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  • 1.
    Allard, Per
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Marcusson, J O
    Ross, S B
    [3H]WIN 35,428 binding in the human brain.1996In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 706, no 2, p. 347-50Article in journal (Refereed)
    Abstract [en]

    The binding of [3H]WIN 35,428 was studied in post-mortem human brain, including extrastriatal regions. In the putamen, dopamine almost completely inhibited the [3H]WIN 35,428 binding. Paroxetine inhibited the binding with similar affinity as cocaine, in the range 200-300 nM. In the frontal cortex, [3H]WIN 35,428 labelled cocaine- and alaproclate sensitive binding sites, of which a major fraction was of protein nature. The elucidation of the cocaine sensitive sites in the frontal cortex should be the subject of further research.

  • 2.
    Allard, Per
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Rinne, J
    Marcusson, J O
    Dopamine uptake sites in Parkinson's disease and in dementia of the Alzheimer type.1994In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 637, no 1-2, p. 262-6Article in journal (Refereed)
    Abstract [en]

    The binding of [3H]GBR-12935 to dopamine (DA) uptake sites was studied in post-mortem putamen from a control group and from patients with Parkinson's disease (PD) or dementia of the Alzheimer type (DAT). The specific binding (Bmax) was almost completely abolished in the PD group and reduced by 65% in the DAT group. There were no significant differences in apparent binding affinity (Kd) between the DAT group and controls. The decreases in [3H]GBR-12935 binding to DA uptake sites in this study indicate a marked degeneration of DA neurites in the putamen in PD and also in DAT.

  • 3.
    Andin, Josefine
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Geriatrics.
    Hallbeck, Martin
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of cell biology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Mohammed, Abdul H
    Marcusson, Jan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Geriatrics. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Geriatric Medicine.
    Influence of environmental enrichment on steady-state mRNA levels for EAAC1, AMPA1 and NMDA2A receptor subunits in rat hippocampus2007In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1174, no 1, p. 18-27Article in journal (Refereed)
    Abstract [en]

    Interaction with the environment has a key role in refining the neuronal circuitry required for normal brain function throughout life. Profound effects of enriched environment have been shown on neuronal structure and chemistry in experimental animals. Epidemiological studies imply that this is true also in man, thus cognitive stimulation has a protective effect on neurodegeneration, e.g., in Alzheimer's disease. Glutamatergic pathways are imperative for cognitive functions, such as memory, learning and long-term potentiation, and relies on the AMPA and NMDA glutamate receptors and the hippocampus, with its specific subregions, is an important anatomical substrate in this. The glutamate signalling is also dependent on a fine-tuned transport system, in the hippocampus primarily achieved by the glutamate transporter EAAC1. In this study we show how environmental enrichment modulates these parts of the glutamatergic system using quantitative in situ hybridisation. This work demonstrates for the first time that environmental enrichment modulates the mRNA expression of EAAC1 which is significantly and region specifically decreased in the hippocampus. We also provide evidence for regional and hemisphere-specific upregulation of NMDA mRNA in the hippocampus after environmental enrichment. The current work also shows that AMPA mRNA of the hippocampus is not per se changed by environmental enrichment in adult animals. Taken together, our results extend the knowledge of the glutamatergic system of specific regions of the hippocampus and its modulation by environmental enrichment and could contribute to the development of strategies aimed at limiting pathological changes associated with glutamatergic dysfunctions. © 2007.

  • 4. Arnelo, Urban
    et al.
    Herrington, Margery
    Theodorsson, Elvar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Clinical Chemistry. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
    Adrian, Thomas
    Reidelberger, Roger
    Larsson, Jörgen
    Marcusson, Jan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Geriatrics. Östergötlands Läns Landsting, MC - Medicincentrum, Geriatrik-LAH.
    Strömmer, Lisa
    Ding, Xianzhong
    Permert, Johan
    Effects of long-term infusion of anorexic concentrations of islet amyloid polypeptide on neurotransmitters and neuropeptides in rat brain.2000In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 887, p. 391-398Article in journal (Refereed)
  • 5.
    Asser, Andres
    et al.
    Univ Tartu, Dept Neurol & Neurosurg, Puusepa 8, EE-50409 Tartu, Estonia..
    Koks, Sulev
    Univ Tartu, Dept Pathophysiol, Tartu, Estonia..
    Snellman, Anniina
    Univ Turku, Turku PET Ctr, Turku, Finland..
    Haaparanta-Solin, Merja
    Univ Turku, Turku PET Ctr, Turku, Finland..
    Arponen, Eveliina
    Univ Turku, Turku PET Ctr, Turku, Finland..
    Gronroos, Tove
    Univ Turku, Turku PET Ctr, Turku, Finland..
    Nairismagi, Jaak
    Tallinn Univ Technol, Inst Gene Technol, Tallinn, Estonia..
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Soomets, Ursel
    Univ Tartu, Dept Biochem, Tartu, Estonia..
    Piip, Piret
    Univ Tartu, Dept Neurol & Neurosurg, Puusepa 8, EE-50409 Tartu, Estonia..
    Eltermaa, Mall
    Univ Tartu, Dept Neurol & Neurosurg, Puusepa 8, EE-50409 Tartu, Estonia..
    Sauk, Martin
    Univ Tartu, Dept Neurol & Neurosurg, Puusepa 8, EE-50409 Tartu, Estonia..
    Lindmae, Hanna
    Univ Tartu, Dept Neurol & Neurosurg, Puusepa 8, EE-50409 Tartu, Estonia..
    Rinne, Juha O.
    Univ Turku, Turku PET Ctr, Turku, Finland.;Turku Univ Hosp, Dept Neurol, Turku, Finland..
    Taba, Pille
    Univ Tartu, Dept Neurol & Neurosurg, Puusepa 8, EE-50409 Tartu, Estonia..
    Increased striatal VMAT2 binding in mice after chronic administration of methcathinone and manganese2016In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1652, p. 97-102Article in journal (Refereed)
    Abstract [en]

    Intravenous use of a psychostimulant drug containing methcathinone (ephedrone) and manganese causes an irreversible extrapyramidal syndrome in drug abusers. We aimed to reproduce the syndrome in mice to evaluate dopaminergic damage. C57/B6 mice were intraperitoneally injected once a day with the study drug or saline for a period of 27 weeks. Motor activity was recorded in an automated motility-box. After 13 and 27 weeks of treatment, ex vivo digital autoradiography was performed using [C-11]dihydrotetrabenazine ([C-11]DTBZ). After 27 weeks of treatment [C-11]DTBZ autoradiography demonstrated a significant increase in the striatum to -cerebellum binding ratio compared with saline treated controls. At the same time point, there was no evident change in motor activity. Increased [C-11]DTBZ binding may indicate vesicular monoamine transporter type 2 (VMAT2) function is altered. The lack of extrapyramidal symptoms in animals could be attributed to low dosing regimen or high metabolic rate.

  • 6.
    Atis, Muge
    et al.
    Koc Univ, Sch Med, Dept Physiol, Istanbul, Turkey.
    Akcan, Ugur
    Koc Univ, Sch Med, Dept Physiol, Istanbul, Turkey.
    Ugur Yilmaz, Canan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Orhan, Nurcan
    Istanbul Univ, Aziz Sancar Expt Med Res Inst, Dept Neurosci, Istanbul, Turkey.
    Duzgun, Poyraz
    Koc Univ, Sch Med, Dept Physiol, Istanbul, Turkey.
    Ceylan, Umut Deniz
    Koc Univ, Sch Med, Dept Physiol, Istanbul, Turkey.
    Arican, Nadir
    Istanbul Univ, Istanbul Fac Med, Dept Forens Sci, Istanbul, Turkey.
    Karahuseyinoglu, Sercin
    Koc Univ, Sch Med, Dept Histol & Embryol, Istanbul, Turkey.
    Sahin, Gizem Nur
    Koc Univ, Sch Med, Dept Histol & Embryol, Istanbul, Turkey.
    Ahishali, Bulent
    Istanbul Fac Med, Dept Histol & Embryol, Istanbul, Turkey.
    Kaya, Mehmet
    Koc Univ, Sch Med, Dept Physiol, Istanbul, Turkey.
    Effects of methyl-beta-cyclodextrin on blood-brain barrier permeability in angiotensin II-induced hypertensive rats2019In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1715, p. 148-155Article in journal (Refereed)
    Abstract [en]

