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  • 151. Landén, M
    et al.
    Thorsell, Annika
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Wallin, A
    Blennow, K
    The apolipoprotein E allele epsilon 4 does not correlate with the number of senile plaques or neurofibrillary tangles in patients with Alzheimer's disease.1996Ingår i: Journal of Neurology, Neurosurgery and Psychiatry, ISSN 0022-3050, E-ISSN 1468-330X, Vol. 61, nr 4, s. 352-256Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND AND OBJECTIVES: Apolipoprotein E (apoE) has been implicated in regenerative processes in the brain after trauma, as well as in the pathogenesis of Alzheimer's disease. Inheritance of a specific apo epsilon allele (apo epsilon 4) determines in part the risk and the mean age at onset of Alzheimer's disease. ApoE has been found to bind isoform specifically to beta-amyloid protein, the major component of senile plaques, and to the microtubule associated protein tau, which forms paired helical filaments and neurofibrillary tangles. The aim was to further examine the relation between apo epsilon alleles, especially apo epsilon 4, and the development of neuropathological changes associated with Alzheimer's disease.

    METHODS: Brains of patients with Alzheimer's disease (n = 44) and vascular dementia (n = 11) and of age matched controls (n = 29) were studied. Senile plaques and neurofibrillary tangles in the hippocampus and frontal cortex were quantified.

    RESULTS: No correlation was found between the number of apo epsilon 4 alleles and the number of senile plaques and neurofibrillary tangles in the hippocampus or the frontal cortex of patients with Alzheimer's disease, or vascular dementia, or control groups. No significant differences in duration or severity of dementia were found between patients with or. without the apo epsilon 4 allele. No increased frequency of apo epsilon 4 was found in vascular dementia. CONCLUSION AND COMMENT: Although the apo epsilon genotype clearly affects whether Alzheimer's disease will develop or not, the present study suggests that it has no influence on pathology or clinical intellectual status, once the dementia has manifested itself. No increased apo epsilon 4 allele frequency was found in neuropathologically diagnosed patients with vascular dementia in whom concomitant Alzheimer's disease can be excluded.

  • 152.
    Larsson, Max
    Department of Anatomy and Centre for Molecular Biology and NeuroscienceUniversity of Oslo, Oslo, Norway.
    Ionotropic glutamate receptors in spinal nociceptive processing.2009Ingår i: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182, Vol. 40, nr 3, s. 260-288Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Glutamate is the predominant excitatory transmitter used by primary afferent synapses and intrinsic neurons in the spinal cord dorsal horn. Accordingly, ionotropic glutamate receptors mediate basal spinal transmission of sensory, including nociceptive, information that is relayed to supraspinal centers. However, it has become gradually more evident that these receptors are also crucially involved in short- and long-term plasticity of spinal nociceptive transmission, and that such plasticity have an important role in the pain hypersensitivity that may result from tissue or nerve injury. This review will cover recent findings on pre- and postsynaptic regulation of synaptic function by ionotropic glutamate receptors in the dorsal horn and how such mechanisms contribute to acute and chronic pain.

  • 153.
    Larsson, Max
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Non-canonical heterogeneous cellular distribution and co-localization of CaMKIIα and CaMKIIβ in the spinal superficial dorsal horn.2018Ingår i: Brain Structure and Function, ISSN 1863-2653, E-ISSN 1863-2661, Vol. 223, nr 3, s. 1437-1457Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a key enzyme in long-term plasticity in many neurons, including in the nociceptive circuitry of the spinal dorsal horn. However, although the role of CaMKII heterooligomers in neuronal plasticity is isoform-dependent, the distribution and co-localization of CaMKII isoforms in the dorsal horn have not been comprehensively investigated. Here, quantitative immunofluorescence analysis was used to examine the distribution of the two major neuronal CaMKII isoforms, α and β, in laminae I–III of the rat dorsal horn, with reference to inhibitory interneurons and neuronal populations defined by expression of parvalbumin, calretinin, and calbindin D28k. Unexpectedly, all or nearly all inhibitory and excitatory neurons showed both CaMKIIα and CaMKIIβ immunoreactivity, although at highly variable levels. Lamina III neurons showed less CaMKIIα immunoreactivity than laminae I–II neurons. Whereas CaMKIIα immunoreactivity was found at nearly similar levels in inhibitory and excitatory neurons, CaMKIIβ generally showed considerably lower immunoreactivity in inhibitory neurons. Distinct populations of inhibitory calretinin neurons and excitatory parvalbumin neurons exhibited high CaMKIIα-to-CaMKIIβ immunoreactivity ratios. CaMKIIα and CaMKIIβ immunoreactivity showed positive correlation at GluA2+ puncta in pepsin-treated tissue. These results suggest that, unlike the forebrain, the dorsal horn is characterized by similar expression of CaMKIIα in excitatory and inhibitory neurons, whereas CaMKIIβ is less expressed in inhibitory neurons. Moreover, CaMKII isoform expression varies considerably within and between neuronal populations defined by laminar location, calcium-binding protein expression, and transmitter phenotype, suggesting differences in CaMKII function both between and within neuronal populations in the superficial dorsal horn.

  • 154.
    Larsson, Max
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Pax2 is persistently expressed by GABAergic neurons throughout the adult rat dorsal horn.2017Ingår i: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 638, s. 96-101Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The transcription factor Pax2 is required for the differentiation of GABAergic neurons in the mouse dorsal horn. Pax2 continues to be expressed in the adult murine spinal cord and has been used as a presumed marker of GABAergic neurons in the superficial dorsal horn of the adult mouse, although a strict association between adult Pax2 expression and presence of GABA throughout the dorsal horn has not been firmly established. Moreover, whether Pax2 is selectively expressed in GABAergic dorsal horn neurons also in the rat is unknown. Here, immunofluorescent labeling of Pax2 and GABA in the lumbar spinal cord of adult rats was used to investigate this issue. Indeed, essentially all GABA immunoreactive neurons in laminae I-V were immunolabeled for Pax2. Conversely, essentially all Pax2 immunopositive neurons in these laminae exhibited somatic GABA immunolabeling. These results indicate persistent Pax2 expression in GABAergic neurons in the adult rat dorsal horn, supporting the hypothesis that Pax2 may be required for the maintenance of a GABAergic phenotype in mature inhibitory dorsal horn neurons in the rat. Furthermore, Pax2 may be used as a selective and specific general somatic marker of such neurons.

  • 155.
    Larsson, Max
    et al.
    Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden; Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Agalave, N
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Watanabe, M
    Department of Anatomy, Hokkaido University School of Medicine, Sapporo, Japan.
    Svensson, C I
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Distribution of transmembrane AMPA receptor regulatory protein (TARP) isoforms in the rat spinal cord.2013Ingår i: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 248, s. 180-193Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The transmembrane α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor regulatory proteins (TARPs) are a family of auxiliary AMPA receptor subunits that differentially modulate trafficking and many functional properties of the receptor. To investigate which TARP isoforms may be involved in AMPA receptor-mediated spinal synaptic transmission, we have mapped the localization of five of the known TARP isoforms, namely γ-2 (also known as stargazin), γ-3, γ-4, γ-7 and γ-8, in the rat spinal cord. Immunoblotting showed expression of all isoforms in the spinal cord to varying degrees. At the light microscopic level, immunoperoxidase labeling of γ-4, γ-7 and γ-8 was found throughout spinal gray matter. In white matter, γ-4 and γ-7 immunolabeling was observed in astrocytic processes and in mature oligodendrocytes. In pepsin-treated spinal cord, γ-7 often colocalized with GluA2 immunopositive puncta in the deep dorsal horn as well as in the ventral horn, but not in the superficial dorsal horn. Postembedding immunogold labeling was further used to assess the synaptic localization of γ-2, γ-7 and γ-8 in the dorsal horn. Synaptic immunogold labeling of γ-2 was sparse throughout the dorsal horn, with some primary afferent synapses weakly labeled, whereas relatively strong γ-7 immunogold labeling was found at deep dorsal horn synapses, including at synapses formed by low-threshold mechanosensitive primary afferent terminals. Prominent immunogold labeling of γ-8 was frequently detected at synapses established by primary afferent fibers. The spinal localization patterns of TARP isoforms reported here suggest that AMPA receptors at spinal synaptic populations and in glial cells may exhibit different functional characteristics owing to differences in auxiliary subunit composition.

  • 156.
    Larsson, Max
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Bergersen, Linda Hildegard
    Department of Oral Biology, University of Oslo, Norway.
    Gundersen, Vidar
    Department of Anatomy, Institute for Basic Medical Sciences, University of Oslo, Norway.
    Immunogold electron microscopic quantification of small molecular compounds and proteins at synapses and other neural profiles2015Ingår i: Immunocytochemistry and related techniques: Part IV / [ed] Adalberto Merighi and Laura Lossi, Springer-Verlag New York, 2015, s. 281-297Kapitel i bok, del av antologi (Övrigt vetenskapligt)
    Abstract [en]

    This chapter describes procedures for quantifi cation of postembedding labeling at brain synapses using computer-based tools. The postembedding electron microscopic immunogold method allows detection of epitopes with a resolution of about 20–30 nm. However, plasma membranes belonging to different cells and membranes of intracellular organelles can often be located even closer together. Localizing epitopes at such membranes can reliably be performed by using computer programs, such as ImageJ, which offers automated quantifi cation of gold particles. The present chapter provides a practical description of how to use ImageJ and plug- ins to obtain an accurate representation of the subcellular localization of proteins and small molecular compounds.

  • 157.
    Larsson, Max
    et al.
    Department of Experimental Medical Science, Division of Neuroscience, Lund University, Lund, Sweden.
    Broman, Jonas
    Department of Experimental Medical Science, Division of Neuroscience, Lund University, Lund, Sweden.
    Different basal levels of CaMKII phosphorylated at Thr286/287 at nociceptive and low-threshold primary afferent synapses.2005Ingår i: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 21, nr 9, s. 2445-2458Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Postsynaptic autophosphorylation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) at Thr286/287 is crucial for the induction of long-term potentiation at many glutamatergic synapses, and has also been implicated in the persistence of synaptic potentiation. However, the availability of CaMKII phosphorylated at Thr286/287 at individual glutamatergic synapses in vivo is unclear. We used post-embedding immunogold labelling to quantitatively analyse the ultrastructural localization of CaMKII phosphorylated at Thr286/287 (pCaMKII) at synapses formed by presumed nociceptive and low-threshold mechanosensitive primary afferent nerve endings in laminae I-IV of rat spinal cord. Immunogold labelling was enriched in the postsynaptic densities of such synapses, consistent with observations in pre-embedding immunoperoxidase-stained dorsal horn. Presynaptic axoplasm also exhibited sparse immunogold labelling, in peptidergic terminals partly associated with dense core vesicles. Analysis of single or serial pCaMKII-immunolabelled sections indicated that the large majority of synapses formed either by presumed peptidergic or non-peptidergic nociceptive primary afferent terminals in laminae I-II of the spinal cord, or by presumed low-threshold mechanosensitive primary afferent terminals in laminae IIi-IV, contained pCaMKII in their postsynaptic density. However, the postsynaptic levels of pCaMKII immunolabelling at low-threshold primary afferent synapses were only approximately 50% of those at nociceptive synapses. These results suggest that constitutively autophosphorylated CaMKII in the postsynaptic density is a common characteristic of glutamatergic synapses, thus potentially contributing to maintenance of synaptic efficacy. Furthermore, pCaMKII appears to be differentially regulated between high- and low-threshold primary afferent synapses, possibly reflecting different susceptibility to synaptic plasticity between these afferent pathways.

  • 158.
    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.2006Ingår i: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 26, nr 16, s. 4198-4205Artikel i tidskrift (Refereegranskat)
    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.

  • 159.
    Larsson, Max
    et al.
    Department of Anatomy and Centre for Molecular Biology and Neuroscience, University of Oslo, Oslo, Norway; Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Broman, Jonas
    Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Synaptic Plasticity and Pain: Role of Ionotropic Glutamate Receptors2011Ingår i: The Neuroscientist, ISSN 1073-8584, E-ISSN 1089-4098, Vol. 17, nr 3Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Pain hypersensitivity that develops after tissue or nerve injury is dependent both on peripheral processes in the affected tissue and on enhanced neuronal responses in the central nervous system, including the dorsal horn of the spinal cord. It has become increasingly clear that strengthening of glutamatergic sensory synapses, such as those established in the dorsal horn by nociceptive thin-caliber primary afferent fibers, is a major contributor to sensitization of neuronal responses that leads to pain hypersensitivity. Here, the authors review recent findings on the roles of ionotropic glutamate receptors in synaptic plasticity in the dorsal horn in relation to acute and persistent pain.

  • 160.
    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.2008Ingår i: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 28, nr 28, s. 7084-7090Artikel i tidskrift (Refereegranskat)
    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.

