclB (also known as hisCl1), both encoding novel members of the Cys-loop receptor superfamily. Drosophila S2 cells transfected with these genes expressed both homomeric and heteromeric histamine-gated chloride channels. The electrophysiological properties of these channels were compared with those from isolated Drosophila LMCs. HCLA homomers had nearly identical HA sensitivity to the native receptors (EC50 = 25 ÎŒm). Single-channel analysis revealed further close similarity in terms of single-channel kinetics and subconductance states (~25, 40, and 60 pS, the latter strongly voltage dependent). In contrast, HCLB homomers and heteromeric receptors were more sensitive to HA (EC50 = 14 and 1.2 ÎŒm, respectively), with much smaller single-channel conductances (~4 pS). Null mutations of hclA (ortUS6096) abolished the synaptic transients in the electroretinograms (ERGs). Surprisingly, the ERG “on” transients in hclB mutants transients were approximately twofold enhanced, whereas intracellular recordings from their LMCs revealed altered responses with slower kinetics. However, HCLB expression within the lamina, assessed by both a GFP (green fluorescent protein) reporter gene strategy and mRNA tagging, was exclusively localized to the glia cells, whereas HCLA expression was confirmed in the LMCs. Our results suggest that the native receptor at the LMC synapse is an HCLA homomer, whereas HCLB signaling via the lamina glia plays a previously unrecognized role in shaping the LMC postsynaptic response.

  • 25.
    Ramamoorthy, Sripriya
    et al.
    Oregon Health and Science University, Portland, USA .
    Zha, Dingjun
    Oregon Health and Science University, Portland, USA.
    Chen, Fangyi
    Oregon Health and Science University, Portland, USA.
    Jacques, Steven L.
    Oregon Health and Science University, Portland, USA.
    Wang, Ruikang
    University of Washington, USA .
    Choudhury, Niloy
    Oregon Health and Science University, Portland, USA.
    Nuttall, Alfred L.
    Oregon Health and Science University, Portland, USA.
    Fridberger, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Filtering of Acoustic Signals within the Hearing Organ2014In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 34, no 27, p. 9051-9058Article in journal (Refereed)
    Abstract [en]

    The detection of sound by the mammalian hearing organ involves a complex mechanical interplay among different cell types. The inner hair cells, which are the primary sensory receptors, are stimulated by the structural vibrations of the entire organ of Corti. The outer hair cells are thought to modulate these sound-evoked vibrations to enhance hearing sensitivity and frequency resolution, but it remains unclear whether other structures also contribute to frequency tuning. In the current study, sound-evoked vibrations were measured at the stereociliary side of inner and outer hair cells and their surrounding supporting cells, using optical coherence tomography interferometry in living anesthetized guinea pigs. Our measurements demonstrate the presence of multiple vibration modes as well as significant differences in frequency tuning and response phase among different cell types. In particular, the frequency tuning at the inner hair cells differs from other cell types, causing the locus of maximum inner hair cell activation to be shifted toward the apex of the cochlea compared with the outer hair cells. These observations show that additional processing and filtering of acoustic signals occur within the organ of Corti before inner hair cell excitation, representing a departure from established theories.

  • 26.
    Rieker, Claus
    et al.
    University of Heidelberg.
    Engblom, David
    University of Heidelberg.
    Kreiner, Grzegorz
    University of Heidelberg.
    Domanskyi, Andrii
    University of Heidelberg.
    Schober, Andreas
    University of Heidelberg.
    Stotz, Stefanie
    University of Heidelberg.
    Neumann, Manuela
    Universitätsspital Zürich, Switzerland .
    (Yuan, Xuejun
    University of Heidelberg.
    Grummt, Ingrid
    University of Heidelberg.
    Schuetz, Guenther
    University of Heidelberg.
    Parlato, Rosanna
    University of Heidelberg.
    Nucleolar Disruption in Dopaminergic Neurons Leads to Oxidative Damage and Parkinsonism through Repression of Mammalian Target of Rapamycin Signaling2011In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 31, no 2, p. 453-460Article in journal (Refereed)
    Abstract [en]