    The blood-brain barrier (BBB) permeability primarily increases in cerebral venules during acute hypertension. Methyl-beta-cyclodextrin (M beta CD), a cholesterol-depleting agent, decreases the expression of caveolins disrupting caveolar structures. We aimed to determine the effects of M beta CD on the BBB permeability of angiotensin (ANG) II-induced hypertensive rats. Three minutes after M beta CD administration (5 mg/kg), acute hypertension was induced by ANG II (60 mu g/kg). Evans blue (EB) and horseradish peroxidase (HRP) tracers were used to assess BBB permeability. Immunohistochemistry for caveolin (Cav)-1 and tight junction protein claudin-5 was performed. EB dye content significantly increased in both cerebral cortices and left hippocampus in M beta CD (P < 0.05), right cerebral cortex and both hippocampi in ANG II (P < 0.05; P < 0.01), and both cerebral cortices and hippocampi in M beta CD plus ANG II groups compared with controls (P < 0.05; P < 0.01). A significant decrease in claudin-5 immunostaining intensity was observed in animals treated with M beta CD compared with controls (P < 0.05). Cav-1 immunostaining intensity increased in ANG II group (P < 0.05). Ultrastructurally, HRP reaction products were observed in endothelial cells of the microvessels in the hippocampus region in M beta CD group while the tracer was mainly localized in astrocytes and neurons in ANG II, and M beta CD plus ANG II groups. The endothelial cells of the venules in the cerebral cortex of the animals in the latter experimental groups also showed an abundance of caveolar vesicles devoid of HRP reaction products. Our results revealed that M beta CD did not provide overall protective effects on BBB integrity in acute hypertension and even led to BBB disruption in normotensive animals.

  • 7.
    Bagheri, Maryam
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Roghani, Mehrdad
    Shahed University.
    Joghataei, Mohammad-Taghi
    Tehran University of Medical Sciences.
    Mohseni, Simin
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Genistein inhibits aggregation of exogenous amyloid-beta(1-40) and alleviates astrogliosis in the hippocampus of rats2012In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1429, p. 145-154Article in journal (Refereed)
    Abstract [en]

    We addressed the question of whether injection of Amyloid beta (Aβ)(1-40) in the rat brain is associated with pathology in the hippocampus, and if genistein has any protective effect against the neuronal damage caused by Aβ(1-40). Genistein is a plant-derived compound with a structure similar to that of the female sex hormone estrogen and it was recently shown that pretreatment with a single dose of genistein ameliorated learning and memory deficits in an (Aβ)(1-40) rat model of Alzheimer's disease. Here, we report that injection of the amyloid peptide into the hippocampus of rats led to formation of Aβ(1-40) positive aggregates close to the lateral blade of the dentate gyrus (DGlb). We also observed the following in the hippocampus: extensive cell death in the DGlb (P<0.0001), CA1 (P=0.03), and CA3 (P=0.002); an increased number of iNOS-expressing cells (P=0.01) and gliosis. Genistein given to rats by gavage 1h before injection of Aβ(1-40) inhibited the formation of Aβ(1-40) positive aggregates in the brain tissue and led to increased number of nNOS(+) (P=0.0001) cells in the hippocampus compared to sham-operated genistein-treated controls. Treatment with genistein also alleviated the extensive astrogliosis that occurred in Aβ(1-40)-injected hippocampus to a level similar to that observed in sham-operated rats. We conclude that the neurons in the DGlb are most sensitive to Aβ(1-40), and a single dose of genistein can ameliorate Aβ(1-40) induced pathology.

  • 8.
    Bergamino, Maurizio
    et al.
    Laureate Institute for Brain Research, Tulsa, OK, USA.
    Farmer, Madison
    Roosevelt University, Department of Industrial and Organizational Psychology, Chicago, IL, USA.
    Yeh, Hung-Wen
    Laureate Institute for Brain Research, Tulsa, OK, USA.
    Paul, Elisabeth
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Hamilton, Paul J.
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Statistical differences in the white matter tracts in subjects with depression by using different skeletonized voxel-wise analysis approaches and DTI fitting procedures2017In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1669, p. 131-140Article in journal (Refereed)
    Abstract [en]

    Major depressive disorder (MDD) is one of the most significant contributors to the global burden of illness. Diffusion tensor imaging (DTI) is a procedure that has been used in several studies to characterize abnormalities in white matter (WM) microstructural integrity in MDD. These studies, however, have provided divergent findings, potentially due to the large variety of methodological alternatives available in conducting DTI research. In order to determine the importance of different approaches to coregistration of DTI-derived metrics to a standard space, we compared results from two different skeletonized voxel-wise analysis approaches: the standard TBBS pipeline and the Advanced Normalization Tools (ANTs) approach incorporating a symmetric image normalization (SyN) algorithm and a group-wise template (ANTs TBSS). We also assessed effects of applying twelve different fitting procedures for the diffusion tensor. For our dataset, lower fractional anisotropy (FA) and axial diffusivity (AD) in depressed subjects compared with healthy controls were found for both methods and for all fitting procedures. No group differences were found for radial and mean diffusivity indices. Importantly, for the AD metric, the normalization methods and fitting procedures showed reliable differences, both in the volume and in the number of significant between-groups difference clusters detected. Additionally, a significant voxel-based correlation, in the left inferior fronto-occipital fasciculus, between AD and self-reported stress was found only for one of the normalization procedure (ANTs TBSS). In conclusion, the sensitivity to detect group-level effects on DTI metrics might depend on the DTI normalization and/or tensor fitting procedures used.

  • 9. Bergenheim, M
    et al.
    Johansson, H
    Pedersen, J
    Öhberg, Fredrik
    Umeå University, Faculty of Medicine, Radiation Sciences.
    Sjölander, P
    Ensamble coding of muscle stretches in afferent populations containing different types of muscle afferents1996In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 734, no 1-2, p. 157-166Article in journal (Refereed)
    Abstract [en]

    Ensemble coding of simple mechanical stimuli (small sinusoidal stretches) was studied in simultaneously recorded mixed ensembles of primary- and secondary muscle spindle afferents (MSAs), and Golgi tendon organ (GTO) afferents recorded from L7-S1 dorsal root filaments. The experiments were made on 48 recorded afferents (29 primary MSAs, 6 secondary MSAs and 13 GTO afferents) in chloralose anaesthetised cats. For the analyses, we used a combination of principal component analysis and algorithms for quantification of stimulus discrimination. Mixed ensembles of primary- and secondary MSAs, and GTO afferents, discriminated significantly better between different muscle stretches than ensembles of only one or two types of these afferents. All kinds of ensembles showed a successive increase in discriminative ability with increased ensemble size, and this ability seemed to level at larger populations. However, the increase in discriminative ability was significantly greater for the mixed ensembles. It is hypothesised that the main reason for the greater discriminative ability achieved by mixed ensembles, might be that the variation in response profiles (sensitivity tuning) among the individual afferents of the mixed ensemble will be larger than that for ensembles of only one type of afferent. Finally, the results in the present study give experimental support to some of the teleological arguments in favour of the ensemble coding theory.

  • 10.
    Birgner, Carolina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kindlundh-Högberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Alsiö, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Lindblom, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Bergström, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    The anabolic androgenic steroid nandrolone decanoate affects mRNA expression of dopaminergic but not serotonergic receptors2008In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1240, p. 221-228Article in journal (Refereed)
    Abstract [en]

    The abuse of anabolic androgenic steroids (AASs) at supratherapeutic doses is a problem not only in the world of sports, but also among non-athletes using AASs to improve physical appearance and to become more bold and courageous. Investigations of the possible neurochemical effects of AAS have focused partially on the monoaminergic systems, which are involved in aggressive behaviours and the development of drug dependence. In the present study, we administered nandrolone decanoate (3 or 15 mg/kg/day for 14 days) and measured mRNA expression of dopaminergic and serotonergic receptors, transporters and enzymes in the male rat brain using quantitative real-time polymerase chain reaction. Expression of the dopamine D1-receptor transcript was elevated in the amygdala and decreased in the hippocampus while the transcript level of the dopamine D4-receptor was increased in the nucleus accumbens. No changes in transcriptional levels were detected among the serotonin-related genes examined in this study. The altered mRNA expression of the dopamine receptors may contribute to some of the behavioural changes often reported in AAS abusers of increased impulsivity, aggression and drug-seeking.