  • 161.
    Larsson, Max
    et al.
    Department of Anatomy and Centre for Molecular Biology and Neuroscience, University of Oslo, Oslo, Norway; Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Morland, Cecilie
    Department of Anatomy and Centre for Molecular Biology and Neuroscience, University of Oslo, Oslo, Norway.
    Poblete-Naredo, Irais
    Departamento de Genética y Biología Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, México D.F., Mexico.
    Biber, Jürg
    Institute of Physiology, University Zürich, Zürich, Switzerland.
    Danbolt, Niels Christian
    Department of Anatomy and Centre for Molecular Biology and Neuroscience, University of Oslo, Oslo, Norway.
    Gundersen, Vidar
    Department of Anatomy and Centre for Molecular Biology and Neuroscience, University of Oslo, Oslo, Norway; Department of Neurology, Oslo University Hospital, Oslo, Norway.
    The sodium-dependent inorganic phosphate transporter SLC34A1 (NaPi-IIa) is not localized in the mouse brain: a case of tissue-specific antigenic cross-reactivity.2011Ingår i: Journal of Histochemistry and Cytochemistry, ISSN 0022-1554, E-ISSN 1551-5044, Vol. 59, nr 9, s. 807-812Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The sodium-dependent inorganic phosphate transporter NaPi-IIa is expressed in the kidney. Here, the authors used a polyclonal antiserum raised against NaPi-IIa- and NaPi-IIa-deficient mice to characterize its expression in nervous tissue. Western blots showed that a NaPi-IIa immunoreactive band (~90 kDa) was only present in wild-type kidney membranes and not in kidney knockout or wild-type brain membranes. In the water-soluble fraction of wild-type and knockout brains, another band (~50 kDa) was observed; this band was not detected in the kidney. Light and electron microscopic immunohistochemistry using the NaPi-IIa antibodies showed immunolabeling of kidney tubules in wild-type but not knockout mice. In the brain, labeling of presynaptic nerve terminals was present also in NaPi-IIa-deficient mice. This labeling pattern was also produced by the NaPi-IIa preimmune serum. The authors conclude that the polyclonal antiserum is specific toward NaPi-IIa in the kidney, but in the brain, immunolabeling is caused by a cross-reaction of the antiserum with an unknown cytosolic protein that is not present in the kidney. This tissue-specific cross-reactivity highlights a potential pitfall when validating antibody specificity using knockout mouse-derived tissue other than the specific tissue of interest and underlines the utility of specificity testing using preimmune sera.

  • 162.
    Larsson, Max
    et al.
    Department of Physiological Sciences, Lund University, Lund, Sweden.
    Persson, Stefan
    Department of Physiological Sciences, Lund University, Lund, Sweden.
    Ottersen, Ole Petter
    Department of Anatomy, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
    Broman, Jonas
    Department of Physiological Sciences, Lund University, Lund, Sweden.
    Quantitative analysis of immunogold labeling indicates low levels and non-vesicular localization of L-aspartate in rat primary afferent terminals.2001Ingår i: Journal of Comparative Neurology, ISSN 0021-9967, E-ISSN 1096-9861, Vol. 430, nr 2, s. 147-159Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The role of L-aspartate as an excitatory neurotransmitter in primary afferent synapses in the spinal cord dorsal horn is disputed. To further investigate this issue, we examined the presence of aspartate-like immunoreactivity in primary afferent nerve terminals and other tissue components of the dorsal horn. We also examined the relationship between aspartate and glutamate immunogold labeling density and the density of synaptic vesicles in primary afferent terminals and presumed inhibitory terminals forming symmetric synapses. Weak aspartate immunosignals, similar to or lower than those displayed by presumed inhibitory terminals, were detected in both C-fiber primary afferent terminals in lamina II (dense sinusoid axon terminals, identified by morphological criteria) and in A-fiber primary afferent terminals in laminae III-IV (identified with anterograde transport of choleragenoid-horseradish peroxidase conjugate). The aspartate immunogold signal in primary afferent terminals was only about one-fourth of that in deep dorsal horn neuronal cell bodies. Further, whereas significant positive correlations were evident between synaptic vesicle density and glutamate immunogold labeling density in both A- and C-fiber primary afferent terminals, none of the examined terminal populations displayed a significant correlation between synaptic vesicle density and aspartate immunogold labeling density. Thus, our results indicate relatively low levels and a non-vesicular localization of aspartate in primary afferent terminals. It is therefore suggested that aspartate, rather than being a primary afferent neurotransmitter, serves a role in the intermediary metabolism in primary afferent terminals.

  • 163.
    Larsson, Max
    et al.
    Department of Anatomy and Centre for Molecular Biology and Neuroscience, University of Oslo, Oslo, Norway.
    Sawada, Keisuke
    Department of Membrane Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
    Morland, Cecilie
    Department of Anatomy and Centre for Molecular Biology and Neuroscience, University of Oslo, Oslo, Norway.
    Hiasa, Miki
    Department of Membrane Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
    Ormel, Lasse
    Department of Anatomy and Centre for Molecular Biology and Neuroscience, University of Oslo, Oslo, Norway.
    Moriyama, Yoshinori
    Department of Membrane Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
    Gundersen, Vidar
    Department of Anatomy and Centre for Molecular Biology and Neuroscience, University of Oslo, N-0317 Oslo, Norway Department of Neurology, Oslo University Hospital, Norway.
    Functional and anatomical identification of a vesicular transporter mediating neuronal ATP release.2012Ingår i: Cerebral Cortex, ISSN 1047-3211, E-ISSN 1460-2199, Vol. 22, nr 5, s. 1203-1214Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    ATP is known to be coreleased with glutamate at certain central synapses. However, the nature of its release is controversial. Here, we demonstrate that ATP release from cultured rat hippocampal neurons is sensitive to RNAi-mediated knockdown of the recently identified vesicular nucleotide transporter (VNUT or SLC17A9). In the intact brain, light microscopy showed particularly strong VNUT immunoreactivity in the cerebellar cortex, the olfactory bulb, and the hippocampus. Using immunoelectron microscopy, we found VNUT immunoreactivity colocalized with synaptic vesicles in excitatory and inhibitory terminals in the hippocampal formation. Moreover, VNUT immunolabeling, unlike that of the vesicular glutamate transporter VGLUT1, was enriched in preterminal axons and present in postsynaptic dendritic spines. Immunoisolation of synaptic vesicles indicated presence of VNUT in a subset of VGLUT1-containing vesicles. Thus, we conclude that VNUT mediates transport of ATP into synaptic vesicles of hippocampal neurons, thereby conferring a purinergic phenotype to these cells.

  • 164.
    Larsson, Richard
    Linköpings universitet, Institutionen för datavetenskap.
    Neural Entrainment to Speech Analyzed with EEG: A Review of Contemporary Theories about the Underlying Mechanisms of Speech Processing2017Självständigt arbete på grundnivå (kandidatexamen), 12 poäng / 18 hpStudentuppsats (Examensarbete)
    Abstract [en]

    Neural entrainment quite recently became considered an important mechanism used by the brain to process stimuli with periodic qualities, such as the frequency and duration time of signals reaching sensory organs. An increasing amount of data strongly implies that the brain might be using neural entrainment as a mechanism to either directly process speech and/or to facilitate speech interpretation. Neural entrainment is therefore a promising marker to use for research of speech perception. This literature review aims to summarize the most recent findings within this area with the end-goal to be used as a basis for designing an EEG experiment intended to analyze speech perception as a means to distinguish human voices.

       For this reason, data was collected from the scientific databases Europe PMC, Academic Search Premier, PsycINFO, PubMed, Scopus and Web of Science, where the keywords “EEG” + either the phrase “neural entrainment”, “neural oscillation”, or “cortical oscillation” were used to gather articles. Inclusion and exclusion criteria were then applied and the data was analyzed with the intention to answer the following research questions: “is it possible to observe neural entrainment to human voice/speech using EEG?”, “if so, what are the possibilities to use such neural entrainment as a marker for differentiating human voices from each other?” and “what is the nature of the mechanisms used by the brain to attain this entrainment?”. The resulting data from the articles indicated that, in order to yield reliable results when investigating neural entrainment to speech, the technique for analysis of brain activity could be done with EEG, a number of participants between 15-30 persons is enough, the spectral bands of interest are delta (<3 Hz), theta (4-8 Hz), beta (15-35 Hz) and gamma (>40 Hz), the method of analysis could be looking at both frequency and amplitude in the speech envelope, and finally the anatomical areas for investigating the brain’s ability to distinguish human voices using speech entrainment could be either areas within the auditory cortex or prefrontal areas involved in behavioral responses to speech processing.

  • 165.
    Laska, Matthias
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    Olfactory Discrimination Learning in an Outbred and an Inbred Strain of Mice.2015Ingår i: Chemical Senses, ISSN 0379-864X, E-ISSN 1464-3553, Vol. 40, nr 7, s. 489-496Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The present study compared olfactory discrimination learning in CD-1 mice, a widely used outbred strain of mice with that of C57BL/6J mice, one of the most widely used inbred mouse strains. Using an automated olfactometer and a standard operant conditioning procedure, I found that CD-1 mice needed 60 trials to reach learning criterion in an initial 2-odor discrimination task. They improved in learning speed in subsequent discrimination tasks in which either the rewarded or the unrewarded stimulus was replaced for a new stimulus. C57BL/6J mice, in contrast, needed 120 trials to reach learning criterion in an initial 2-odor discrimination task and also needed significantly more trials than the CD-1 mice in 3 of the 4 subsequent discrimination tasks. Further, the results showed that discrimination learning performance of both mouse strains was largely unaffected by the odor stimuli used. The results of the present study demonstrate differences between an outbred and an inbred strain of mice with regard to odor discrimination learning, a classical measure of cognitive performance in comparative psychology. Thus, they emphasize the need to be careful with generalizing statements as to cognitive or sensory abilities of Mus musculus when inbred strains of mice are used.

  • 166.
    Lee, Ji Soo
    et al.
    NIAAA, MD USA.
    Sorcher, Jill L.
    NIAAA, MD USA.
    Rosen, Allison D.
    NIAAA, MD USA.
    Damadzic, Ruslan
    NIAAA, MD USA.
    Sun, Hui
    NIAAA, MD USA.
    Schwandt, Melanie
    NIAAA, MD USA.
    Heilig, Markus
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Närsjukvården i centrala Östergötland, Psykiatriska kliniken.
    Kelly, John
    Johns Hopkins Univ, MD 21205 USA.
    Mauro, Kelsey L.
    NIAAA, MD USA.
    Luo, Audrey
    NIAAA, MD USA.
    Rosoff, Daniel
    NIAAA, MD USA.
    Muench, Christine
    NIAAA, MD USA.
    Jung, Jeesun
    NIAAA, MD USA.
    Kaminsky, Zachary A.
    Johns Hopkins Univ, MD 21205 USA.
    Lohoff, Falk W.
    NIAAA, MD USA.
    Genetic Association and Expression Analyses of the Phosphatidylinositol-4-Phosphate 5-Kinase (PIP5K1C) Gene in Alcohol Use DisorderRelevance for Pain Signaling and Alcohol Use2018Ingår i: Alcoholism: Clinical and Experimental Research, ISSN 0145-6008, E-ISSN 1530-0277, Vol. 42, nr 6, s. 1034-1043Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BackgroundThe gene encoding phosphatidylinositol-4-phosphate 5-kinase (PIP5K1C) has been recently implicated in pain regulation. Interestingly, a recent cross-tissue and cross-phenotypic epigenetic analysis identified the same gene in alcohol use disorder (AUD). Given the high comorbidity between AUD and chronic pain, we hypothesized that genetic variation in PIP5K1C might contribute to susceptibility to AUD. MethodsWe conducted a case-control association study of genetic variants in PIP5K1C. Association analyses of 16 common PIP5K1C single nucleotide polymorphisms (SNPs) were conducted in cases and controls of African (427 cases and 137 controls) and European ancestry (488 cases and 324 controls) using standard methods. In addition, given the prominent role of the opioid system in pain signaling, we investigated the effects of acute alcohol exposure on PIP5K1C expression in humanized transgenic mice for the -opioid receptor that included the OPRM1 A118G polymorphism, a widely used mouse model to study analgesic response to opioids in pain. PIP5K1C expression was measured in the thalamus and basolateral amygdala (BLA) in mice after short-term administration (single 2g/kg dose) of alcohol or saline using immunohistochemistry and analyzed by 2-way analysis of variance. ResultsIn the case-control association study using an NIAAA discovery sample, 8 SNPs in PIP5K1C were significantly associated with AUD in the African ancestry (AA) group (pamp;lt;0.05 after correction; rs4807493, rs10405681, rs2074957, rs10432303, rs8109485, rs1476592, rs10419980, and rs4432372). However, a replication analysis using an independent sample (N=3,801) found no significant associations after correction for multiple testing. In the humanized transgenic mouse model with the OPRM1 polymorphism, PIP5K1C expression was significantly different between alcohol and saline-treated mice, regardless of genotype, in both the thalamus (pamp;lt;0.05) and BLA (pamp;lt;0.01). ConclusionsOur discovery sample shows that genetic variants in PIP5K1C are associated with AUD in the AA group, and acute alcohol exposure leads to up-regulation of PIP5K1C, potentially explaining a mechanism underlying the increased risk for chronic pain conditions in individuals with AUD.

  • 167.
    Leijon, Sara
    Linköpings universitet, Institutionen för fysik, kemi och biologi.
    Molecular characterization of cholinergic vestibular and olivocochlear efferent neurons in the rodent brainstem.2010Självständigt arbete på avancerad nivå (masterexamen), 40 poäng / 60 hpStudentuppsats (Examensarbete)
    Abstract [en]

    The neural code from the inner ear to the brain is dynamically controlled by central nervous efferent feedback to the audio-vestibular epithelium. Although such efference provides the basis for a cognitive control of our hearing and balance, we know surprisingly little about this feedback system. This project has investigated the applicability of a transgenic mouse model, expressing a fluorescent protein under the choline-acetyltransferase (ChAT) promoter, for targeting the cholinergic audio-vestibular efferent neurons in the brainstem. It was found that the mouse model is useful for targeting the vestibular efferents, which are fluorescent, but not the auditory efferents, which are not highlighted. This model enables, for the first time, physiological studies of the vestibular efferent neurons and their synaptic inputs. We next assessed the expression of the potassium channel family Kv4, known to generate transient potassium currents upon depolarization. Such potassium currents are found in auditory efferent neurons, but it is not known whether Kv4 subunits are expressed in these neurons. Moreover, it is not known if Kv4 is present and has a function in the vestibular efferent neurons. Double labelling with anti-ChAT and anti-Kv4.2 or Kv4.3 demonstrates that the Kv4.3 subunits are abundantly expressed in audio-vestibular efferents, thus indicating that this subunit is a large contributor to the excitability and firing properties of the auditory efferent neurons, and most probably also for the vestibular efferent neurons. In addition, we also unexpectedly found a strong expression of Kv4.3 in principal cells of the superior olive, the neurons which are important for sound localization.