    The nucleolus represents an essential stress sensor for the cell. However, the molecular consequences of nucleolar damage and their possible link with neurodegenerative diseases remain to be elucidated. Here, we show that nucleolar damage is present in both genders in Parkinson's disease (PD) and in the pharmacological PD model induced by the neurotoxin 1,2,3,6-tetrahydro-1-methyl-4-phenylpyridine hydrochloride (MPTP). Mouse mutants with nucleolar disruption restricted to dopaminergic (DA) neurons show phenotypic alterations that resemble PD, such as progressive and differential loss of DA neurons and locomotor abnormalities. At the molecular level, nucleolar disruption results in increased p53 levels and downregulation of mammalian target of rapamycin (mTOR) activity, leading to mitochondrial dysfunction and increased oxidative stress, similar to PD. In turn, increased oxidative stress induced by MPTP causes mTOR and ribosomal RNA synthesis inhibition. Collectively, these observations suggest that the interplay between nucleolar dysfunction and increased oxidative stress, involving p53 and mTOR signaling, may constitute a destructive axis in experimental and sporadic PD.

  • 27.
    Seki, Soju
    et al.
    Univ Calif Los Angeles, CA 90095 USA.
    Yamamoto, Toru
    Univ Calif Los Angeles, CA 90095 USA.
    Quinn, Kiara
    Univ Calif Los Angeles, CA 90095 USA.
    Spigelman, Igor
    Univ Calif Los Angeles, CA 90095 USA; Univ Calif Los Angeles, CA 90095 USA.
    Pantazis, Antonios
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Univ Calif Los Angeles, CA 90095 USA.
    Olcese, Riccardo
    Univ Calif Los Angeles, CA 90095 USA.
    Wiedau-Pazos, Martina
    Univ Calif Los Angeles, CA 90095 USA.
    Chandler, Scott H.
    Univ Calif Los Angeles, CA 90095 USA.
    Venugopal, Sharmila
    Univ Calif Los Angeles, CA 90095 USA.
    Circuit-Specific Early Impairment of Proprioceptive Sensory Neurons in the SOD1(G93A) Mouse Model for ALS2019In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 39, no 44, p. 8798-8815Article in journal (Refereed)
    Abstract [en]

    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease in which motor neurons degenerate, resulting in muscle atrophy, paralysis, and fatality. Studies using mouse models of ALS indicate a protracted period of disease development with progressive motor neuron pathology, evident as early as embryonic and postnatal stages. Key missing information includes concomitant alterations in the sensorimotor circuit essential for normal development and function of the neuromuscular system. Leveraging unique brainstem circuitry, we show in vitro evidence for reflex circuit-specific postnatal abnormalities in the jaw proprioceptive sensory neurons in the well-studied SOD1(G)(93A) mouse. These include impaired and arrhythmic action potential burst discharge associated with a deficit in Nav 1.6 Na+ channels. However, the mechanoreceptive and nociceptive trigeminal ganglion neurons and the visual sensory retinal ganglion neurons were resistant to excitability changes in age-matched SOD1(G)(93A )mice. Computational modeling of the observed disruption in sensory patterns predicted asynchronous self-sustained motor neuron discharge suggestive of imminent reflexive defects, such as muscle fasciculations in ALS. These results demonstrate a novel reflex circuit-specific proprioceptive sensory abnormality in ALS.