  • 11.
    Birgner, Carolina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Pharmaceutical Pharmacology.
    Kindlundh-Högberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Oreland, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Alsiö, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Lindblom, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Bergström, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Reduced activity of monoamine oxidase in the rat brain following repeated nandrolone decanoate administration2008In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1219, p. 103-110Article in journal (Refereed)
    Abstract [en]

    Anabolic androgenic steroids (AAS) are known as doping agents within sports and body-building, but are currently also abused by other groups in society in order to promote increased courage and aggression. We previously showed that 14 days of daily intramuscular injections of the AAS nandrolone decanoate (15 mg/kg) reduced the extracellular levels of the dopaminergic metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the nucleus accumbens shell using microdialysis. The aim of the present study was to investigate whether the same dose regimen of nandrolone decanoate may affect the activities of the dopamine-metabolizing enzymes monoamine oxidases A and B (MAO-A and MAO-B). A radiometric assay was used to determine the activities of MAO-A and MAO-B in rat brain tissues after 14 days of daily i.m. nandrolone decanoate injections at the doses 3 and 15 mg/kg. Gene transcript contents of MAO-A, MAO-B and cathecol-O-methyltransferase (COMT) were measured with quantitative real-time reverse transcription PCR. 3 mg/kg of nandrolone decanoate significantly reduced the activity of both MAO-A and -B in the caudate putamen. 15 mg/kg of nandrolone decanoate significantly reduced the activity of MAO-A in the amygdala and increased the gene transcript level of MAO-B in the substantia nigra. In conclusion, imbalanced MAO activities may contribute to explain the impulsive and aggressive behaviour often described in AAS abusers. The reduced MAO activities observed are in line with our previously presented findings of decreased extracellular levels of DOPAC and HVA in the rat brain, indicating decreased monoaminergic activity following repeated AAS administration.

  • 12.
    Bjartmar, Lisa
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Geriatric . Linköping University, Faculty of Health Sciences.
    Alkhori, Liza
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Ruud, Johan
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Marcusson, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Geriatric . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Geriatric Medicine.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Cytology.
    Long-term treatment with antidepressants, but not environmental stimulation, induces expression of NP2 mRNA in hippocampus and medial habenula2010In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1328, p. 24-33Article in journal (Refereed)
    Abstract [en]

    Neuronal Pentraxin 2 (NP2, Narp), known to mediate clustering of glutamatergic AMPA receptors at synapses, is involved in activity-dependent synaptogenesis and synaptic plasticity. In experimental settings, antidepressant treatment as well as a stimulating environment has a positive influence on cognition and hippocampal plasticity. This study demonstrates that NP2 mRNA is robustly expressed in the hippocampus and the medial habenula (MHb), both regions implicated in cognitive functions. Furthermore, NP2 mRNA expression is enhanced in the hippocampal subregions as well as in the MHb after long-term treatment with antidepressant drugs of various monoaminergic profiles, indicating a common mode of action of different antidepressant drugs. This effect occurs at the time frame where clinical response is normally achieved. In contrast, neither environmental enrichment nor deprivation has any influence on long-term NP2 mRNA expression. These findings support an involvement of NP2 in the pathway of antidepressant induced plasticity, but not EE induced plasticity; that NP2 might constitute a common link for the action of different types of antidepressant drugs and that the MHb could be a putative region for further studies of NP2.

  • 13. Bjartmar, Lisa
    et al.
    Alkhori, Liza
    Ruud, Johan
    Mohammed, Abdul K. H.
    Linnaeus University, Faculty of Health, Social Work and Behavioural Sciences, School of Education, Psychology and Sport Science. Karolinska Institutet.
    Marcusson, Jan
    Hallbeck, Martin
    Long-term treatment with antidepressants, but not environmental stimulation, induces expression of NP2 mRNA in hippocampus and medial habenula.2010In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1328, p. 25-33Article in journal (Refereed)
    Abstract [en]

    In experimental settings, antidepressant treatment as well as a stimulating environment has a positive influence on cognition and hippocampal plasticity. One putative mediator of this process is Neuronal Pentraxin 2 (NP2, Narp), known to mediate clustering of glutamatergic AMPA receptors at synapses, and demonstrated to play a role in activity-dependent synaptogenesis and synaptic plasticity. This study demonstrates that NP2 mRNA is robustly expressed in all hippocampal subregions and the medial habenula (MHb), both regions implicated in cognitive functions. Furthermore, NP2 mRNA expression is upregulated in the hippocampal subregions as well as in the MHb after long-term treatment with different antidepressant drugs regardless of monoaminergic profile, suggesting NP2 as a common mode of action of different antidepressant drugs. This effect occurs at the time frame where clinical response is normally achieved. In contrast, neither environmental enrichment nor deprivation has any influence on long-term NP2 mRNA expression. These findings support an involvement of NP2 in the pathway of antidepressant-induced plasticity, but not EE-induced plasticity; that NP2 might constitute a common link for the action of different types of antidepressant drugs and that the MHb could be a putative region for further studies of NP2.

  • 14. Bytner, Beta
    et al.
    Huang, Yan-Huang
    Yu, Long-Chuan
    Lundeberg, Thomas
    Nylander, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Rosén, Annika
    Nociceptin/orphanin FQ into the rat periaqueductal gray decreases the withdrawal latency to heat and loading, an effect reversed by (Nphe1)nociceptin(1-13)NH22001In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 922, no 1, p. 118-124Article in journal (Refereed)
    Abstract [en]

    The present study investigated the effect of intraperiaqueductal grey injection of nociceptin/orphanin FQ (N/OFQ) and an antagonist (Nphe(1))nociceptin(1-13)NH(2) on the hindpaw withdrawal response to thermal and mechanical stimulation in rats. N/OFQ (5 nmol) significantly decreased the nociceptive thresholds in both tests and 1, 5 and 10 nmol of (Nphe(1))nociceptin(1-13)NH(2) significantly reversed this effect in a dose dependent way. Our results demonstrate, that N/OFQ has a nociceptive action, possibly through inhibition of PAG neurons. This effect is blocked by the antagonist (Nphe(1))nociceptin(1-13)NH(2) probably via ORL1 receptors in the periaqueductal grey.

  • 15.
    Carlsson, Mikael A.
    et al.
    Stockholm University, Faculty of Science, Department of Zoology.
    Swedberg, Michael D. B.
    A behavioural operant discrimination model for assessment and pharmacological manipulation of visual function in rats2010In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1321, p. 78-87Article in journal (Refereed)
    Abstract [en]

    A large number of commercially available drugs are known to cause visual side effects in humans. Therefore, it would be advantageous to screen for alterations in visual function at a pre-clinical stage. Available methods, however, lack control for motivational and motoric side effects. The aim of the present study was therefore to develop a behavioural test to detect and quantify drug-induced visual side effects while simultaneously controlling for other side effects. We here present a novel model based on operant conditioning methodology with a food rewarded two-choice design to assess visual acuity and contrast sensitivity in rats. Rats were trained to discriminate between computer-generated sine-wave gratings and homogenous grey stimuli of equal luminance. They were subsequently tested with novel stimuli differing to training stimuli according to either spatial frequency or contrast. Finally, we tested how visual acuity was affected by oral administration of quinine HCl, a compound known to affect visual function in man. The rats learned to discriminate visual stimuli within 4-5 weeks of twice daily training. A training procedure with moving stimuli achieved faster learning than with static stimuli. The visual detection threshold for discrimination of grating patterns decreased as a function of the contrast level, ranging from a spatial frequency of 0.8 cycles/degree (c/d) at 100% contrast to 0.2 c/d at 12.5%. Administration of quinine HCl was shown to affect the visual acuity threshold in a dose- and time dependent manner. In addition, response rate was affected by quinine administration but temporally isolated from the attenuation of visual acuity demonstrating that this model can separate the visual effects from motoric and motivational side effects.

  • 16.
    Clausen, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Lindh, Tone
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Shabnam, Salimi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Combination of growth factor treatment and scaffold deposition following traumatic brain injury has only a temporary effect on regeneration2014In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1588, p. 37-48Article in journal (Refereed)
    Abstract [en]

    The recovery after traumatic brain injury (TBI) is hampered by the poor regenerative capacity of the brain. Today there is no treatment available that effectively restores lost brain tissue, but much research is focused on the stimulation of endogenous neural stem cells to viably and functionally repopulate the injured parenchyma. It is crucial that the therapies have a proven long-term effect on both regeneration and functional recovery to be clinically interesting. Here we have studied the induction of stem cell activation in rats at three weeks and six weeks after inducing TBI using controlled cortical impact model at a severe setting. We combined intracerebroventricular growth factor and scaffold treatment in order to accomplish an optimal effect on the stem cell regeneration. Immediately after TBI epidermal growth factor infusion with osmotic minipumps was started and continued for seven days. The pumps were removed and an extracellular matrix scaffold containing vascular endothelial growth factor was deposited into the cortical cavity. Three weeks after injury there was a positive effect of the treatment with a significant increase in neuronal and astrocytic regeneration. However, after six weeks there was no difference in the number of newly generated neurons and astrocytes in treated or untreated rats. Evaluation of tissue loss and spatial learning in the Morris water maze corroborated that the treatment had no effect at the later time point. Our results highlight the importance of long-term studies to ensure that a promising effect on tissue regeneration and functional outcome is not only temporary.