  • 168.
    Liljencrantz, Jaquette
    et al.
    Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
    Björnsdotter, Malin
    Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
    Morrison, India
    Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
    Bergstrand, Simon
    Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
    Ceko, Marta
    Alan Edwards Centre for Research on Pain, McGill University, Montreal, Canada.
    Seminowicz, David A
    Alan Edwards Centre for Research on Pain, McGill University, Montreal, Canada.
    Cole, Jonathan
    Department of Clinical Neurophysiology, Poole Hospital and University of Bournemouth, Bournemouth, UK.
    Bushnell, Catherine M
    Alan Edwards Centre for Research on Pain, McGill University, Montreal, Canada.
    Olausson, Håkan
    Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden; Department of Integrative Physiology, School of Medicine, University of Western Sydney, Sydney, Australia.
    Altered C-tactile processing in human dynamic tactile allodynia.2013Ingår i: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 154, nr 2, s. 227-234Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Human unmyelinated (C) tactile afferents signal the pleasantness of gentle skin stroking on hairy (nonglabrous) skin. After neuronal injury, that same type of touch can elicit unpleasant sensations: tactile allodynia. The prevailing pathophysiological explanation is a spinal cord sensitization, triggered by nerve injury, which enables Aβ afferents to access pain pathways. However, a recent mouse knockout study demonstrates that C-tactile afferents are necessary for allodynia to develop, suggesting a role for not only Aβ but also C-tactile afferent signaling. To examine the contribution of C-tactile afferents to the allodynic condition in humans, we applied the heat/capsaicin model of tactile allodynia in 43 healthy subjects and in 2 sensory neuronopathy patients lacking Aβ afferents. Healthy subjects reported tactile-evoked pain, whereas the patients did not. Instead, patients reported their C-touch percept (faint sensation of pleasant touch) to be significantly weaker in the allodynic zone compared to untreated skin. Functional magnetic resonance imaging in 18 healthy subjects and in 1 scanned patient indicated that stroking in the allodynic and control zones evoked different responses in the primary cortical receiving area for thin fiber signaling, the posterior insular cortex. In addition, reduced activation in the medial prefrontal cortices, key areas for C-tactile hedonic processing, was identified. These findings suggest that dynamic tactile allodynia is associated with reduced C-tactile mediated hedonic touch processing. Nevertheless, because the patients did not develop allodynic pain, this seems dependent on Aβ signaling, at least under these experimental conditions.

  • 169.
    Lowén, Mats B. O.
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Mayer, E.
    Oppenheimer Center for Neurobiology of Stress, Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
    Tillisch, K.
    Oppenheimer Center for Neurobiology of Stress, Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
    Labus, J.
    Oppenheimer Center for Neurobiology of Stress, Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
    Naliboff, B.
    Oppenheimer Center for Neurobiology of Stress, Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
    Lundberg, Peter
    Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV. Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Radiofysikavdelningen US.
    Thorell, Lars-Håkan
    Emotra AB, Gothenburg, Sweden.
    Ström, Magnus
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Magtarmmedicinska kliniken.
    Engström, Maria
    Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV. Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Walter, Susanna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Magtarmmedicinska kliniken.
    Deficient habituation to repeated rectal distensions in irritable bowel syndrome patients with visceral hypersensitivity2015Ingår i: Neurogastroenterology and Motility, ISSN 1350-1925, E-ISSN 1365-2982, Vol. 27, nr 5, s. 646-655Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background Irritable bowel syndrome (IBS) patients show evidence of altered central processing of visceral signals. One of the proposed alterations in sensory processing is an altered engagement of endogenous pain modulation mechanisms. The aim was to test the hypothesis that IBS patients with (IBS-S) and without visceral hypersensitivity (IBS-N) differ in their ability to engage endogenous pain modulation mechanism during habituation to repeated visceral stimuli.

    Methods Brain blood oxygen level dependent (BOLD) response was measured during repeated rectal distension and its anticipation in 33 IBS patients with and without visceral hypersensitivity and 18 healthy controls (HCs). BOLD response to early and late phase of the distension series was compared within and between groups.

    Key Results While BOLD response was similar during the early phase of the experiment, IBS-S showed greater BOLD response than IBS-N and HCs during the late phase of the distension series. IBS-S showed increasing BOLD response both to the anticipation and delivery of low intensity rectal distensions in brain regions including insula, anterior and mid cingulate cortex. IBS-N showed decreasing BOLD response to repeated rectal distensions in brain regions including insula, prefrontal cortex and amygdala.

    Conclusions & Inferences These findings are consistent with compromised ability of IBS-S to respond to repeated delivery of rectal stimuli, both in terms of sensitization of sensory pathways and habituation of emotional arousal. The fact that both IBS subgroups met Rome criteria, and did not differ in terms of reported symptom severity demonstrates that similar symptom patterns can result from different underlying neurobiological mechanisms.

  • 170.
    Lundin Palmerius, Karljohan
    et al.
    Linköpings universitet, Institutionen för teknik och naturvetenskap, Medie- och Informationsteknik. Linköpings universitet, Tekniska högskolan.
    Johansson, Daniel
    Linköpings universitet, Institutionen för teknik och naturvetenskap, Medie- och Informationsteknik. Linköpings universitet, Tekniska högskolan.
    Höst, Gunnar
    Linköpings universitet, Institutionen för teknik och naturvetenskap, Medie- och Informationsteknik. Linköpings universitet, Tekniska högskolan.
    Schönborn, Konrad
    Linköpings universitet, Institutionen för teknik och naturvetenskap, Medie- och Informationsteknik. Linköpings universitet, Tekniska högskolan.
    An Analysis of the Influence of a Pseudo-haptic Cue on the Haptic Perception of Weight2014Ingår i: Haptics: Neuroscience, Devices, Modeling, and Applications: 9th International Conference, EuroHaptics 2014, Versailles, France, June 24-26, 2014, Proceedings, Part I, Springer, 2014, Vol. 8618/8619, s. 117-125Konferensbidrag (Refereegranskat)
    Abstract [en]

    Haptics provides powerful cues about forces but cannot easily be integrated in all relevant applications, such as education. Pseudo-haptic cues, visual information that simulate haptic sensations, have been raised as an alternative. It is, however, largely unknown how (or even if) pseudo-haptic cues are perceived by the haptic sensory modality. In this paper we present an approach that applies theories on multimodal integration to testing if a pseudo-haptic cue is triggering haptic perception. This approach is subsequently applied in designing an experiment that tests a pseudo-haptic cue based on a visual force-causes-displacement metaphor, similar to a rubber band.

  • 171.
    MacSweeney, Mairead
    et al.
    UCL, England; UCL, England.
    Cardin, Velia
    Linköpings universitet, Institutionen för beteendevetenskap och lärande. Linköpings universitet, Institutionen för beteendevetenskap, Institutet för handikappvetenskap, IHV. University College London3 Linnaeus Centre HEAD.
    Editorial Material: What is the function of auditory cortex without auditory input? in BRAIN, vol 138, issue , pp 2468-24702015Ingår i: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 138, s. 2468-2470Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    This scientific commentary refers to Cross-modal activation of auditory regions during visuo-spatial working memory in early deafness, by Ding et al. (doi:10.1093/brain/awv165).

  • 172.
    Magnusson, Anna K.
    et al.
    Linköpings universitet, Institutionen för biomedicin och kirurgi. Linköpings universitet, Hälsouniversitetet.
    Tham, Richard
    Linköpings universitet, Institutionen för nervsystem och rörelseorgan. Linköpings universitet, Hälsouniversitetet.
    Vestibulo-Oculomotor Behavior in Rats after a Transient Unilateral Vestibular Loss Induced by Lidocaine2003Ingår i: THE OCULOMOTOR AND VESTIBULAR SYSTEMS: THEIR FUNCTION AND DISORDERS / [ed] Thomas Brandt, Bernard Cohen, and Christoph Siebold, New York, NY, USA: New York Academy of Sciences, 2003, Vol. 1004, s. 422-423Konferensbidrag (Övrigt vetenskapligt)
  • 173.
    Mahmoud, Saifeldin
    et al.
    Penn State College of Medicine, Hershey, PA, USA.
    Thorsell, Annika
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Sommer, Wolfgang H.
    University of Heidelberg, Germany.
    Heilig, Markus
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Holgate, Joan K.
    Ernest Gallo Clinic and Research Center, University of California-San Francisco, Emeryville, CA, USA.
    Bartlett, Selena E.
    Ernest Gallo Clinic and Research Center, University of California-San Francisco, Emeryville, CA, USA.
    Ruiz-Velasco, Victor
    Penn State College of Medicine, Hershey, PA, USA.
    Pharmacological consequence of the A118G μ opioid receptor polymorphism on morphine- and fentanyl-mediated modulation of Ca²⁺ channels in humanized mouse sensory neurons2011Ingår i: Anesthesiology, ISSN 0003-3022, E-ISSN 1528-1175, Vol. 115, nr 5, s. 1054-1062Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: The most common functional single nucleotide polymorphism of the human OPRM1 gene, A118G, has been shown to be associated with interindividual differences in opioid analgesic requirements, particularly with morphine, in patients with acute postoperative pain. The purpose of this study was to examine whether this polymorphism would modulate the morphine and fentanyl pharmacological profile of sensory neurons isolated from a humanized mouse model homozygous for either the 118A or 118G allele.

    METHODS: The coupling of wild-type and mutant μ opioid receptors to voltage-gated Ca channels after exposure to either ligand was examined by employing the whole cell variant of the patch-clamp technique in acutely dissociated trigeminal ganglion neurons. Morphine-mediated antinociception was measured in mice carrying either the 118AA or 118GG allele.

    RESULTS: The biophysical parameters (cell size, current density, and peak current amplitude potential) measured from both groups of sensory neurons were not significantly different. In 118GG neurons, morphine was approximately fivefold less potent and 26% less efficacious than that observed in 118AA neurons. On the other hand, the potency and efficacy of fentanyl were similar for both groups of neurons. Morphine-mediated analgesia in 118GG mice was significantly reduced compared with the 118AA mice.

    CONCLUSIONS: This study provides evidence to suggest that the diminished clinical effect observed with morphine in 118G carriers results from an alteration of the receptor's pharmacology in sensory neurons. In addition, the impaired analgesic response with morphine may explain why carriers of this receptor variant have an increased susceptibility to become addicted to opioids.

  • 174.
    Majlesi, Ali Reza
    et al.
    Linköpings universitet. Department of Education, Stockholm University, Stockholm, Sweden.
    Nilsson, Elin
    Linköpings universitet, Institutionen för samhälls- och välfärdsstudier, Socialt arbete. Linköpings universitet, Filosofiska fakulteten.
    Ekström, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Logopedi, Audiologi och Otorhinolaryngologi. Linköpings universitet, Filosofiska fakulteten.
    Video data as a method to understand non-verbal communication in couples where one person is living wih dementia2018Ingår i: Social research methods in dementia studies: inclusion and innovation / [ed] John Keady, Lars-Christer Hydén, Ann Johnson, Caroline Swarbrink, Abingdon, Oxon: Routledge, 2018, s. 56-76Kapitel i bok, del av antologi (Övrigt vetenskapligt)
  • 175.
    Malik, Saima
    et al.
    Ctr Addict and Mental Hlth, Canada.
    Jacobs, Mark
    Ctr Addict and Mental Hlth, Canada; Univ Toronto, Canada.
    Cho, Sang-Soo
    Ctr Addict and Mental Hlth, Canada; Univ Toronto, Canada.
    Boileau, Isabelle
    Ctr Addict and Mental Hlth, Canada.
    Blumberger, Daniel
    Univ Toronto, Canada; Ctr Addict and Mental Hlth, Canada; Ctr Addict and Mental Hlth, Canada.
    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.
    Wilson, Alan
    Ctr Addict and Mental Hlth, Canada.
    Daskalakis, Zafiris J.
    Univ Toronto, Canada; Ctr Addict and Mental Hlth, Canada; Ctr Addict and Mental Hlth, Canada.
    Strafella, Antonio P.
    Ctr Addict and Mental Hlth, Canada; Univ Toronto, Canada; Univ Toronto, Canada; Univ Toronto, Canada.
    Zangen, Abraham
    Ben Gurion Univ Negev, Israel.
    Le Foll, Bernard
    Ctr Addict and Mental Hlth, Canada; Univ Toronto, Canada; Ctr Addict and Mental Hlth, Canada; Ctr Addict and Mental Hlth, Canada.
    Deep TMS of the insula using the H-coil modulates dopamine release: a crossover [C-11] PHNO-PET pilot trial in healthy humans2018Ingår i: Brain Imaging and Behavior, ISSN 1931-7557, E-ISSN 1931-7565, Vol. 12, nr 5, s. 1306-1317Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Modulating the function of the insular cortex could be a novel therapeutic strategy to treat addiction to a variety of drugs of abuse as this region has been implicated in mediating drug reward and addictive processes. The recent advent of the H-coil has permitted the targeting of deeper brain structures which was not previously feasible. The goal of this study was to bilaterally target the insular region using the H-coil with repetitive Transcranial Magnetic Stimulation (rTMS) and subsequently measure changes in dopamine levels using Positron Emission Tomography (PET) with [11C]-(+)-propyl-hexahydro-naphtho-oxazin (PHNO). This was a within-subject, crossover, blinded and sham-controlled pilot study. Eight healthy, right-handed subjects, aged 19-45, participated in the investigation. All subjects underwent 3 PHNO-PET scans preceded by rTMS (sham, 1Hz or 10Hz), on 3 separate days. Low frequency rTMS (1Hz), targeting the insular cortex, significantly decreased dopamine levels in the substantia nigra, sensorimotor striatum and associative striatum. Replicating this study in tobacco smokers or alcoholics would be a logical follow-up to assess whether H-coil stimulation of the bilateral insula can be employed as a treatment option for addiction. Trial registration: NCT02212405

  • 176.
    Matsuwaki, Takashi
    et al.
    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.
    Jönsson, Jan-Ingvar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet.
    Blomqvist, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Interleukin-1 beta induced activation of the hypothalamus-pituitary-adrenal axis is dependent on interleukin-1 receptors on non-hematopoietic cells2014Ingår i: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 40, s. 166-173Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The proinflammatory cytokine interleukin-1 beta (IL-beta) plays a major role in the signal transduction of immune stimuli from the periphery to the central nervous system, and has been shown to be an important mediator of the immune-induced stress hormone release. The signaling pathway by which IL-1 beta exerts this function involves the blood-brain-barrier and induced central prostaglandin synthesis, but the identity of the blood-brain-barrier cells responsible for this signal transduction has been unclear, with both endothelial cells and perivascular macrophages suggested as critical components. Here, using an irradiation and transplantation strategy, we generated mice expressing IL-1 type 1 receptors (IL-1 RI) either in hematopoietic or non-hematopoietic cells and subjected these mice to peripheral immune challenge with IL-beta. Following both intraperitoneal and intravenous administration of IL-beta, mice lacking IL-1R1 in hematopoietic cells showed induced expression of the activity marker c-Fos in the paraventricular hypothalamic nucleus, and increased plasma levels of ACTH and corticosterone. In contrast, these responses were not observed in mice with IL-1R1 expression only in hematopoietic cells. Immunoreactivity for IL-1R1 was detected in brain vascular cells that displayed induced expression of the prostaglandin synthesizing enzyme cyclooxygenase-2 and that were immunoreactive for the endothelial cell marker CD31, but was not seen in cells positive for the brain macrophage marker CD206. These results imply that activation of the HPA-axis by IL-1 beta is dependent on IL-1R1 s on non-hematopoietic cells, such as brain endothelial cells, and that IL-1R1 on perivascular macrophages are not involved.