  • 28.
    Sigurdson, Christina J
    et al.
    University of California San Diego.
    Joshi-Barr, Shivanjali
    University of California San Diego.
    Bett, Cyrus
    University of California San Diego.
    Winson, Olivia
    University of California San Diego.
    Manco, Giuseppe
    University of Vet Medical Vienna.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Margalith, Ilan
    Prionics AG.
    Peretz, David
    University of California San Diego.
    Hornemann, Simone
    Swiss Federal Institute of Technology.
    Wuethrich, Kurt
    Scripps Research Institute.
    Aguzzi, Adriano
    University of Spital Zurich.
    Spongiform Encephalopathy in Transgenic Mice Expressing a Point Mutation in the beta 2-alpha 2 Loop of the Prion Protein2011In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 31, no 39, p. 13840-13847Article in journal (Refereed)
    Abstract [en]

    Transmissible spongiform encephalopathies are fatal neurodegenerative diseases attributed to misfolding of the cellular prion protein, PrP(C), into a beta-sheet-rich, aggregated isoform, PrP(Sc). We previously found that expression of mouse PrP with the two amino acid substitutions S170N and N174T, which result in high structural order of the beta 2-alpha 2 loop in the NMR structure at pH 4.5 and 20 C, caused transmissible de novo prion disease in transgenic mice. Here we report that expression of mouse PrP with the single-residue substitution D167S, which also results in a structurally well ordered beta 2-alpha 2 loop at 20 degrees C, elicits spontaneous PrP aggregation in vivo. Transgenic mice expressing PrP(D167S) developed a progressive encephalopathy characterized by abundant PrP plaque formation, spongiform change, and gliosis. These results add to the evidence that the beta 2-alpha 2 loop has an important role in intermolecular interactions, including that it may be a key determinant of prion protein aggregation.

  • 29.
    Thorsell, Annika
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    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 Rats2013In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 33, no 24, p. 10132-10142Article in journal (Refereed)
    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.

  • 30.
    Wild, Conor J
    et al.
    Queen's University, Canada.
    Yusuf, Afiqah
    Queen's University, Canada.
    Wilson, Daryl E
    Queen's University, Canada.
    Peelle, Jonathan E
    MRC Cognition and Brain Sciences Unit, United Kingdom.
    Davis, Matthew H
    MRC Cognition and Brain Sciences Unit, United Kingdom.
    Johnsrude, Ingrid S
    Linköping University, Department of Behavioural Sciences and Learning, Disability Research. Linköping University, Faculty of Arts and Sciences.
    Effortful listening: the processing of degraded speech depends critically on attention.2012In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 32, no 40, p. 14010-21Article in journal (Refereed)
    Abstract [en]

    The conditions of everyday life are such that people often hear speech that has been degraded (e.g., by background noise or electronic transmission) or when they are distracted by other tasks. However, it remains unclear what role attention plays in processing speech that is difficult to understand. In the current study, we used functional magnetic resonance imaging to assess the degree to which spoken sentences were processed under distraction, and whether this depended on the acoustic quality (intelligibility) of the speech. On every trial, adult human participants attended to one of three simultaneously presented stimuli: a sentence (at one of four acoustic clarity levels), an auditory distracter, or a visual distracter. A postscan recognition test showed that clear speech was processed even when not attended, but that attention greatly enhanced the processing of degraded speech. Furthermore, speech-sensitive cortex could be parcellated according to how speech-evoked responses were modulated by attention. Responses in auditory cortex and areas along the superior temporal sulcus (STS) took the same form regardless of attention, although responses to distorted speech in portions of both posterior and anterior STS were enhanced under directed attention. In contrast, frontal regions, including left inferior frontal gyrus, were only engaged when listeners were attending to speech and these regions exhibited elevated responses to degraded, compared with clear, speech. We suggest this response is a neural marker of effortful listening. Together, our results suggest that attention enhances the processing of degraded speech by engaging higher-order mechanisms that modulate perceptual auditory processing.

  • 31.
    Wilhelms, Daniel Björk
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Acute Health Care in Linköping.
    Kirilov, Milen
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Mirrasekhian, Elahe
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Eskilsson, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Örtegren Kugelberg, Unn
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Klar, Christine
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    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
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Engblom, David
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Deletion of Prostaglandin E-2 Synthesizing Enzymes in Brain Endothelial Cells Attenuates Inflammatory Fever2014In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 34, no 35, p. 11684-11690Article in journal (Refereed)
    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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