  • 17.
    Dawidson, I
    et al.
    Karolinska Inst, Dept Cardiol, Stockholm, Sweden Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden Linkoping Univ Hosp, Dept Clin Chem, S-58185 Linkoping, Sweden.
    Blom, M
    Karolinska Inst, Dept Cardiol, Stockholm, Sweden Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden Linkoping Univ Hosp, Dept Clin Chem, S-58185 Linkoping, Sweden.
    Angmar-Mansson, B
    Karolinska Inst, Dept Cardiol, Stockholm, Sweden Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden Linkoping Univ Hosp, Dept Clin Chem, S-58185 Linkoping, Sweden.
    Theodorsson, Elvar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry.
    Lundeberg, T
    Karolinska Inst, Dept Cardiol, Stockholm, Sweden Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden Linkoping Univ Hosp, Dept Clin Chem, S-58185 Linkoping, Sweden.
    Sensory stimulation (acupuncture) increases the release of CGRP and VIP in the saliva of xerostomic patients1999In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 848, no 1-2, p. P62-Conference paper (Other academic)
  • 18.
    Decety, Jean
    et al.
    Department of Clinical Neurophysiology, University Hospital, Lund.
    Sjöholm, Hans
    Department of Clinical Neurophysiology, University Hospital, Lund.
    Ryding, Erik
    Department of Clinical Neurophysiology, University Hospital, Lund.
    Stenberg, Georg
    Department of Clinical Neurophysiology, University Hospital, Lund.
    Ingvar, David H.
    Department of Clinical Neurophysiology, University Hospital, Lund.
    The cerebellum participates in mental activity: tomographic measurements of regional cerebral blood flow1990In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 535, no 2, p. 313-317Article in journal (Refereed)
    Abstract [en]

    Measurements in man of regional cerebral blood flow (rCBF) have demonstrated a number of cortical and subcortical events coupled to sensory stimulation or motor performance. It has also been shown that local activity changes take place in the cortex during 'pure' mental activity such as motor imagery (unaccompanied by sensory input or motor output). Thus, our group has previously shown that imagination of hand movements gives predominantly a frontal cortical rCBF activation while the corresponding hand movement activates the rolandic hand area mainly. In this paper we report tomographic rCBF measurements with a 133-Xenon SPECT technique during imagined tennis movements and silent counting. Both procedures gave rise to a significant cerebellar activation in addition to cortical rCBF changes. Apparently, the cerebellum may participate in pure mental activity. It possibly plays a role for the temporal organization of neuronal events related to cognition.

  • 19. Diaconescu, Andreea Oliviana
    et al.
    Menon, Mahesh
    Jensen, Jimmy
    Department of Psychiatry, University of Oslo and Oslo University Hospital, Ullevål, Oslo, Norway.
    Kapur, Shitij
    McIntosh, Anthony Randal
    Dopamine-induced changes in neural network patterns supporting aversive conditioning.2010In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1313, p. 143-161Article in journal (Refereed)
    Abstract [en]

    The aim of the present paper is to assess the effects of altered dopamine (DA) transmission on the functional connectivity among brain regions mediating aversive conditioning in humans. To this aim, we analyzed a previous published data set from a double-blind design combined with functional magnetic resonance imaging (fMRI) recordings in which healthy volunteers were randomly assigned to one of three drug groups: amphetamine (an indirect DA agonist), haloperidol (DA D2 receptor antagonist), and placebo. Participants were exposed to an aversive classical conditioning paradigm using cutaneous electrical stimulation as the unconditioned stimulus (US), and visual cues as the conditioned stimuli (CS) where one colour (CS+) was followed by the US in 33% of the trials and another colour (CS-) had no consequences. All participants reported awareness of stimulus contingencies. Group analysis of fMRI data revealed that the left ventral striatum (VS) and amygdala activated in response to the CS+ in all the three groups. Because of their activation patterns and documented involvement in aversive conditioning, both regions were used as seeds in the functional connectivity analysis. To constrain the functional networks obtained to relate to the conditioned response, we also correlated seed activity with the Galvanic Skin Response (GSR). In the placebo group, the right ventral tegmental area/substantia nigra (VTA/SN), bilateral caudate, right parahippocampal gyrus, left inferior parietal lobule (IPL), bilateral postcentral gyrus, bilateral middle frontal (BA 46), orbitofrontal, and ventromedial prefrontal cortices (PFC, BA 10/11) correlated with the VS and amygdala seeds in response to the CS+ compared to the CS-. Enhancing dopamine transmission via amphetamine was associated with reduced task differences and significant functional connectivity for both CS+ and CS- conditions between the left VS seed and regions modulated by DA, such as the left VTA/SN, right caudate, left amygdala, left middle frontal gyrus (BA 46), and bilateral ventromedial PFC (BA 10). Blocking dopamine transmission via haloperidol was associated with significant functional connectivity across an alternate network of regions including the left amygdala seed and the right insula, the left ACC (BA 24/32), bilateral IPL (BA 40), precuneus (BA 7), post-central gyrus, middle frontal gyrus (BA 46), and supplementary motor area (SMA, BA 6) to the CS+ versus the CS-. These data provide insight into the distinct effects of DA agents on the functional connectivity between striatal, limbic, and prefrontal areas.

  • 20.
    Duarte, Joana
    et al.
    Univ Porto, Inst Invest & Inovacao Saude, Porto, Portugal;Univ Porto, Neuronal Networks Grp, IBMC, Rua Alfredo Allen 208, P-4200135 Porto, Portugal.
    Fernandes, Elisabete C.
    Univ Porto, Inst Invest & Inovacao Saude, Porto, Portugal;Univ Porto, Neuronal Networks Grp, IBMC, Rua Alfredo Allen 208, P-4200135 Porto, Portugal.
    Kononenko, Olga
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Sarkisyan, Daniil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Luz, Liliana L.
    Univ Porto, Inst Invest & Inovacao Saude, Porto, Portugal;Univ Porto, Neuronal Networks Grp, IBMC, Rua Alfredo Allen 208, P-4200135 Porto, Portugal.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Safronov, Boris V.
    Univ Porto, Inst Invest & Inovacao Saude, Porto, Portugal;Univ Porto, Neuronal Networks Grp, IBMC, Rua Alfredo Allen 208, P-4200135 Porto, Portugal.
    Differential suppression of the ipsi- and contralateral nociceptive reflexes in the neonatal rat spinal cord by agonists of μ-, δ- and κ-opioid receptors2019In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1717, p. 182-189Article in journal (Refereed)
    Abstract [en]

    Nociceptive discharges caused by the unilateral tissue damage are processed in the spinal cord by both ipsi- and contralateral neuronal circuits. The mechanisms of the neurotransmitter control of this bilateral excitation spread is poorly understood. Spinally administered opiates are known to suppress nociceptive transmission and nociceptive withdrawal reflexes. Here we investigated whether three major types of opioid receptors are involved in the bilateral control of the spinal nociceptive sensorimotor processing. Effects of the μ-, δ- and κ-opioid receptor agonists on the ipsi- and contralateral nociceptive reflexes were studied by recording slow ventral root potentials in an isolated spinal cord preparation of the new-born rat. Absolute levels of expression of the opioid genes were analyzed by the droplet digital PCR. Ipsi- and contralateral slow ventral root potentials were most strongly suppressed by the μ-opioid receptor agonist DAMGO, by 63% and 85%, followed by the κ-opioid receptor agonist U-50488H, by 44% and 73%, and δ-opioid receptor agonist leucine-enkephalin, by 27% and 49%, respectively. All these agonists suppressed stronger contra- than ipsilateral responses. Naloxone prevented effects of the agonists indicating that they act through opioid receptors, which, as we show, are expressed in the neonatal spinal cord at the levels similar to those in adults. Thus, opioid receptor agonists suppress the segmental nociceptive reflexes. Stronger contralateral effects suggest that the endogenous opioid system regulates sensorimotor processing in the spinal commissural pathways. These effects of opioids may be relevant for treatment of symmetric clinical pain symptoms caused by unilateral tissue injury.