  • 177.
    Mayo, Leah
    et al.
    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.
    A Hippocampal Signature of Posttraumatic Stress Disorder Vulnerability2018Ingår i: Biological Psychiatry, ISSN 0006-3223, E-ISSN 1873-2402, Vol. 84, nr 2, s. 78-79Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    n/a

  • 178.
    Mayo, Leah M.
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Asratian, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Lindé, Johan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Holm, Lovisa
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Nätt, Daniel
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Augier, Gaëlle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Stensson, Niclas
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för samhällsmedicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Smärt och rehabiliteringscentrum.
    Vecchiarelli, Haley A.
    Hotchkiss Brain Institute and Mathison Centre for Mental Health Research and Education, Departments of Cell Biology and Anatomy and Psychiatry, University of Calgary, Canada.
    Balsevich, Georgia
    Hotchkiss Brain Institute and Mathison Centre for Mental Health Research and Education, Departments of Cell Biology and Anatomy and Psychiatry, University of Calgary, Canada.
    Aukema, Robert J.
    Hotchkiss Brain Institute and Mathison Centre for Mental Health Research and Education, Departments of Cell Biology and Anatomy and Psychiatry, University of Calgary, Canada.
    Ghafouri, Bijar
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för samhällsmedicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Smärt och rehabiliteringscentrum.
    Spagnolo, Primavera A.
    National Institute on Alcohol Abuse and Alcoholism and National Institute of Neurological Disorders and Stroke, NIH, Bethesda, USA.
    Lee, Francis S.
    Institute for Developmental Psychobiology, Weill Cornell Medical College of Cornell University, New York, USA.
    Hill, Matthew N.
    Hotchkiss Brain Institute and Mathison Centre for Mental Health Research and Education, Departments of Cell Biology and Anatomy and Psychiatry, University of Calgary, Canada.
    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.
    Protective effects of elevated anandamide on stress and fear-related behaviors: translational evidence from humans and mice2018Ingår i: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Post-traumatic stress disorder (PTSD) is a common, debilitating condition with limited treatment options. Extinction of fear memories through prolonged exposure therapy, the primary evidence-based behavioral treatment for PTSD, has only partial efficacy. In mice, pharmacological inhibition of fatty acid amide hydrolase (FAAH) produces elevated levels of anandamide (AEA) and promotes fear extinction, suggesting that FAAH inhibitors may aid fear extinction-based treatments. A human FAAH 385C-greater thanA substitution encodes an FAAH enzyme with reduced catabolic efficacy. Individuals homozygous for the FAAH 385A allele may therefore offer a genetic model to evaluate the impact of elevations in AEA signaling in humans, helping to inform whether FAAH inhibitors have the potential to facilitate fear extinction therapy for PTSD. To overcome the challenge posed by low frequency of the AA genotype (appr. 5%), we prospectively genotyped 423 individuals to examine the balanced groups of CC, AC, and AA individuals (n = 25/group). Consistent with its loss-of-function nature, the A allele was dose dependently associated with elevated basal AEA levels, facilitated fear extinction, and enhanced the extinction recall. Moreover, the A-allele homozygotes were protected against stress-induced decreases in AEA and negative emotional consequences of stress. In a humanized mouse model, AA homozygous mice were similarly protected against stress-induced decreases in AEA, both in the periphery, and also in the amygdala and prefrontal cortex, brain structures critically involved in fear extinction and regulation of stress responses. Collectively, these data suggest that AEA signaling can temper aspects of the stress response and that FAAH inhibition may aid the treatment for stress-related psychiatric disorders, such as PTSD.

  • 179.
    Medin, T
    et al.
    The Brain and Muscle Energy Group, Centre for Molecular Biology and Neuroscience and Department of Anatomy, Institute of Basic Medical Sciences, University of Oslo, Blindern, Oslo, Norway; The Synaptic Neurochemistry Laboratory Centre for Molecular Biology and Neuroscience and Department of Anatomy, Institute of Basic Medical Sciences, University of Oslo, Blindern, Oslo, Norway.
    Owe, S G
    Department of Physiology, Institute of Basic Medical Sciences, University of Oslo, Blindern, Oslo, Norway.
    Rinholm, J E
    The Brain and Muscle Energy Group, Centre for Molecular Biology and Neuroscience and Department of Anatomy, Institute of Basic Medical Sciences, University of Oslo, Blindern, Oslo, Norway; The Synaptic Neurochemistry Laboratory Centre for Molecular Biology and Neuroscience and Department of Anatomy, Institute of Basic Medical Sciences, University of Oslo, Blindern, Oslo, Norway.
    Larsson, Max
    The Synaptic Neurochemistry Laboratory Centre for Molecular Biology and Neuroscience and Department of Anatomy, Institute of Basic Medical Sciences, University of Oslo, Blindern, Oslo, Norway.
    Sagvolden, T
    Department of Physiology, Institute of Basic Medical Sciences, University of Oslo, Blindern, Oslo, Norway.
    Storm-Mathisen, J
    The Synaptic Neurochemistry Laboratory Centre for Molecular Biology and Neuroscience and Department of Anatomy, Institute of Basic Medical Sciences, University of Oslo, Blindern, Oslo, Norway.
    Bergersen, L H
    The Brain and Muscle Energy Group, Centre for Molecular Biology and Neuroscience and Department of Anatomy, Institute of Basic Medical Sciences, University of Oslo, Blindern, Oslo, Norway; The Synaptic Neurochemistry Laboratory Centre for Molecular Biology and Neuroscience and Department of Anatomy, Institute of Basic Medical Sciences, University of Oslo, Blindern, Oslo, Norway.
    Dopamine D5 receptors are localized at asymmetric synapses in the rat hippocampus.2011Ingår i: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 192, s. 164-171Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Functional studies indicate that the dopamine D5 receptor is involved in synaptic transmission in the hippocampus. However, previous anatomical studies have detected D5 receptor labelling primarily on the soma and main dendrites of CA1 pyramidal cells and on dendritic spines in monkey but not in rats. In order to get a better understanding of putative dopamine function in the hippocampus, we quantified the D5 receptor immunoreactivity on the pyramidal cell somas and on spines and dendrites in stratum radiatum and stratum oriens in the hippocampal CA1 region of rats by quantitative immunofluorescence and immunogold electron microscopy. The quantitative immunogold results revealed a higher labelling density on dendritic spines, notably at their synaptic membranes, compared to pyramidal cell somas and dendrites. Hence, dopamine could have effects on spines as well as on somas and dendrites. The labelling density was similar on spines in stratum oriens and stratum radiatum, but the presence of labelling varied between the spines within each stratum, indicating that the effect of dopamine could be diverse between different spines.

  • 180.
    Mishra, Sushmit
    et al.
    Linköpings universitet, Institutet för handikappvetenskap (IHV). Linköpings universitet, Filosofiska fakulteten.
    Rudner, Mary
    Linköpings universitet, Institutet för handikappvetenskap (IHV). Linköpings universitet, Filosofiska fakulteten.
    Lunner, Thomas
    Linköpings universitet, Institutet för handikappvetenskap (IHV). Linköpings universitet, Filosofiska fakulteten. Eriksholm Research Centre, Oticon A/S, Snekkersten.
    Stenfelt, Stefan
    Linköpings universitet, Institutet för handikappvetenskap (IHV). Linköpings universitet, Filosofiska fakulteten.
    Rönnberg, Jerker
    Linköpings universitet, Institutet för handikappvetenskap (IHV). Linköpings universitet, Filosofiska fakulteten.
    Audiovisual presentation supports cognitive processing of information heard in modulated noise2013Konferensbidrag (Refereegranskat)
    Abstract [en]

    The cognitive spare capacity test (CSCT) assesses the ability to process heardinformation stored in working memory. This is important because listening that iseffortful, due to noise or hearing impairment, consumes cognitive resources leavingless capacity available for further processing. The CSCT pinpoints the effectsof modality of presentation (Audiovisual, Audio-only); memory load (High, Low)and different kinds of executive processing demands (Updating, Inhibition). Inthe present study, 24 participants with mild to moderate hearing loss performedCSCT with amplification in quiet, in steady-state noise at an individually adaptedsignal to noise ratio (SNR) rendering intelligibility of ~95% and in modulatednoise (International Speech Test Signal; ISTS) at the same SNR. An independentbattery of cognitive tests was also administered. Analysis of variance showedmain effects of all factors, including better performance with Audiovisual thanAudio-only modality. However, a significant interaction revealed that the Audiovisualbenefit was most prominent in ISTS. The benefit of Audiovisual presentationover Audio-only presentation correlated with the independent measure of workingmemory capacity. The pattern of results suggests that for the hearing impairedpopulation, Audiovisual presentation supports cognitive processing of informationheard in modulated noise and that the magnitude of this benefit is related toworking memory capacity.

  • 181.
    Mishra, Sushmit
    et al.
    Linköpings universitet, Institutionen för beteendevetenskap och lärande, Handikappvetenskap. Linköpings universitet, Filosofiska fakulteten. Linköpings universitet, Institutet för handikappvetenskap (IHV).
    Stenfelt, Stefan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neurovetenskap. Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutet för handikappvetenskap (IHV).
    Lunner, Thomas
    Linköpings universitet, Institutionen för beteendevetenskap och lärande, Handikappvetenskap. Linköpings universitet, Filosofiska fakulteten. Linköpings universitet, Institutet för handikappvetenskap (IHV). 3Eriksholm Research Centre, Oticon A/S, Snekkersten, Denmark.
    Rönnberg, Jerker
    Linköpings universitet, Institutionen för beteendevetenskap och lärande, Handikappvetenskap. Linköpings universitet, Filosofiska fakulteten. Linköpings universitet, Institutet för handikappvetenskap (IHV).
    Rudner, Mary
    Linköpings universitet, Institutionen för beteendevetenskap och lärande, Handikappvetenskap. Linköpings universitet, Filosofiska fakulteten. Linköpings universitet, Institutet för handikappvetenskap (IHV).
    Cognitive spare capacity in older adults with hearing loss2014Ingår i: Frontiers in Aging Neuroscience, ISSN 1663-4365, E-ISSN 1663-4365, Vol. 6, nr 96Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Individual differences in working memory capacity (WMC) are associated with speech recognition in adverse conditions, reflecting the need to maintain and process speech fragments until lexical access can be achieved. When working memory resources are engaged in unlocking the lexicon, there is less Cognitive Spare Capacity (CSC) available for higher level processing of speech. CSC is essential for interpreting the linguistic content of speech input and preparing an appropriate response, that is, engaging in conversation. Previously, we showed, using a Cognitive Spare Capacity Test (CSCT) that in young adults with normal hearing, CSC was not generally related to WMC and that when CSC decreased in noise it could be restored by visual cues. In the present study, we investigated CSC in 24 older adults with age-related hearing loss, by administering the CSCT and a battery of cognitive tests. We found generally reduced CSC in older adults with hearing loss compared to the younger group in our previous study, probably because they had poorer cognitive skills and deployed them differently. Importantly, CSC was not reduced in the older group when listening conditions were optimal. Visual cues improved CSC more for this group than for the younger group in our previous study. CSC of older adults with hearing loss was not generally related to WMC but it was consistently related to episodic long term memory, suggesting that the efficiency of this processing bottleneck is important for executive processing of speech in this group.