  • 21.
    Eriksson, I S
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Allard, P
    Umeå University, Faculty of Medicine, Department of Clinical Sciences. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Marcusson, J
    [3H]tiagabine binding to GABA uptake sites in human brain.1999In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 851, no 1-2, p. 183-8Article in journal (Refereed)
    Abstract [en]

    The binding of [3H]tiagabine ((RS-1-(4,4-(3-methyl-2-thienyl)-3-butenyl)-3-piperidine carboxylic acid) to homogenates of frozen post-mortem human brain has been characterized. Inhibition experiments with gamma-aminobutyric acid (GABA), GABA uptake inhibitors, ligands active at postsynaptic GABA receptors and receptors for other neurotransmitters, suggest that [3H]tiagabine binds with high affinity to GABA uptake sites. Inhibition and kinetic experiments suggests that 70%-80% of the binding is to a high affinity site. Saturation experiments showed that the binding was saturable. Bmax was 3.4 pmol/mg protein and Kd 16 nM in frontal cortex. The dissociation constants (Kd) measured in kinetic and equilibrium experiments were in the same range (16-56 nM). The regional distribution was studied in nine brain regions and the binding was heterogenous, with the highest binding in frontal cortex and parietal cortex and the lowest binding in nucleus caudatus and putamen. This is, to our knowledge, the first study on [3H]tiagabine binding in human tissue. It is concluded that [3H]tiagabine binding can be used as a specific marker for the GABA transporter GAT-1 in homogenates of human brain.

  • 22. Eriksson, IS
    et al.
    Allard, P.
    Marcusson, Jan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Geriatrics. Östergötlands Läns Landsting, MC - Medicincentrum, Geriatrik-LAH.
    (3H)tiagabine binding to GABA uptake sites in human brain.1999In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 18, no 1-2, p. 183-188Article in journal (Refereed)
    Abstract [en]

    The binding of [H-3]tiagabine ((RS-1-(4,4-(3-methyl-2-thienyl)-3-butenyl)-3 carboxylic acid) to homogenates of frozen post-mortem human brain has been characterized. Inhibition experiments with gamma-aminobutyric acid (GAB,4), GABA uptake inhibitors, ligands active at postsynaptic GABA receptors and receptors for other neurotransmitters, suggest that [H-3]tiagabine binds with high affinity to GABA uptake sites. Inhibition and kinetic experiments suggests that 70%-80% of the binding is to a high affinity site. Saturation experiments showed that the binding was saturable. B-max was 3.4 pmol/mg protein and K-d 16 nM in frontal cortex. The dissociation constants (K-d) measured in kinetic and equilibrium experiments were in the same range (16-56 nM). The regional distribution was studied in nine brain regions and the binding was heterogenous, with the highest binding in frontal cortex and parietal cortex and the lowest binding in nucleus caudatus and putamen. This is, to our knowledge, the first study on [H-3]tiagabine binding in human tissue. It is concluded that [H-3]tiagabine binding can be used as a specific marker for the GABA transporter GAT-1 in homogenates of human brain.

  • 23. Etholm, L
    et al.
    Lindén, Henrik
    Norwegian Univ Life Sci, Dept Math Sci & Technol.
    Eken, T
    Heggelund, P
    Electroencephalographic characterization of seizure activity in the Synapsin I/II double knockout mouse2011In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1383, p. 270-288Article in journal (Refereed)
    Abstract [en]

    We present a detailed comparison of the behavioral and electrophysiological development of seizure activity in mice genetically depleted of synapsin land synapsin II (SynDKO mice), based on combined video and surface EEG recordings. SynDKO mice develop handling-induced epileptic seizures at the age of 2 months. The seizures show a very regular behavioral pattern, where activity is initially dominated by truncal muscle contractions followed by various myoclonic elements. Whereas seizure behavior goes through clearly defined transitions, cortical activity as reflected by EEG recordings shows a more gradual development with respect to the emergence of different EEG components and the frequency of these components. No EEG pattern was seen to define a particular seizure behavior. However, myoclonic activity was characterized by more regular patterns of combined sharp waves and spikes. Where countable, the number of myoclonic jerks was significantly correlated to the number of such EEG complexes. Furthermore, some EEG recordings revealed epileptic regular discharges without clear behavioral seizure correlates. Our findings suggest that seizure behavior in SynDKO mice is not solely determined by cortical activity but rather reflects interplay between cortical activity and activity in other brain regions. (C) 2011 Elsevier BM. All rights reserved.

  • 24.
    Farnsworth, B.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology.
    Radomska, K.J.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology. IBENS, Dept Biol, Paris, France..
    Zimmermann, B.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology.
    Kettunen, P.
    Univ Gothenburg, Sahlgrenska Acad, Dept Psychiat & Neurochem, Inst Neurosci & Physiol, Gothenburg, Sweden.;Univ Oxford, John Radcliffe Hosp, Nuffield Dept Clin Neurosci, Dept Neuropathol, Oxford, England..
    Jazin, E.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology.
    Emilsson, L.S.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology.
    QKI6B mRNA levels are upregulated in schizophrenia and predict GFAP expression2017In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1669, p. 63-68Article in journal (Refereed)
    Abstract [en]

    Schizophrenia is a highly heritable disorder with a heterogeneous symptomatology. Research increasingly indicates the importance of the crucial and often overlooked glial perturbations within schizophrenia. Within this study, we examined an isoform of quaking (a gene encoding an RNA-binding protein that is exclusively expressed in glial cells), known as QKI6B, and a prototypical astrocyte marker, glial fibrillary acidic protein (GFAP), postulated to be under the regulation of QKI. The expression levels of these genes were quantified across post-mortem brain samples from 55 schizophrenic individuals, and 55 healthy controls, using real-time PCR. We report, through an analysis of covariance (ANCOVA) model, an upregulation of both QKI6B, and GFAP in the prefrontal cortex of brain samples of schizophrenic individuals, as compared to control samples. Previous research has suggested that the QKI protein directly regulates the expression of several genes through interaction with a motif in the target's sequence, termed the Quaking Response Element (QRE). We therefore examined if QICI6B expression can predict the outcome of GFAP, and several oligodendrocyte-related genes, using a multiple linear regression approach. We found that QKI6B significantly predicts the expression of GFAP, but does not predict oligodendrocyte-related gene outcome, as previously seen with other QKI isoforms. (C) 2017 Elsevier B.V. All rights reserved.

  • 25.
    Forkstam, Christian
    et al.
    Karolinska Institutet.
    Elwér, Åsa
    Karolinska Institutet.
    Ingvar, Martin
    Karolinska Institutet.
    Petersson, Karl Magnus
    Karolinska Institutet.
    Instruction effects in implicit artificial grammar learning: A preference for grammaticality2008In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1221, no 24, p. 80-92Article in journal (Refereed)
    Abstract [en]

    Human implicit learning can be investigated with implicit artificial grammar learning, a paradigm that has been proposed as a simple model for aspects of natural language acquisition. In the present study we compared the typical yes–no grammaticality classification, with yes–no preference classification. In the case of preference instruction no reference to the underlying generative mechanism (i.e., grammar) is needed and the subjects are therefore completely uninformed about an underlying structure in the acquisition material. In experiment 1, subjects engaged in a short-term memory task using only grammatical strings without performance feedback for 5 days. As a result of the 5 acquisition days, classification performance was independent of instruction type and both the preference and the grammaticality group acquired relevant knowledge of the underlying generative mechanism to a similar degree. Changing the grammatical stings to random strings in the acquisition material (experiment 2) resulted in classification being driven by local substring familiarity. Contrasting repeated vs. non-repeated preference classification (experiment 3) showed that the effect of local substring familiarity decreases with repeated classification. This was not the case for repeated grammaticality classifications. We conclude that classification performance is largely independent of instruction type and that forced-choice preference classification is equivalent to the typical grammaticality classification.