  • 182.
    Mohseni, Simin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Neurologic damage in hypoglycemia.2014Ingår i: Handbook of Clinical Neurology, Elsevier, 2014, Vol. 126, s. 513-32Kapitel i bok, del av antologi (Refereegranskat)
    Abstract [en]

    Hypoglycemia occurs in diabetic patients as a consequence of treatment with hypoglycemic agents, in insulinoma patients as a result of excessive insulin production, and in infants as a result of abnormal regulation of metabolism. Profound hypoglycemia can cause structural and functional disturbances in both the central (CNS) and the peripheral nervous system (PNS). The brain is damaged by a short and severe episode of hypoglycemia, whereas PNS pathology appears after a mild and prolonged episode. In the CNS, damaged mitochondria, elevated intracellular Ca2(+) level, released cytochrome c to the cytosol, extensive production of superoxide, increased caspase-3 activity, release of aspartate and glutamate from presynaptic terminals, and altered biosynthetic machinery can lead to neuronal cell death in the brain. Considering the PNS, chronic hypoglycemia is associated with delayed motor and sensory conduction velocities in peripheral nerves. With respect to pathology, hypoglycemic neuropathy in the PNS is characterized by Wallerian-like axonal degeneration that starts at the nerve terminal and progresses to a more proximal part of the axon, and motor axons to the muscles may be more severely damaged than sensory axons. Since excitatory neurotransmitters primarily involve the neuron in the CNS, this "dying back" pattern of axonal damage in the PNS may involve mechanisms other than excitotoxicity.

  • 183.
    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 Norepinephrine2009Ingår i: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 29, nr 50, s. 15745-15755Artikel i tidskrift (Refereegranskat)
    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).

  • 184.
    Morland, Cecilie
    et al.
    Department of Anatomy and Center for Molecular Biology and Neuroscience, University of Oslo, Oslo, Norway.
    Nordengen, Kaja
    Department of Anatomy and Center for Molecular Biology and Neuroscience, University of Oslo, Oslo, Norway.
    Larsson, Max
    Center for Molecular Biology and Neuroscience, University of Oslo, Oslo, Norway; Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Prolo, Laura M
    Department of Neurology and Neurological Sciences and Graduate Program in Neuroscience, Stanford University School of Medicine, Stanford, California, USA.
    Farzampour, Zoya
    Department of Neurology and Neurological Sciences and Graduate Program in Neuroscience, Stanford University School of Medicine, Stanford, California, USA.
    Reimer, Richard J
    Department of Neurology and Neurological Sciences and Graduate Program in Neuroscience, Stanford University School of Medicine, Stanford, California, USA.
    Gundersen, Vidar
    Center for Molecular Biology and Neuroscience, University of Oslo, Oslo, Norway; Department of Neurology, Oslo University Hospital, Rikshospitalet Oslo, Oslo, Norway.
    Vesicular uptake and exocytosis of L-aspartate is independent of sialin.2013Ingår i: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 27, nr 3, s. 1264-1274Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The mechanism of release and the role of l-aspartate as a central neurotransmitter are controversial. A vesicular release mechanism for l-aspartate has been difficult to prove, as no vesicular l-aspartate transporter was identified until it was found that sialin could transport l-aspartate and l-glutamate when reconstituted into liposomes. We sought to clarify the release mechanism of l-aspartate and the role of sialin in this process by combining l-aspartate uptake studies in isolated synaptic vesicles with immunocyotchemical investigations of hippocampal slices. We found that radiolabeled l-aspartate was taken up into synaptic vesicles. The vesicular l-aspartate uptake, relative to the l-glutamate uptake, was twice as high in the hippocampus as in the whole brain, the striatum, and the entorhinal and frontal cortices and was not inhibited by l-glutamate. We further show that sialin is not essential for exocytosis of l-aspartate, as there was no difference in ATP-dependent l-aspartate uptake in synaptic vesicles from sialin-knockout and wild-type mice. In addition, expression of sialin in PC12 cells did not result in significant vesicle uptake of l-aspartate, and depolarization-induced depletion of l-aspartate from hippocampal nerve terminals was similar in hippocampal slices from sialin-knockout and wild-type mice. Further, there was no evidence for nonvesicular release of l-aspartate via volume-regulated anion channels or plasma membrane excitatory amino acid transporters. This suggests that l-aspartate is exocytotically released from nerve terminals after vesicular accumulation by a transporter other than sialin.

  • 185.
    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.2011Ingår i: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 31, nr 26, s. 9554-9562Artikel i tidskrift (Refereegranskat)
    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.

  • 186.
    Mukwaya, Anthonny
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Mirabelli, Pierfrancesco
    Region Östergötland, Sinnescentrum, Ögonkliniken US/LiM.
    Lennikov, Anton
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Univ Missouri, MO USA.
    Thangavelu, Muthukumar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Chonbuk Natl Univ, South Korea.
    Jensen, Lasse
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk farmakologi.
    Peebo, Beatrice
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Ögonkliniken US/LiM.
    Lagali, Neil
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Ögonkliniken US/LiM. Sorlandet Hosp Arendal, Norway.
    Repeat Corneal Neovascularization is Characterized by More Aggressive Inflammation and Vessel Invasion Than in the Initial Phase2019Ingår i: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 60, nr 8, s. 2990-3001Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Purpose: Treatment of corneal neovascularization can lead to vessel regression and recovery of corneal transparency. Here, we examined the response of the cornea to a repeated stimulus after initial vessel regression comparing the second wave of neovascularization with the first.

    Methods: Corneal neovascularization was induced by surgical suture placement in the rat cornea for 7 days, followed by suture removal and a 30-day regression period. Corneas were then re-sutured and examined for an additional 4 days. Longitudinal slit-lamp imaging, in vivo confocal microscopy, and microarray analysis of global gene expression was conducted to assess the inflammatory and neovascularization response. Inhibitory effect of topical dexamethasone for repeat neovascularization was assessed.

    Results: After initial robust neovascularization, 30 days of regression resulted in the recovery of corneal transparency; however, a population of barely functional persistent vessels remained at the microscopic level. Upon re-stimulation, inflammatory cell invasion, persistent vessel dilation, vascular invasion, and gene expression of VegfaIl1βIl6Ccl2Ccl3, and Cxcl2 all doubled relative to initial neovascularization. Repeat neovascularization occurred twice as rapidly as initially, with activation of nitric oxide and reactive oxygen species, matrix metalloproteinase, and leukocyte extravasation signaling pathways, and suppression of anti-inflammatory LXR/RXR signaling. While inhibiting initial neovascularization, a similar treatment course of dexamethasone did not suppress repeat neovascularization.

    Conclusions: Persistent vessels remaining after the initial resolution of neovascularization can rapidly reactivate to facilitate more aggressive inflammation and repeat neovascularization, highlighting the importance of achieving and confirming complete vessel regression after an initial episode of corneal neovascularization.

  • 187.
    Nasr Esfahani, Ali
    Linköpings universitet, Institutionen för fysik, kemi och biologi.
    Validation of a transgenic mouse line with knockdown of mGluR5 selectively in dopamine D1receptor expressing neurons2010Självständigt arbete på avancerad nivå (masterexamen), 40 poäng / 60 hpStudentuppsats (Examensarbete)
    Abstract [en]

    One of the main difficulties of addiction treatment is the high risk of relapse even after a longabstinence and fully detoxification. Therefore, discovering the underlying molecular principlesof relapse is essential. The metabotropic glutamate receptor, mGluR5, is considered to beinvolved in this aspect. One of the brain structures expressing mGluR5 is the striatum, an areawith well-established role in addiction which is largely composed of medium-sized spinyneurons (MSNs). These neurons are basically divided into two major subpopulationscharacterized based on their projections and protein properties. It is known that the mGluR5receptor is expressed on both subpopulations of MSNs. Consequently, it can be used to establishthe proportional contribution of each of MSNs subpopulations in relapse to addiction. In ourconstellation, we have generated a mouse line designed to have a selective mGluR5 knock-downin one of these subpopulations – the dopamine D1 receptor (D1R) expressing neurons. It hashowever been unclear if the expression of the transgene is indeed limited to only D1R-expressingneurons. By immunofluorescence technique, I here show that the construct is expressed only inMSNs and is restricted to the D1R-expressing cell population in the striatum. Thus the transgenicmouse line is a good tool for the study of mGluR5 selectively in D1R expressing neurons.

  • 188.
    Nedlund, Ann-Charlotte
    et al.
    Linköpings universitet, Institutionen för samhälls- och välfärdsstudier, Avdelningen Åldrande och social förändring. Linköpings universitet, Filosofiska fakulteten.
    Nordh, Jonas
    Linköpings universitet, Institutionen för samhälls- och välfärdsstudier. Linköpings universitet, Filosofiska fakulteten.
    Critical discourse and policy analysis as a method to understand dementia policies2018Ingår i: Social research methods in dementia studies: inclusion and innovation / [ed] John Keady, Lars-Christer Hydén, Ann Johnson, Caroline Swarbrick, Abingdon, Oxon: Routledge, 2018, s. 192-204Kapitel i bok, del av antologi (Övrigt vetenskapligt)
  • 189.
    Neng, Lingling
    et al.
    Oregon Health & Science University, Portland, USA.
    Zhang, Wenjing
    Oregon Health & Science University, Portland, USA.
    Hassan, Ahmed
    Lawrence Berkeley National Laboratory, California, USA.
    Zemla, Marcin
    Lawrence Berkeley National Laboratory, California, USA.
    Kachelmeier, Allan
    Oregon Health & Science University, Portland, USA.
    Fridberger, Anders
    Karolinska Institutet, Stockholm, Sweden.
    Auer, Manfred
    Lawrence Berkeley National Laboratory, California, USA.
    Shi, Xiaorui
    Oregon Health & Science University, Portland, USA.
    Isolation and culture of endothelial cells, pericytes and perivascular resident macrophage-like melanocytes from the young mouse ear2013Ingår i: Nature Protocols, ISSN 1754-2189, E-ISSN 1750-2799, Vol. 8, nr 4, s. 709-720Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    This protocol describes a growth medium-based approach for obtaining cochlear endothelial cells (ECs), pericytes (PCs) and perivascular resident macrophage-like melanocytes (PVM/Ms) from the stria vascularis of mice aged between P10 and P15 (P, postnatal day). The procedure does not involve mechanical or enzymatic digestion of the sample tissue. Explants of stria vascularis, 'mini-chips', are selectively cultured in growth medium, and primary cell lines are obtained in 7-10 d. The method is simple and reliable, and it provides high-quality ECs, PVM/Ms and PCs with a purity >90% after two passages. This protocol is suitable for producing primary culture cells from organs and tissues of small volume and high anatomical complexity, such as the inner ear capillaries. The highly purified primary cell lines enable cell culture-based in vitro modeling of cell-cell interactions, barrier control function and drug action.

  • 190.
    Nennig, S. E.
    et al.
    Univ Georgia, GA 30602 USA.
    Fulenwider, H. D.
    Univ Georgia, GA 30602 USA.
    Chimberoff, S. H.
    Univ Georgia, GA 30602 USA.
    Smith, B. M.
    Univ Georgia, GA 30602 USA.
    Eskew, J. E.
    Univ Georgia, GA 30602 USA.
    Sequeira, M. K.
    Univ Georgia, GA 30602 USA.
    Karlsson, Camilla
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Liang, C.
    Univ Georgia, GA 30602 USA.
    Chen, J. F.
    Univ Southern Calif, CA USA.
    Heilig, Markus
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Närsjukvården i centrala Östergötland, Psykiatriska kliniken.
    Schank, J. R.
    Univ Georgia, GA 30602 USA.
    Selective Lesioning of Nuclear Factor-kappa B Activated Cells in the Nucleus Accumbens Shell Attenuates Alcohol Place Preference2018Ingår i: Neuropsychopharmacology, ISSN 0893-133X, E-ISSN 1740-634X, Vol. 43, nr 5, s. 1032-1040Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Nuclear factor.-light chain enhancer of activated B cells (NF-kappa B) is a transcription factor commonly associated with innate immunity and is activated by infection and inflammation. NF-kappa B has recently gained attention as a mediator of complex psychiatric phenomena such as stress and addiction. In regards to alcohol, most research on NF-kappa B has focused on neurotoxicity and few studies have explored the role of NF-kappa B in alcohol reward, reinforcement, or consumption. In these studies, we used conditioned place preference to assess the activity of NF-kappa B in response to rewarding doses of alcohol. To measure NF-kappa B activity we used a line of transgenic mice that express the LacZ gene under the control of an NF-kappa B-regulated promoter. In these animals, staining for beta-galactosidase (beta-gal) identifies cells in which NF-kappa B has been activated. We then used the Daun02 inactivation method to specifically silence NF-kappa B-expressing cells during place preference conditioning. Daun02 is an inactive prodrug that is converted to the inhibitory molecule daunorubicin by beta-gal. After alcohol place conditioning, we observed increased beta-gal staining in the nucleus accumbens (NAC) shell and dorsal raphe nucleus, and found that disruption of NF-kappa B-expressing cells using Daun02 attenuated the development of alcohol place preference when infused into the NAC shell following conditioning sessions. We found this effect to be regionally and temporally specific. These results suggest that, in addition to its role in alcohol-induced neurotoxicity, NF-kappa B mediates the development of alcohol place preference via its actions in the NAC shell.

  • 191.
    Nersisyan, Syune
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Bekisz, Marek
    Department of Neurophysiology, Nencki Institute of Experimental Biology, Warsaw, Poland.
    Kublik, Ewa
    Department of Neurophysiology, Nencki Institute of Experimental Biology, Warsaw, Poland.
    Granseth, Björn
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Wrobel, Andrzej
    Department of Neurophysiology, Nencki Institute of Experimental Biology, Warsaw, Poland.
    Cholinergic modulation of synaptic properties of cortical layer VI input to posteromedial thalamic nucleus of the rat investigated in vitro2012Ingår i: Acta Neurobiologiae Experimentalis, ISSN 0065-1400, E-ISSN 1689-0035, Vol. 72, nr 4, s. 461-467Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The second order somatosensory thalamic nucleus (posteromedial nucleus, PoM) receives excitatory projection from layer VI of somatosensory cortex. While it is known that layer VI cortical input to first order, ventrobasal nucleus (VB) is modulated by cholinergic projections from the brainstem, no such data exists concerning the PoM nucleus. In order to study if layer VI corticothalamic transmission to PoM is also modulated we used patch-clamp recording in thalamocortical slices from the rat's brain. Excitatory postsynaptic potentials (EPSPs) were evoked in PoM cells by trains of 5 electrical pulses at 20 Hz frequency applied to corticothalamic fibers. After carbachol was applied to mimic activation of the cholinergic neuromodulatory system corticothalamic EPSP amplitudes were reduced, while facilitation of EPSP amplitudes was enhanced for each next pulse in the series. Such cholinergic control of layer VI corticothalamic synapses in PoM may be used as gain modulator for the transfer of the peripheral sensory information to the cortex.

  • 192.
    Nickchen, Katharina
    et al.
    Charite University of Medical Berlin, Germany; Fliedner Klin Berlin, Germany.
    Böhme, Rebecca
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten. Charite University of Medical Berlin, Germany.
    del Mar Amador, Maria
    Charite University of Medical Berlin, Germany.
    Haelbig, Thomas D.
    Charite University of Medical Berlin, Germany.
    Dehnicke, Katharina
    Charite University of Medical Berlin, Germany; Helios Klinikum Bad Saarow, Germany.
    Panneck, Patricia
    Charite University of Medical Berlin, Germany.
    Behr, Joachim
    Charite University of Medical Berlin, Germany; Medical School Brandenburg, Germany.
    Prass, Konstantin
    Helios Klinikum Bad Saarow, Germany.
    Heinz, Andreas
    Charite University of Medical Berlin, Germany.
    Deserno, Lorenz
    Charite University of Medical Berlin, Germany; Max Planck Institute Human Cognit and Brain Science, Germany.
    Schlagenhauf, Florian
    Charite University of Medical Berlin, Germany; Max Planck Institute Human Cognit and Brain Science, Germany.
    Priller, Josef
    Charite University of Medical Berlin, Germany; BIH, Germany; DZNE, Germany.
    Reversal learning reveals cognitive deficits and altered prediction error encoding in the ventral striatum in Huntingtons disease2017Ingår i: Brain Imaging and Behavior, ISSN 1931-7557, E-ISSN 1931-7565, Vol. 11, nr 6, s. 1862-1872Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Huntingtons disease (HD) is an autosomal dominant neurodegenerative condition characterized by a triad of movement disorder, neuropsychiatric symptoms and cognitive deficits. The striatum is particularly vulnerable to the effects of mutant huntingtin, and cell loss can already be found in presymptomatic stages. Since the striatum is well known for its role in reinforcement learning, we hypothesized to find altered behavioral and neural responses in HD patients in a probabilistic reinforcement learning task performed during functional magnetic resonance imaging. We studied 24 HD patients without central nervous system (CNS)-active medication and 25 healthy controls. Twenty HD patients and 24 healthy controls were able to complete the task. Computational modeling was used to calculate prediction error values and estimate individual parameters. We observed that gray matter density and prediction error signals during the learning task were related to disease stage. HD patients in advanced disease stages appear to use a less complex strategy in the reversal learning task. In contrast, HD patients in early disease stages show intact encoding of learning signals in the degenerating left ventral striatum. This effect appears to be lost with disease progression.

  • 193.
    Nicklagård, Erik
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biokemi.
    Diabetes typ 3?: Molekylärfysiologiska länkar och samband från den samlade litteraturen2011Självständigt arbete på grundnivå (kandidatexamen), 10,5 poäng / 16 hpStudentuppsats (Examensarbete)
    Abstract [sv]

    Alzheimers sjukdom (AD) är den vanligaste formen av demens och kännetecknas av intracellulärt neurofibrillärt trassel (NFT) bestående av proteinet tau och extracellulära plack, uppbyggda av peptiden amyloid beta (Aβ). En växande skara studier har börjat peka mot att AD är en hjärnspecifik typ av diabetes. Insulinresistens följt av hyperinsulinemi och hyperglykemi är kännetecken för diabetes mellitus typ 2 (DMT2) och har visat sig vara en riskfaktor för AD. Insulin, ett hormon som kontrollerar glukoshomeostasen i perifera nervsystemet (PNS) och är viktigt för minne och inlärning, transporteras över blod-hjärnbarriären i en mättnadsbar transportmekanism och dess koncentration i centrala nervsystemet (CNS) minskar vid DMT2 och AD. Insulin-like growth factor 1 (IGF-1), ett neuronskyddande protein som minskar ogynnsam β-sekretasklyvning av amyloid precursor protein (APP) i amyloidkaskadhypotesen, minskar i koncentration i hjärnan när mycket insulin transporteras in i CNS. γ-sekretas ökar sin aktivitet på APP vid höga halter kolesterol som är vanligt vid DMT2, Aβ fungerar då som en negativ inhibitor till HMG-Coa reduktas (HMGR), enzymet som bildar kolesterol och kan därmed reglera kolesterolhalterna. Regleringssystem för Aβ i blod-hjärnbarriären (BBB) som p-GP, LRP-1 och RAGE rubbas vid DMT2. Aβ och insulin delar samma degraderingssystem, insulin degrading enzyme (IDE), som reglerar halterna Aβ och insulin. Dessutom har Aβ oligomerer visat sig kunna bryta ned insulinreceptorer (IR). Vidare har läkemedel mot diabetes visat sig lindra demens hos AD patienter. I den här rapporten gås de molekylärfysiologiska sambanden igenom i detalj. Slutligen finns det fog för ett samband mellan metabolt syndrom, en riskfaktor för DMT2, och AD.

  • 194.
    Nilsson, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Mechanisms Behind Illness-Induced Anorexia2016Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Loss of appetite is together with fever and malaise hallmarks of infection. Loosing appetite during an acute infection such as influenza does not result in any longlasting effects, but loosing appetite during chronic diseases such as cancer or AIDS constitutes a risk factor for mortality. Food intake regulation during inflammation is orchestrated by the brain in response to peripheral inflammatory signals. It is known that expression of the prostaglandin synthesizing enzyme cyclooxygenase 2 (COX-2) is crucial for the mechanisms underlying inflammation-induced anorexia, and that prostaglandin E2 (PGE2) is involved in anorexia induced by interleukin-1 beta (IL-1β). In this thesis I examined the prostaglandin-pathways proposed to be involved in anorexia. We show that acute anorexia is dependent on COX-2 expression, while cancer-induced anorexia is mediated by cyclooxygenase 1 (COX-1), at least in the initial stages, suggesting that the signaling pathways for chronic- and acute anorexia are distinct. We were able to demonstrate that the pathway underlying acute anorexia is distinct from that of fever, and that taste aversion is prostaglandin independent. We could also show that both acute and chronic anorexia-cachexia is dependent on expression of myeloid differentiation primary response gene (MyD88) in hematopoietic/myeloid cells.

    In summary, the findings presented in this thesis suggest that anorexia is a result of many different signaling pathways, as opposed to what is the case for several other inflammatory symptoms such as fever and malaise, where the pathways have been shown to be very exclusive. This provides new insight into the diversity of the pathways underlying inflammatory symptoms, which is fundamental for the ability to present potential, symptom-specific drug targets.

    Delarbeten
    1. Cancer-induced anorexia in tumor-bearing mice is dependent on cyclooxygenase-1
    Öppna denna publikation i ny flik eller fönster >>Cancer-induced anorexia in tumor-bearing mice is dependent on cyclooxygenase-1
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    2013 (Engelska)Ingår i: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 29, s. 124-135Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    It is well-established that prostaglandins (PGs) affect tumorigenesis, and evidence indicates that PGs also are important for the reduced food intake and body weight loss, the anorexia–cachexia syndrome, in malignant cancer. However, the identity of the PGs and the PG producing cyclooxygenase (COX) species responsible for cancer anorexia–cachexia is unknown. Here, we addressed this issue by transplanting mice with a tumor that elicits anorexia. Meal pattern analysis revealed that the anorexia in the tumor-bearing mice was due to decreased meal frequency. Treatment with a non-selective COX inhibitor attenuated the anorexia, and also tumor growth. When given at manifest anorexia, non-selective COX-inhibitors restored appetite and prevented body weight loss without affecting tumor size. Despite COX-2 induction in the cerebral blood vessels of tumor-bearing mice, a selective COX-2 inhibitor had no effect on the anorexia, whereas selective COX-1 inhibition delayed its onset. Tumor growth was associated with robust increase of PGE2 levels in plasma – a response blocked both by non-selective COX-inhibition and by selective COX-1 inhibition, but not by COX-2 inhibition. However, there was no increase in PGE2-levels in the cerebrospinal fluid. Neutralization of plasma PGE2 with specific antibodies did not ameliorate the anorexia, and genetic deletion of microsomal PGE synthase-1 (mPGES-1) affected neither anorexia nor tumor growth. Furthermore, tumor-bearing mice lacking EP4 receptors selectively in the nervous system developed anorexia. These observations suggest that COX-enzymes, most likely COX-1, are involved in cancer-elicited anorexia and weight loss, but that these phenomena occur independently of host mPGES-1, PGE2 and neuronal EP4 signaling.

    Ort, förlag, år, upplaga, sidor
    Elsevier, 2013
    Nyckelord
    Cancer anorexia-cachexia, Cyclooxygenase, Microsomal prostaglandin E synthase-1, Prostaglandin E2
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-90188 (URN)10.1016/j.bbi.2012.12.020 (DOI)000315365400013 ()
    Anmärkning

    Funding Agencies|Swedish Cancer Foundation||Swedish Research Council||Swedish Brain Foundation||

    Tillgänglig från: 2013-04-04 Skapad: 2013-03-21 Senast uppdaterad: 2017-12-06Bibliografiskt granskad
    2. Inflammation- and tumor-induced anorexia and weight loss require MyD88 in hematopoietic/myeloid cells but not in brain endothelial or neural cells
    Öppna denna publikation i ny flik eller fönster >>Inflammation- and tumor-induced anorexia and weight loss require MyD88 in hematopoietic/myeloid cells but not in brain endothelial or neural cells
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    2013 (Engelska)Ingår i: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 27, nr 5, s. 1973-1980Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Loss of appetite is a hallmark of inflammatory diseases. The underlying mechanisms remain undefined, but it is known that myeloid differentiation primary response gene 88 (MyD88), an adaptor protein critical for Toll-like and IL-1 receptor family signaling, is involved. Here we addressed the question of determining in which cells the MyD88 signaling that results in anorexia development occurs by using chimeric mice and animals with cell-specific deletions. We found that MyD88-knockout mice, which are resistant to bacterial lipopolysaccharide (LPS)-induced anorexia, displayed anorexia when transplanted with wild-type bone marrow cells. Furthermore, mice with a targeted deletion of MyD88 in hematopoietic or myeloid cells were largely protected against LPS-induced anorexia and displayed attenuated weight loss, whereas mice with MyD88 deletion in hepatocytes or in neural cells or the cerebrovascular endothelium developed anorexia and weight loss of similar magnitude as wild-type mice. Furthermore, in a model for cancer-induced anorexia-cachexia, deletion of MyD88 in hematopoietic cells attenuated the anorexia and protected against body weight loss. These findings demonstrate that MyD88-dependent signaling within the brain is not required for eliciting inflammation-induced anorexia. Instead, we identify MyD88 signaling in hematopoietic/myeloid cells as a critical component for acute inflammatory-driven anorexia, as well as for chronic anorexia and weight loss associated with malignant disease.

    Ort, förlag, år, upplaga, sidor
    Federation of American Society of Experimental Biology (FASEB), 2013
    Nyckelord
    lipopolysaccharide; methylcholanthrene-induced sarcoma; food intake; chimeric mice; Cre-LoxP; inducible cell-specific deletion
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-96147 (URN)10.1096/fj.12-225433 (DOI)000318226100017 ()
    Tillgänglig från: 2013-08-14 Skapad: 2013-08-14 Senast uppdaterad: 2017-12-06
    3. The involvement of prostaglandin E2 in interleukin-1β evoked anorexia is strain dependent
    Öppna denna publikation i ny flik eller fönster >>The involvement of prostaglandin E2 in interleukin-1β evoked anorexia is strain dependent
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    2017 (Engelska)Ingår i: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 60, s. 27-31Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    From experiments in mice in which the prostaglandin E2 (PGE2) synthesizing enzyme mPGES-1 was genetically deleted, as well as from experiments in which PGE2 was injected directly into the brain, PGE2 has been implicated as a mediator of inflammatory induced anorexia. Here we aimed at examining which PGE2 receptor (EP1–4) that was critical for the anorexic response to peripherally injected interleukin-1β (IL-1β). However, deletion of neither EP receptor in mice, either globally (for EP1, EP2, and EP3) or selectively in the nervous system (EP4), had any effect on the IL-1β induced anorexia. Because these mice were all on a C57BL/6 background, whereas previous observations demonstrating a role for induced PGE2 in IL-1β evoked anorexia had been carried out on mice on a DBA/1 background, we examined the anorexic response to IL-1β in mice with deletion of mPGES-1 on a C57BL/6 background and a DBA/1 background, respectively. We confirmed previous findings that mPGES-1 knock-out mice on a DBA/1 background displayed attenuated anorexia to IL-1β; however, mice on a C57BL/6 background showed the same profound anorexia as wild type mice when carrying deletion of mPGES-1, while displaying almost normal food intake after pretreatment with a cyclooxygenase-2 inhibitor. We conclude that the involvement of induced PGE2 in IL-1β evoked anorexia is strain dependent and we suggest that different routes that probably involve distinct prostanoids exist by which inflammatory stimuli may evoke an anorexic response and that these routes may be of different importance in different strains of mice.