  • 26. Gellein, Kristin
    et al.
    Roos, Per M.
    Evje, Lars
    Vesterberg, Olof
    Uppsala University, Disciplinary Domain of Science and Technology, Faculty of Science and Technology.
    Flaten, Trond Peder
    Nordberg, Monica
    Syversen, Tore
    Separation of proteins including metallothionein in cerebrospinal fluid by size exclusion HPLC and determination of trace elements by HR-ICP-MS2007In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1174, p. 136-142Article in journal (Refereed)
    Abstract [en]

    A method to study the protein binding patterns of trace elements in human cerebrospinal fluid (CSF) is described. Proteins in CSF samples were separated by size exclusion chromatography combined with high performance liquid chromatography (SEC-HPLC). The column was calibrated to separate proteins in the molecular weight range 6-70 kDa. Fractions were then analyzed off-line for trace elements using high resolution inductively coupled plasma mass spectrometry (HR-ICP-MS). We were able to accurately determine more than 10 elements of clinical interest in the CSF fractions. Results are presented for Cd, Mn, Fe, Pb, Cu and Zn. The total concentrations of 16 trace elements in human plasma and CSF are also presented. The method was able to differentiate the relative contribution of metallothionein and other proteins towards metal binding in human CSF.

  • 27.
    Granholm, Linnea
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Todkar, Aniruddah
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Bergman, Sofia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Nillson, Kent
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Comasco, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Nylander, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    The expression of opioid genes in non-classical reward areas depends on early life conditions and ethanol intake2017In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1668, p. 36-45Article in journal (Refereed)
    Abstract [en]

    The young brain is highly sensitive to environmental influences that can cause long-term changes in neuronal function, possibly through altered gene expression. The endogenous opioid system continues to mature after birth and because of its involvement in reward, an inadequate maturation of this system could lead to enhanced susceptibility for alcohol use disorder. Recent studies show that the classical reward areas nucleus accumbens and ventral tegmental area are less affected by early life stress whereas endogenous opioids in non-classical areas, e.g. dorsal striatum and amygdala, are highly responsive. The aim was to investigate the interaction between early life conditions and adult voluntary ethanol intake on opioid gene expression. Male Wistar rats were exposed to conventional rearing, 15, or 360min of daily maternal separation (MS) postnatal day 1-21, and randomly assigned to ethanol or water drinking postnatal week 10-16. Rats exposed to early life stress (MS360) had increased opioid receptor gene (Oprm1, Oprd1 and Oprk1) expression in the dorsal striatum. Ethanol drinking was associated with lower striatal Oprd1 and Oprk1 expression solely in rats exposed to early life stress. Furthermore, rats exposed to early life stress had high inherent Pomc expression in the amygdala but low expression after ethanol intake. Thus, adverse events early in life induced changes in opioid gene expression and also influenced the central molecular response to ethanol intake. These long-term consequences of early life stress can contribute to the enhanced risk for excessive ethanol intake and alcohol use disorder seen after exposure to childhood adversity.

  • 28.
    Haage, David
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Druzin, Michael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Laboratory of Ionic Channels of Cell Membranes, Institute of Cytology, Russian Academy of Sciences, Russia.
    Johansson, Staffan
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Allopregnanolone modulates spontaneous GABA release via presynaptic Cl- permeability in rat preoptic nerve terminals2002In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 958, no 2, p. 405-413Article in journal (Refereed)
    Abstract [en]

    The endogenous neurosteroid 3alpha-hydroxy-5alpha-pregnane-20-one (allopregnanolone) affects presynaptic nerve terminals and thereby increases the frequency of spontaneous GABA release. The present study aimed at clarifying the mechanisms underlying this presynaptic neurosteroid action, by recording the frequency of spontaneous GABA-mediated inhibitory postsynaptic currents (sIPSCs) in neurons from the medial preoptic nucleus (MPN) of rat. Acutely dissociated neurons with functional adhering nerve terminals were studied by perforated-patch recording under voltage-clamp conditions. It was shown that the sIPSC frequency increased with the external K(+) concentration ([K(+)](o)). Further, the effect of allopregnanolone on the sIPSC frequency was strongly dependent on [K(+)](o). In a [K(+)](o) of 5 mM, 2.0 microM allopregnanolone caused a clear increase in sIPSC frequency. However, the effect declined rapidly with increased [K(+)](o) and at high [K(+)](o) allopregnanolone reduced the sIPSC frequency. The effect of allopregnanolone was also strongly dependent on the external Cl(-) concentration ([Cl(-)](o)). In a reduced [Cl(-)](o) (40 mM, but with a standard [K(+)](o) of 5 mM), the effect on sIPSC frequency was larger than that in the standard [Cl(-)](o) of 146 mM. The dependence of the effect of allopregnanolone on [K(+)](o) and on estimated presynaptic membrane potential was also altered by the reduction in [Cl(-)](o). As in standard [Cl(-)](o), the effect in low [Cl(-)](o) declined when [K(+)](o) was raised, but reversed at a higher [K(+)](o). The GABA(A) receptor agonist muscimol also potentiated the sIPSC frequency. Altogether, the results suggest that allopregnanolone exerts its presynaptic effect by increasing the presynaptic Cl(-) permeability, most likely via GABA(A) receptors.

  • 29.
    Hammarberg, Anders
    et al.
    Karolinska Institutet.
    Nylander, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Zhou, Qin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Jayaram-Lindström, Nitya
    Karolinska Institutet.
    Reid, Malcolm S
    Franck, Johan
    Karolinska Institutet.
    The effect of acamprosate on alcohol craving and correlation with hypothalamic pituitary adrenal (HPA) axis hormones and beta-endorphin2009In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1305, no Suppl., p. S2-S6Article in journal (Refereed)
    Abstract [en]

    Acamprosate is a widely utilized, efficacious treatment for relapse prevention in alcohol dependent patients. The mechanism of acamprosate action is hypothesized to be by modulation of craving responses. Previous research has suggested that acamprosate may affect the hypothalamic pituitary adrenal (HPA) axis as well as beta-endorphin. The aim of the present study was to investigate if acamprosate attenuates alcohol craving following a short-term treatment, and if craving and drinking measures are correlated to changes in HPA-axis hormones and beta-endorphin. In a double-blind design, 56 alcohol dependent treatment seeking patients were randomized to 21 days of either acamprosate (1998 mg/day) or placebo treatment. Subjective, physiological and biological measurements were recorded at inclusion and on day 21. The results showed that acamprosate treated patients showed significantly reduced craving compared to placebo. Further, a significant correlation was shown between craving and alcohol consumption during study. No changes in hormonal levels were found in acamprosate treated patients compared to placebo.

  • 30. Hascup, Erin R
    et al.
    af Bjerkén, Sara
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Hascup, Kevin N
    Pomerleau, Francois
    Huettl, Peter
    Strömberg, Ingrid
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Gerhardt, Greg A
    Histological studies of the effects of chronic implantation of ceramic-based microelectrode arrays and microdialysis probes in rat prefrontal cortex.2009In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1291, p. 12-20Article in journal (Refereed)
    Abstract [en]

    Chronic implantation of neurotransmitter measuring devices is essential for awake, behavioral studies occurring over multiple days. Little is known regarding the effects of long term implantation on surrounding brain parenchyma and the resulting alterations in the functional properties of this tissue. We examined the extent of tissue damage produced by chronic implantation of either ceramic microelectrode arrays (MEAs) or microdialysis probes. Histological studies were carried out on fixed tissues using stains for neurons (cresyl violet), astrocytes (GFAP), microglia (Iba1), glutamatergic nerve fibers (VGLUT1), and the blood-brain barrier (SMI-71). Nissl staining showed pronounced tissue body loss with microdialysis implants compared to MEAs. The MEAs produced mild gliosis extending 50-100 microm from the tracks, with a significant change in the affected areas starting at 3 days. By contrast, the microdialysis probes produced gliosis extending 200-300 microm from the track, which was significant at 3 and 7 days. Markers for microglia and glutamatergic fibers supported that the MEAs produce minimal damage with significant changes occurring only at 3 and 7 days that return to control levels by 1 month. SMI-71 staining supported the integrity of the blood-brain barrier out to 1 week for both the microdialysis probes and the MEAs. This data support that the ceramic MEA's small size and biocompatibility are necessary to accurately measure neurotransmitter levels in the intact brain. The minimal invasiveness of the MEAs reduce tissue loss, allowing for long term (>6 month) electrochemical and electrophysiological monitoring of brain activity.

  • 31.
    Hashemian, Sanaz
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Marschinke, Franziska
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    af Bjerkén, Sara
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Strömberg, Ingrid
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Degradation of proteoglycans affects astrocytes and neurite formation in organotypic tissue cultures2014In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1564, p. 22-32Article in journal (Refereed)
    Abstract [en]

    Chondroitin sulfate proteoglycans (CSPGs) promote nerve growth during development, and inhibit axonal growth in the adult CNS after injury. Chondroitinase ABC (ChABC) and methyl-umbelliferyl-β-d-xyloside (β-xyloside), two enzymes that degrade CSPGs, promote regeneration after injury, however, they demonstrate opposing results in tissue culture. To elucidate the effect of the two enzymes, organotypic tissue cultures, treated with ChABC or β-xyloside, were employed to monitor nerve fiber outgrowth and astrocytic migration. Rat ventral mesencephalon (VM) and spinal cord (SC) from embryonic day (E) 14 and E18 were treated early, from the plating day for 14 days in vitro, or late where treatment was initiated after being cultured for 14 days. In the early treatment of E14 VM and SC cultures, astrocytic migration and nerve fiber outgrowth were hampered using both enzymes. Early treatment of E18 cultures reduced the astrocytic migration, while nerve growth was promoted by β-xyloside, but not by ChABC. In the late treated cultures of both E14 and E18 cultures, no differences in distances that astrocytes migrated or nerve fiber growth were observed. However, in β-xyloside-treated cultures, the confluency of astrocytic monolayer was disrupted. In E18 cultures both early and late treatments, neuronal migration was present in control cultures, which was preserved using ChABC but not β-xyloside. In conclusion, ChABC and β-xyloside had similar effects and hampered nerve fiber growth and astrocytic migration in E14 cultures. In E18 cultures nerve fiber growth was stimulated and neuronal migration was hampered after β-xyloside treatment while ChABC treatment did not exert these effects.

  • 32.
    Hayashi, Hisamitsu
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery. Gifu Univ, Grad Sch Med, Dept Otolaryngol, 1-1 Yanagido, Gifu 5011194, Japan.
    Edin, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Li, Hao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Liu, Wei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Rask-Andersen, Helge
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    The effect of pulsed electric fields on the electrotactic migration of human neural progenitor cells through the involvement of intracellular calcium signaling2016In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1652, p. 195-203Article in journal (Refereed)
    Abstract [en]

    Endogenous electric fields (EFs) are required for the physiological control of the central nervous system development. Application of the direct current EFs to neural stem cells has been studied for the possibility of stem cell transplantation as one of the therapies for brain injury. EFs generated within the nervous system are often associated with action potentials and synaptic activity, apparently resulting in a pulsed current in nature. The aim of this study is to investigate the effect of pulsed EF, which can reduce the cytotoxicity, on the migration of human neural progenitor cells (hNPCs). We applied the mono-directional pulsed EF with a strength of 250mV/mm to hNPCs for 6h. The migration distance of the hNPCs exposed to pulsed EF was significantly greater compared with the control not exposed to the EF. Pulsed EFs, however, had less of an effect on the migration of the differentiated hNPCs. There was no significant change in the survival of hNPCs after exposure to the pulsed EF. To investigate the role of Ca(2+) signaling in electrotactic migration of hNPCs, pharmacological inhibition of Ca(2+) channels in the EF-exposed cells revealed that the electrotactic migration of hNPCs exposed to Ca(2+) channel blockers was significantly lower compared to the control group. The findings suggest that the pulsed EF induced migration of hNPCs is partly influenced by intracellular Ca(2+) signaling.

  • 33.
    Hellgren Kotaleski, Jeanette
    et al.
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Kellerth, J-O
    A physiological study of the monosynaptic reflex responses of cat spinal alpha-motoneurons after lumbusacral deafferentation1989In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 488, p. 149-162Article in journal (Refereed)
    Abstract [en]

    In adult cats the whole S1 and rostral half of the L7 dorsal roots were cut on the left side of the spinal cord to produce a partial monosynaptic deafferentation of the ipsilateral alpha-motoneurons. Three, 6 or 12 weeks later, monosynaptic reflexes (MSRs) were recorded from the L6, L7 and S1 ventral roots or from various peripheral nerves during stimulation of the L6 and remaining parts of the L7 dorsal roots. Also, monosynaptic excitatory postsynaptic potentials (EPSPs) were recorded intracellularly in different types of medial gastrocnemius alpha-motoneurons of the L7 segment during stimulation of various hind limb muscle nerves. The right side with an identical acute deafferentation served as control. On the chronically lesioned side the MSRs were increased in size, also during post-tetanic potentiation. The monosynaptic EPSPs had increased amplitudes in all motoneuron types, but the relation in EPSP size between different motoneuron types as well as between different synergistic inputs remained largely unchanged. EPSP rise times were not changed, and aberrant monosynaptic connections from non-synergist muscles were not observed. It is concluded that the extent of reactive reflex changes may be related to both the number of vacant synaptic sites and the degree of functional synergism between the eliminated and remaining monosynaptic pathways. Possible underlying mechanisms are discussed.

  • 34.
    Herman, Pawel Andrzej
    et al.
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB. Stockholm University.
    Lundqvist, Mikael
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB. Stockholm University.
    Lansner, Anders
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB. Stockholm University.
    Nested theta to gamma oscillations and precise spatiotemporal firing during memory retrieval in a simulated attractor network2013In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1536, no SI, p. 68-87Article in journal (Refereed)
    Abstract [en]

    Nested oscillations, where the phase of the underlying slow rhythm modulates the power of faster oscillations, have recently attracted considerable research attention as the increased phase-coupling of cross-frequency oscillations has been shown to relate to memory processes. Here we investigate the hypothesis that reactivations of memory patterns, induced by either external stimuli or internal dynamics, are manifested as distributed cell assemblies oscillating at gamma-like frequencies with life-times on a theta scale. For this purpose, we study the spatiotemporal oscillatory dynamics of a previously developed meso-scale attractor network model as a correlate of its memory function. The focus is on a hierarchical nested organization of neural oscillations in delta/theta (2-5Hz) and gamma frequency bands (25-35Hz), and in some conditions even in lower alpha band (8-12Hz), which emerge in the synthesized field potentials during attractor memory retrieval. We also examine spiking behavior of the network in close relation to oscillations. Despite highly irregular firing during memory retrieval and random connectivity within each cell assembly, we observe precise spatiotemporal firing patterns that repeat across memory activations at a rate higher than expected from random firing. In contrast to earlier studies aimed at modeling neural oscillations, our attractor memory network allows us to elaborate on the functional context of emerging rhythms and discuss their relevance. We provide support for the hypothesis that the dynamics of coherent delta/theta oscillations constitute an important aspect of the formation and replay of neuronal assemblies. This article is part of a Special Issue entitled Neural Coding 2012.

  • 35.
    Herman, Pawel Andrzej
    et al.
    Stockholm University, Faculty of Science, Numerical Analysis and Computer Science (NADA). Royal Institute of Technology, Sweden.
    Lundqvist, Mikael
    Stockholm University, Faculty of Science, Numerical Analysis and Computer Science (NADA). Royal Institute of Technology, Sweden.
    Lansner, Anders
    Stockholm University, Faculty of Science, Numerical Analysis and Computer Science (NADA). Royal Institute of Technology, Sweden.
    Nested theta to gamma oscillations and precise spatiotemporal firing during memory retrieval in a simulated attractor network2013In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1536, no S1, p. 68-87Article in journal (Refereed)
    Abstract [en]

    Nested oscillations, where the phase of the underlying slow rhythm modulates the power of faster oscillations, have recently attracted considerable research attention as the increased phase-coupling of cross-frequency oscillations has been shown to relate to memory processes. Here we investigate the hypothesis that reactivations of memory patterns, induced by either external stimuli or internal dynamics, are manifested as distributed cell assemblies oscillating at gamma-like frequencies with life-times on a theta scale. For this purpose, we study the spatiotemporal oscillatory dynamics of a previously developed meso-scale attractor network model as a correlate of its memory function. The focus is on a hierarchical nested organization of neural oscillations in delta/theta (2–5 Hz) and gamma frequency bands (25–35 Hz), and in some conditions even in lower alpha band (8–12 Hz), which emerge in the synthesized field potentials during attractor memory retrieval. We also examine spiking behavior of the network in close relation to oscillations. Despite highly irregular firing during memory retrieval and random connectivity within each cell assembly, we observe precise spatiotemporal firing patterns that repeat across memory activations at a rate higher than expected from random firing. In contrast to earlier studies aimed at modeling neural oscillations, our attractor memory network allows us to elaborate on the functional context of emerging rhythms and discuss their relevance. We provide support for the hypothesis that the dynamics of coherent delta/theta oscillations constitute an important aspect of the formation and replay of neuronal assemblies.