    Ort, förlag, år, upplaga, sidor
    Academic Press, 2017
    Nyckelord
    Anorexia, Prostaglandin E2, EP receptors, Interleukin-1, Cyclooxygenase-2, Mice
    Nationell ämneskategori
    Immunologi Cellbiologi Farmakologi och toxikologi
    Identifikatorer
    urn:nbn:se:liu:diva-132639 (URN)10.1016/j.bbi.2016.06.014 (DOI)000391908200004 ()27375005 (PubMedID)
    Anmärkning

    Funding agencies: Swedish Research Council [07879, 20725]; Swedish Cancer Foundation [213/692]; County Council of Ostergotland; Knut and Alice Wallenberg Foundation

    Tillgänglig från: 2016-11-18 Skapad: 2016-11-18 Senast uppdaterad: 2018-05-02Bibliografiskt granskad
    4. Inflammation-induced anorexia and fever are elicited by distinct prostaglandin dependent mechanisms, whereas conditioned taste aversion is prostaglandin independent.
    Öppna denna publikation i ny flik eller fönster >>Inflammation-induced anorexia and fever are elicited by distinct prostaglandin dependent mechanisms, whereas conditioned taste aversion is prostaglandin independent.
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    2017 (Engelska)Ingår i: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 61, s. 236-243, artikel-id S0889-1591(16)30549-9Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Systemic inflammation evokes an array of brain-mediated responses including fever, anorexia and taste aversion. Both fever and anorexia are prostaglandin dependent but it has been unclear if the cell-type that synthesizes the critical prostaglandins is the same. Here we show that pharmacological inhibition or genetic deletion of cyclooxygenase (COX)-2, but not of COX-1, attenuates inflammation-induced anorexia. Mice with deletions of COX-2 selectively in brain endothelial cells displayed attenuated fever, as demonstrated previously, but intact anorexia in response to peripherally injected lipopolysaccharide (10μg/kg). Whereas intracerebroventricular injection of a cyclooxygenase inhibitor markedly reduced anorexia, deletion of COX-2 selectively in neural cells, in myeloid cells or in both brain endothelial and neural cells had no effect on LPS-induced anorexia. In addition, COX-2 in myeloid and neural cells was dispensable for the fever response. Inflammation-induced conditioned taste aversion did not involve prostaglandin signaling at all. These findings collectively show that anorexia, fever and taste aversion are triggered by distinct routes of immune-to-brain signaling.

    Ort, förlag, år, upplaga, sidor
    Elsevier, 2017
    Nyckelord
    Anorexia, Conditioned place aversion, Cyclooxygenase, Fever, Inflammation, Lipopolysaccharide
    Nationell ämneskategori
    Immunologi inom det medicinska området
    Identifikatorer
    urn:nbn:se:liu:diva-136127 (URN)10.1016/j.bbi.2016.12.007 (DOI)000395365900026 ()27940259 (PubMedID)
    Anmärkning

    Funding agencies: Swedish Medical Research Council [20725, 07879]; European Research Council; Knut and Alice Wallenberg foundation; Swedish Brain Foundation; Swedish Cancer Foundation [213/692]; County Council of Ostergotland

    Tillgänglig från: 2017-03-28 Skapad: 2017-03-28 Senast uppdaterad: 2018-05-02Bibliografiskt granskad
  • 195.
    Nord, Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Närsjukvården i centrala Östergötland, Neurologiska kliniken.
    Levodopa pharmacokinetics -from stomach to brain: A study on patients with Parkinson’s disease2017Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [sv]

    Parkinsons sjukdom (PS) är en av de vanligaste s.k. neurodegenerativasjukdomarna och orsakas av förlust av dopamin(DA)producerande nervceller i hjärnan. Detta orsakar motoriska symptom såsom skakningar, stelhet och förlångsammade rörelser. Levodopa (LD) är ett ämne, som kan omvandlas till DA i hjärnan och ge symptomlindring och det är oftast förstahandsval vid behandling av patienter med PS. Flera faktorer påverkar tillgängligheten av LD, bl.a. den hastighet som magsäcken tömmer sig med och denna verkar förlångsammad hos personer med PS vilket ger sämre tillgänglighet av LD i blodet och därmed i hjärnan. LD bryts även ner i hög grad av olika enzym ute i kroppen vilket leder till mindre mängd LD som hamnar i hjärnan och till fler nedbrytningsprodukter som orsakar biverkningar. Tillägg av enzymhämmare leder till ökad mängd LD som kan nå hjärnan och omvandlas till DA. Det anses viktigt att undvika höga toppar av LD i hjärnan då dessa verkar bidra till utvecklandet av besvärliga motoriska komplikationer hos patienter med PS. Om LD ges mer kontinuerligt, exempelvis som en kontinuerlig infusion in i tarmen eller i blodet, så minskar dessa motoriska komplikationer. Inopererande av stimulatorer i vissa delar av hjärnan (DBS) har också visat sig minska dessa motoriska komplikationer och även resultera i att man kan minska LD-dosen.

    Huvudsyftet med den här avhandlingen är att studera LD hos patienter med PS; i blod och fettvävnad då LD ges i tablettform och se om det finns något samband med LD-upptag och hastigheten på magsäckstömningen (MT) och om kontinuerligt given LD påverkar LD-upptaget eller MT; i blod och i ryggmärgsvätska då enzymhämmarna entakapon och karbidopa tillsätts LD; i hjärna vid behandling med DBS och då LD ges både som tablett och som infusion i blodet.

    Sammanfattningsvis kan vi se att LD-upptaget är mer gynnsamt hos patienter med PS i tidigare skede av sjukdomens komplikationsfas. MT är förlångsammad hos patienter med PS och det är inget tydligt samband mellan LD-upptag och MT eller mellan MT och sjukdomsgrad. Kontinuerligt given LD minskar LDnivåerna. Enzymhämmaren entakapon ökar den maximala koncentrationen av LD i blod och ryggmärgsvätska och effekten är mer tydlig vid tillägg av karbidopa vilket är viktigt att ta i beaktande vid behandling av PS för att undvika höga toppar av LD i hjärnan. LD ökar i hjärnan då man behandlar med LD i tablettform och som infusion i blodet och DA-nivåerna i hjärnan följer LD väl vilket visar på att patienter med PS fortfarande kan omvandla LD till DA trots trolig uttalad brist av de DA-producerande nervcellerna i hjärnan. DBS verkar öka DA i vissa områden i hjärnan och tillsammans med LD-infusion i blodet verkar det även öka LD i hjärnan och det kan förklara varför man kan sänka LDdosen efter DBS-operation.

    Delarbeten
    1. Is Levodopa Pharmacokinetics in Patients with Parkinson’s Disease Depending on Gastric Emptying?
    Öppna denna publikation i ny flik eller fönster >>Is Levodopa Pharmacokinetics in Patients with Parkinson’s Disease Depending on Gastric Emptying?
    2017 (Engelska)Ingår i: Advances in Parkinsons Disease, ISSN 2169-9712, Vol. 06, nr 01Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Levodopa uptake from the gastrointestinal tract in patients with Parkinson’s disease (PD) can be affected by delayed gastric emptying (GE). This might lead to fluctuating levodopa levels resulting in increased motor fluctuations. Continuous dopaminergic stimulation (CDS) improves motor fluctuations and could be a result of smoothening in levodopa uptake. In this study we wanted to study the levodopa pharmacokinetics peripherally in PD patients with motor fluctuations and investigate the relation between levodopa uptake and GE and the effect of CDS. PD patients with wearing off (group 1) and on-off syndrome (group 2) were included. Breath tests were performed to evaluate the half time (T1/2) of GE. Concomitantly 1 tablet of Madopark® was given and the levodopa concentrations in blood and subcutaneous (SC) tissue were analyzed for both groups. Group 2 was then given a 10-d continuous intravenous levodopa treatment and the tests were repeated. Higher levels of levodopa in group 1 compared to group 2 in blood (p = 0.014) were seen. The GE was delayed in both group 1 (p < 0.001) and group 2 (p < 0.05) compared to a reference group with healthy volunteers with T1/2 median values 105 and 78 min vs. 72 min. There was no difference in GE between the two PD groups (p = 0.220) or in group 2 before and after infusion period (p = 0.861). CDS resulted in lower levodopa levels in blood (p < 0.001) and SC tissue (p < 0.01). In conclusion, PD patients in early complication phase have a more favourable levodopa uptake than patients later in disease. We found delayed GE in PD patients with motor fluctuations but no obvious relation between GE and levodopa uptake or GE and PD stage. The effect of CDS indicates no effect of CDS on the mechanisms of GE but on the mechanisms of levodopa uptake.

    Ort, förlag, år, upplaga, sidor
    Scientific Research Publishing, 2017
    Nationell ämneskategori
    Neurologi Gastroenterologi Anestesi och intensivvård Kirurgi Kardiologi
    Identifikatorer
    urn:nbn:se:liu:diva-136685 (URN)10.4236/apd.2017.61001 (DOI)
    Tillgänglig från: 2017-04-20 Skapad: 2017-04-20 Senast uppdaterad: 2018-01-12
    2. The Effect of Peripheral Enzyme Inhibitors on Levodopa Concentrations in Blood and CSF
    Öppna denna publikation i ny flik eller fönster >>The Effect of Peripheral Enzyme Inhibitors on Levodopa Concentrations in Blood and CSF
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    2010 (Engelska)Ingår i: Movement Disorders, ISSN 0885-3185, E-ISSN 1531-8257, Vol. 25, nr 3, s. 363-367Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Levodopa combined with a dopa-decarboxylase inhibitor, such as carbidopa. shifts the metabolism to the COMT pathway. Adding the peripheral acting COMT inhibitor entacapone provides improvement for patients with PD suffering from motor fluctuations. We studied the effects of the enzyme inhibitors entacapone and carbidopa on the levodopa concentrations in CSF and in blood. Five PD patients with wearing-off underwent lumbar drainage and intravenous microdialysis. Samples were taken 12 h daily for 3 days. Day I; intravenous levodopa was given, day 2; additional oral entacapone 200 mg tid, day 3; additional oral entacapone 200 mg bid and carbidopa 25 mg bid. Levodopa in CSF and in dialysates was analysed. The AUC for levodopa increased both in blood and CSF when additional entacapone was given alone and in combination with carbidopa. The C-max of levodopa in both CSF and blood increased significantly. Additional entacapone to levodopa therapy gives an increase of C-max in CSF and in blood. The increase is more evident when entacapone is combined with carbidopa.

    Ort, förlag, år, upplaga, sidor
    John Wiley & Sons, 2010
    Nyckelord
    Parkinsons Disease, levodopa, continuous infusion, COMT
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-54855 (URN)10.1002/mds.22613 (DOI)000276136900016 ()
    Tillgänglig från: 2010-04-16 Skapad: 2010-04-16 Senast uppdaterad: 2018-01-12
    3. Neurotransmitter levels in basal ganglia during levodopa and deep brain stimulation treatment in Parkinson’s disease
    Öppna denna publikation i ny flik eller fönster >>Neurotransmitter levels in basal ganglia during levodopa and deep brain stimulation treatment in Parkinson’s disease
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    2014 (Engelska)Ingår i: Neurology and Clinical Neuroscience, ISSN 2049-4173, Vol. 2, nr 5, s. 149-155Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Background The mechanism by which deep brain stimulation of the nucleus subthalamicus improves Parkinson’s disease symptoms remains unclear. In a previous perioperative study, we showed that there might be alterations of neurotransmitter levels in the globus pallidum interna during deep brain stimulation of the nucleus subthalamicus. Aim In this study, we examined whether deep brain stimulation of the nucleus subthalamicus and levodopa infusion interact and affect the levels of neurotransmitters. Methods Five patients with advanced Parkinson’s disease took part in the study. During subthalamic nucleus surgery, microdialysis catheters were inserted bilaterally in the globus pallidum interna and unilaterally in the right putamen. A study protocol was set up and was followed for 3 days. Levodopa infusion with and without concomitant bilateral deep brain stimulation of the nucleus subthalamicus was also carried out. Results The putaminal dopamine levels increased during deep brain stimulation of the nucleus subthalamicus. In addition, an increase of gamma amino buturic acid concentrations in the globus pallidum interna during deep brain stimulation of the nucleus subthalamicus and during levodopa infusion was found. Conclusions These findings provide evidence that the subthalamic nucleus has a direct action on the substantia nigra pars compacta, and that deep brain stimulation of the nucleus subthalamicus might indirectly release putaminal dopamine. There is also evidence that deep brain stimulation of the nucleus subthalamicus interferes with levodopa therapy resulting in higher levels of levodopa in the brain, explaining why it is possible to decrease levodopa medication after deep brain stimulation surgery.

    Ort, förlag, år, upplaga, sidor
    John Wiley & Sons, 2014
    Nyckelord
    deep brain stimulation, levodopa, microdialysis, neurotransmitters, Parkinson
    Nationell ämneskategori
    Medicinsk biovetenskap Medicinsk bioteknologi Medicinska och farmaceutiska grundvetenskaper
    Identifikatorer
    urn:nbn:se:liu:diva-113590 (URN)10.1111/ncn3.109 (DOI)
    Tillgänglig från: 2015-01-23 Skapad: 2015-01-23 Senast uppdaterad: 2019-02-11Bibliografiskt granskad
    4. Levodopa Pharmacokinetics in Brain after Both Oral and Intravenous Levodopa in One Patient with Advanced Parkinson’s Disease
    Öppna denna publikation i ny flik eller fönster >>Levodopa Pharmacokinetics in Brain after Both Oral and Intravenous Levodopa in One Patient with Advanced Parkinson’s Disease
    2017 (Engelska)Ingår i: Advances in Parkinsons Disease, ISSN 2169-9712, Vol. 6, nr 2, s. 52-66Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Objective: One patient received oral levodopa during a study aiming for better understanding of the basal ganglia and of the mechanisms of deep brain stimulation of the subthalamic nucleus (STN DBS) with and without intravenous (IV) levodopa infusion in patients with Parkinson’s disease (PD). The results from oral and IV levodopa treatment are presented.

    Methods: Five patients with advanced PD were included in the original study. During planned STN DBS surgery microdialysis probes were implanted in the right putamen and in the right and left globus pallidus interna (Gpi). During the study, microdialysis was performed continuously and STN DBS, with and without IV levodopa infusion, was performed according to a specific protocol. After DBS surgery, but before STN DBS was started, one patient received oral levodopa/ benserazide and entacapone tablets out of protocol due to distressing parkinsonism.

    Results: The levodopa levels increased prompt in the central nervous system after the first PD medication intakes but declined after the last. Immediately the levodopa seemed to be metabolized to dopamine (DA) since the levels of DA correlated well with levodopa concentrations. Left STN DBS seemed to further increase DA levels in left Gpi while right STN DBS seemed to increase DA levels in the right putamen and right Gpi. There was no obvious effect on levodopa levels.

    Conclusions: The results indicate that PD patients still have capacity to metabolize levodopa to DA despite advanced disease with on-off symptoms and probably pronounced nigral degeneration. STN DBS seems to increase DA levels with a more pronounced effect on ipsilateral structures in striatum.

    Ort, förlag, år, upplaga, sidor
    Scientific Research Publishing Inc, 2017
    Nyckelord
    Parkinson’s Disease, Levodopa, Dopamine, Brain, Microdialysis, Deep Brain Stimulation
    Nationell ämneskategori
    Neurologi Kardiologi Gastroenterologi Anestesi och intensivvård Annan klinisk medicin
    Identifikatorer
    urn:nbn:se:liu:diva-139251 (URN)10.4236/apd.2017.62006 (DOI)
    Tillgänglig från: 2017-07-07 Skapad: 2017-07-07 Senast uppdaterad: 2018-01-12Bibliografiskt granskad
  • 196.
    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
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    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 Model2016Ingår i: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 36, nr 18, s. 5084-5093Artikel i tidskrift (Refereegranskat)
    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.

  • 197. Nuttall, Alfred L
    et al.
    Fridberger, Anders
    Karolinska Institutet, Stockholm, Sweden.
    Instrumentation for studies of cochlear mechanics: from von Békésy forward2012Ingår i: Hearing Research, ISSN 0378-5955, E-ISSN 1878-5891, Vol. 293, nr 1-2, s. 3-11Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Georg von Békésy designed the instruments needed for his research. He also created physical models of the cochlea allowing him to manipulate the parameters (such as volume elasticity) that could be involved in controlling traveling waves. This review is about the specific devices that he used to study the motion of the basilar membrane thus allowing the analysis that lead to his Nobel Prize Award. The review moves forward in time mentioning the subsequent use of von Békésy's methods and later technologies important for motion studies of the organ of Corti. Some of the seminal findings and the controversies of cochlear mechanics are mentioned in relation to the technical developments.

  • 198.
    Nuttall, Alfred L.
    et al.
    Oregon Hlth and Sci Univ, OR 97239 USA.
    Ricci, Anthony J.
    Stanford Univ, CA 94025 USA; Stanford Univ, CA 94025 USA.
    Burwood, George
    Oregon Hlth and Sci Univ, OR 97239 USA.
    Harte, James M.
    Tech Univ Denmark, Denmark.
    Stenfelt, Stefan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Logopedi, Audiologi och Otorhinolaryngologi. Linköpings universitet, Medicinska fakulteten.
    Caye-Thomasen, Per
    Copenhagen Univ Hosp, Denmark.
    Ren, Tianying
    Oregon Hlth and Sci Univ, OR 97239 USA.
    Ramamoorthy, Sripriya
    Indian Inst Technol, India.
    Zhang, Yuan
    Oregon Hlth and Sci Univ, OR 97239 USA.
    Wilson, Teresa
    Oregon Hlth and Sci Univ, OR 97239 USA.
    Lunner, Thomas
    Linköpings universitet, Institutionen för beteendevetenskap och lärande, Handikappvetenskap. Linköpings universitet, Filosofiska fakulteten. Linköpings universitet, Institutet för handikappvetenskap (IHV). Oticon AS, Denmark.
    Moore, Brian C. J.
    Univ Cambridge, England.
    Fridberger, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten. Oregon Hlth and Sci Univ, OR 97239 USA.
    A mechanoelectrical mechanism for detection of sound envelopes in the hearing organ2018Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, artikel-id 4175Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    To understand speech, the slowly varying outline, or envelope, of the acoustic stimulus is used to distinguish words. A small amount of information about the envelope is sufficient for speech recognition, but the mechanism used by the auditory system to extract the envelope is not known. Several different theories have been proposed, including envelope detection by auditory nerve dendrites as well as various mechanisms involving the sensory hair cells. We used recordings from human and animal inner ears to show that the dominant mechanism for envelope detection is distortion introduced by mechanoelectrical transduction channels. This electrical distortion, which is not apparent in the sound-evoked vibrations of the basilar membrane, tracks the envelope, excites the auditory nerve, and transmits information about the shape of the envelope to the brain.

  • 199.
    Okuda, Darin T
    et al.
    UT Southwestern Medical Center, Department of Neurology & Neurotherapeutics, Clinical Center for Multiple Sclerosis, Dallas, Tx, USA.
    Melmed, Kara
    University of Arizona College of Medicine, Phoenix, 550 E. Van Buren, Phoenix, Az, USA.
    Matsuwaki, Takashi
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Blomqvist, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Craig, Arthur D Bud
    Atkinson Research Laboratory, Barrow Neurological Institute, 350 W. Thomas Road, Phoenix, Az, USA.
    Central neuropathic pain in MS is due to distinct thoracic spinal cord lesions.2014Ingår i: Annals of clinical and translational neurology, ISSN 2328-9503, Vol. 1, nr 8, s. 554-61Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE: To determine a neuro-anatomic cause for central neuropathic pain (CNP) observed in multiple sclerosis (MS) patients.

    METHODS: Parallel clinical and neuro-anatomical studies were performed. A clinical investigation of consecutively acquired MS patients with and without CNP (i.e. cold allodynia or deep hyperesthesia) within a single MS center was pursued. A multivariate logistic regression model was used to assess the relationship between an upper central thoracic spinal cord focus to central pain complaints. To identify the hypothesized autonomic interneurons with bilateral descending projections to lumbosacral sensory neurons, retrograde single- and double-labeling experiments with CTb and fluorescent tracers were performed in three animal species (i.e. rat, cat, and monkey).

    RESULTS: Clinical data were available in MS patients with (n = 32; F:23; median age: 34.6 years (interquartile range [IQR]: 27.4-45.5)) and without (n = 30; F:22; median age: 36.6 years [IQR: 31.6-47.1]) CNP. The value of a central focus between T1-T6 in relation to CNP demonstrated a sensitivity of 96.9% (95% confidence interval [CI]: 83.8-99.9) and specificity of 83.3% (95% CI: 65.3-94.4). A significant relationship between CNP and a centrally located focus within the thoracic spine was also observed (odds ratio [OR]: 155.0 [95% CI lower limit: 16.0]; P < 0.0001, two-tailed Fisher exact test). In all animal models, neurons with bilateral descending projections to the lumbosacral superficial dorsal horn were concentrated in the autonomic intermediomedial nucleus surrounding the mid-thoracic central canal.

    INTERPRETATION: Our observations provide the first evidence for the etiology of CNP. These data may assist with the development of refined symptomatic therapies and allow for insights into unique pain syndromes observed in other demyelinating subtypes.

  • 200.
    Osman, Ayman
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Autophagy in Peripheral Neuropathy2017Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Peripheral neuropathy includes a wide range of diseases affecting millions around the world, and many of these diseases have unknown etiology. Peripheral neuropathy in diabetes represents a large proportion of peripheral neuropathies. Nerve damage can also be caused by trauma. Peripheral neuropathies are a significant clinical problem and efficient treatments are largely lacking. In the case of a transected nerve, different methods have been used to repair or reconstruct the nerve, including the use of nerve conduits, but functional recovery is usually poor.

    Autophagy, a cellular mechanism that recycles damaged proteins, is impaired in the brain in many neurodegenerative diseases affecting animals and humans. No research, however, has investigated the presence of autophagy in the human peripheral nervous system. In this study, I present the first structural evidence of autophagy in human peripheral nerves. I also show that the density of autophagy structures is higher in peripheral nerves of patients with chronic idiopathic axonal polyneuropathy (CIAP) and inflammatory neuropathy than in controls. The density of these structures increases with the severity of the neuropathy.

    In animal model, using Goto-Kakizaki (GK) rats with diabetes resembling human type 2 diabetes, activation of autophagy by local administration of rapamycin incorporated in collagen conduits that were used for reconnection of the transected sciatic nerve led to an increase in autophagy proteins LC3 and a decrease in p62 suggesting that the autophagic flux was activated. In addition, immunoreactivity of neurofilaments, which are parts of the cytoskeleton of axons, was increased indicating increased axonal regeneration. I also show that many proteins involved in axonal regeneration and cell survival were up-regulated by rapamycin in the injured sciatic nerve of GK rats four weeks after injury.

    Taken together, these findings provide new knowledge about the involvement of autophagy in neuropathy and after peripheral nerve injury and reconstruction using collagen conduits.

    Delarbeten
    1. Autophagy in the posterior interosseous nerve of patients with type 1 and type 2 diabetes mellitus: an ultrastructural study
    Öppna denna publikation i ny flik eller fönster >>Autophagy in the posterior interosseous nerve of patients with type 1 and type 2 diabetes mellitus: an ultrastructural study
    2015 (Engelska)Ingår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 58, nr 3, s. 625-632Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    We addressed the question of whether the autophagy pathway occurs in human peripheral nerves and whether this pathway is associated with peripheral neuropathy in diabetes mellitus. By using electron microscopy, we evaluated the presence of autophagy-related structures and neuropathy in the posterior interosseous nerve of patients who had undergone carpal tunnel release and had type 1 or type 2 diabetes mellitus, and in patients with no diabetes (controls). Autophagy-related ultrastructures were observed in the samples taken from all patients of the three groups. The number of autophagy-associated structures was significantly higher (p less than 0.05) in the nerves of patients with type 1 than type 2 diabetes. Qualitative and quantitative evaluations of fascicle area, diameter of myelinated and unmyelinated nerve fibres, the density of myelinated and unmyelinated fibres and the g-ratio of myelinated fibres were performed. We found degeneration and regeneration of a few myelinated axons in controls, and a well-developed neuropathy with the loss of large myelinated axons and the presence of many small ones in patients with diabetes. The pathology in type 1 diabetes was more extensive than in type 2 diabetes. The results of this study show that the human peripheral nerves have access to the autophagy machinery, and this pathway may be regulated differently in type 1 and type 2 diabetes; insulin, presence of extensive neuropathy, and/or other factors such as duration of diabetes and HbA(1c) level may underlie this differential regulation.

    Ort, förlag, år, upplaga, sidor
    Springer Verlag (Germany), 2015
    Nyckelord
    Autophagy; Diabetes; Electron microscopy; Human; Neuropathy; Peripheral nerve
    Nationell ämneskategori
    Klinisk medicin
    Identifikatorer
    urn:nbn:se:liu:diva-115314 (URN)10.1007/s00125-014-3477-4 (DOI)000349244100024 ()25523623 (PubMedID)
    Tillgänglig från: 2015-03-13 Skapad: 2015-03-13 Senast uppdaterad: 2017-12-04
    2. Study of Autophagy and Microangiopathy in Sural Nerves of Patients with Chronic Idiopathic Axonal Polyneuropathy.
    Öppna denna publikation i ny flik eller fönster >>Study of Autophagy and Microangiopathy in Sural Nerves of Patients with Chronic Idiopathic Axonal Polyneuropathy.
    Visa övriga...
    2016 (Engelska)Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, nr 9, artikel-id e0163427Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Twenty-five percent of polyneuropathies are idiopathic. Microangiopathy has been suggested to be a possible pathogenic cause of chronic idiopathic axonal polyneuropathy (CIAP). Dysfunction of the autophagy pathway has been implicated as a marker of neurodegeneration in the central nervous system, but the autophagy process is not explored in the peripheral nervous system. In the current study, we examined the presence of microangiopathy and autophagy-related structures in sural nerve biopsies of 10 patients with CIAP, 11 controls with inflammatory neuropathy and 10 controls without sensory polyneuropathy. We did not find any significant difference in endoneurial microangiopathic markers in patients with CIAP compared to normal controls, though we did find a correlation between basal lamina area thickness and age. Unexpectedly, we found a significantly larger basal lamina area thickness in patients with vasculitic neuropathy. Furthermore, we found a significantly higher density of endoneurial autophagy-related structures, particularly in patients with CIAP but also in patients with inflammatory neuropathy, compared to normal controls. It is unclear if the alteration in the autophagy pathway is a consequence or a cause of the neuropathy. Our results do not support the hypothesis that CIAP is primarily caused by a microangiopathic process in endoneurial blood vessels in peripheral nerves. The significantly higher density of autophagy structures in sural nerves obtained from patients with CIAP and inflammatory neuropathy vs. controls indicates the involvement of this pathway in neuropathy, particularly in CIAP, since the increase in density of autophagy-related structures was more pronounced in patients with CIAP than those with inflammatory neuropathy. To our knowledge this is the first report investigating signs of autophagy process in peripheral nerves in patients with CIAP and inflammatory neuropathy.

    Ort, förlag, år, upplaga, sidor
    : San Francisco, CA : Public Library of Science, 2016
    Nationell ämneskategori
    Reumatologi och inflammation
    Identifikatorer
    urn:nbn:se:liu:diva-132168 (URN)10.1371/journal.pone.0163427 (DOI)000383893500033 ()27662650 (PubMedID)
    Anmärkning

    Funding agencies: patient association for neurological disorders in Sweden; NeurofoErbundet(NHR-Foundation); foundation Promobilia, Sweden

    Tillgänglig från: 2016-10-19 Skapad: 2016-10-19 Senast uppdaterad: 2017-11-29Bibliografiskt granskad
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