  • 36.
    Heurling, Kerstin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Wallenberg Centre for Molecular and Translational Medicine and the Department of Psychiatry and Neurochemistry, University of Gothenburg, Sweden.
    Leuzy, Antoine
    Jonasson, My
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Medical Physics, Uppsala University Hospital, Uppsala, Sweden.
    Frick, Andreas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology. Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Zimmer, Eduardo R
    Nordberg, Agneta
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Quantitative positron emission tomography in brain research2017In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1670, p. 220-234, article id S0006-8993(17)30270-6Article, review/survey (Refereed)
    Abstract [en]

    The application of positron emission tomography (PET) in brain research has increased substantially during the past 20 years, and is still growing. PET provides a unique insight into physiological and pathological processes in vivo. In this article we introduce the fundamentals of PET, and the methods available for acquiring quantitative estimates of the parameters of interest. A short introduction to different areas of application is also given, including basic research of brain function and in neurology, psychiatry, drug receptor occupancy studies, and its application in diagnostics of neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. Our aim is to inform the unfamiliar reader of the underlying basics and potential applications of PET, hoping to inspire the reader into considering how the technique could be of benefit for his or her own research.

  • 37.
    Hilke, Susanne
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry.
    Hokfelt, T.
    Hökfelt, T., Department of Neuroscience, Karolinska Institutet, Retzius väg 8, SE-171 77 Stockholm, Sweden.
    Darwish, M.
    Faculty of Veterinary Medicine, Department of Animal Hygiene, Assuit University, Egypt.
    Theodorsson, Elvar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry.
    Cholecystokinin levels in the rat brain during the estrous cycle2007In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1144, no 1, p. 70-73Article in journal (Refereed)
    Abstract [en]

    Cholecystokinin (CCK) is widely distributed in the brain, and its expression has been shown to be regulated by estrogen. In the present study we used radioimmunoassay to monitor CCK levels in rat brain during a normal estrous cycle. Compared to di-estrous and estrous, CCK-like immunoreactivity was significantly reduced in cingulate and frontal cortex, hippocampus, striatum and hypothalamus during pro-estrous, that is the phase with the highest plasma estradiol levels. These results provide further evidence that circulating steroid hormones in the female rat can influence expression of a brain peptide, in this case CCK, and primarily in the limbic system, which is interesting in the context that CCK has been associated with anxiety and depression in both animals and humans. © 2007 Elsevier B.V. All rights reserved.

  • 38.
    Hu, XiaoLei
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Gu, Weigang
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Wester, Per
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    A photothrombotic ring stroke model in rats with or without late spontaneous reperfusion in the region at risk1999In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 849, no 1-2, p. 175-186Article in journal (Refereed)
    Abstract [en]

    This study aimed at developing a dual setup of the photothrombotic ring stroke model with or without late spontaneous reperfusion in the region at risk and to explore the morphological consequences. The exposed crania of adult male Wistar rats were subjected to a ring-shaped laser-irradiation beam (o.d. 5.0 mm, 0.35 mm thick) for 2 min simultaneously with intravenous erythrosin B (17 mg/kg) infusion. Transcardial carbon-black perfusion revealed that a laser intensity of 0.90 W/cm(2) resulted in late, that is, starting at 72 h, spontaneous reperfusion, whereas the lowest laser intensity that produced lack of reperfusion at 7 days post-irradiation was 1.84 W/cm(2). Laser-Doppler flowmetry showed prompt cortical cerebral blood flow (cCBF) reduction both in the ring lesion and region at risk (12% and 25% of control values) after high-intensity irradiation; these reduced flow values were more rapid and pronounced than in the low-intensity irradiation setup as previously shown. The high- compared with low-intensity irradiation setup produced more frequent occurrence of thrombi in the ring-lesion region and a larger ischemic cortical lesion with a more rapid pace of ischemic cellular changes in the ring-lesion region and the region at risk. The region at risk transformed into pannecrosis in the high-intensity, but recovered morphologically in the low-intensity irradiation setup. This dual photothrombotic setup with or without spontaneous reperfusion enables the study of events related to ischemic cell survival or death in an anatomically predefined region at risk.

  • 39.
    Johansson, I-M
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Birzniece, Vita
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Lindblad, Charlotte
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Olsson, T
    Bäckström, T
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Allopregnanolone inhibits learning in the Morris water maze2002In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 934, no 2, p. 125-131Article in journal (Refereed)
    Abstract [en]

    The progesterone metabolite allopregnanolone (3alpha-OH-5alpha-pregnane-20-one) inhibits neural functions, enhancing the GABA induced GABA(A) receptor activation. This effect is benzodiazepine like and benzodiazepines are known to impair memory. Acute effects of allopregnanolone on the hippocampus dependent spatial learning in the Morris water maze have not been studied. Adult male Wistar rats where injected (i.v.) with allopregnanolone (2 mg/kg), or vehicle, daily for 11 days. At 8 or 20 min after each injection, studies of place navigation were performed in the Morris water maze. Allopregnanolone concentrations in plasma and in nine different brain areas where analyzed by radioimmunoassay. The latency to find the platform was increased 8 min after the allopregnanolone injection, while normal learning was seen after 20 min. Swim speed did not differ between groups. A higher number of rats were swimming close to the pool wall (thigmotaxis) in the 8 min allopregnanolone group compared to the other groups. Allopregnanolone concentrations in the brain tissue at 8 min were 1.5 to 2.5 times higher then at 20 min after the allopregnanolone injections. After vehicle injections the brain concentrations of allopregnanolone were at control levels. Plasma concentrations of allopregnanolone followed the same pattern as in the brain, with the exception of an increase 8 min after vehicle injections. The natural progesterone metabolite allopregnanolone can inhibit learning in the Morris water maze, an effect not caused by motor impairment. The learning impairment might be due to a combination of changed swimming behavior and difficulties in navigation.

  • 40.
    Johansson, Sofia
    et al.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Fuchs, Andrea
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Ökvist, Anna
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Karimi, Mohsen
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden and Department of Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
    Harper, Clive
    Discipline of Pathology, University of Sydney, NSW Australia.
    Garrick, Therese
    Discipline of Pathology, University of Sydney, NSW Australia.
    Sheedy, Donna
    Discipline of Pathology, University of Sydney, NSW Australia.
    Hurd, Yasmin
    Departments of Psychiatry and Pharmacology and Biological Chemistry at Mount Sinai School of Medicine, New York, USA.
    Bakalkin, Georgy
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Ekström, Tomas J.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Validation of endogenous controls for quantitative gene expression analysis: Application on brain cortices of human chronic alcoholics2007In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1132, no 1, p. 20-8Article in journal (Refereed)
    Abstract [en]

    Real-time PCR is frequently used for gene expression quantification due to its methodological sensitivity and reproducibility. The gene expression is quantified by normalization to one or more reference genes, usually beta-actin (ACTB), glyceraldehyde-3-phosphate dehydrogenase (GAPD) or to ribosomal RNA (18S). However, different environmental or pathological conditions might also influence the expression of normalizing genes, which could severely skew the interpretation of quantitative results. This study evaluates whether 16 genes frequently used as endogenous controls in expression studies, can serve as such for comparison of human brain tissues of chronic alcoholics and control subjects. The prefrontal and motor cortices that are affected differently by chronic alcohol consumption were analyzed. The reference genes that have no or small differences in expression in alcoholics and control subjects, were found to be specific for each region: beta-actin (ACTB) and ribosomal large P0 (RPLP0) for the prefrontal cortex while importin 8 (IPO8) and RNA polymerase II (POLR2A) for the motor cortex. Four out of sixteen analyzed genes demonstrated significant differences in expression between alcoholics and controls: phosphoglycerate kinase (PGK1), hypoxanthine phosphoribosyl transferase (HPRT1) and peptidylprolyl isomerase A (PPIA) in the motor cortex and beta-2-microglobulin (B2M) in the prefrontal cortex. Our study demonstrates the importance of validation of endogenous control genes prior to real-time PCR analysis of human brain tissues. Prescribed and non-prescribed drugs, pathological or environmental conditions along with alcohol abuse may differentially influence expression of reference genes.

  • 41.
    Kaiser, Andreas
    et al.
    Karolinska University Hospital, Sweden .
    Kale, Ajay
    Karolinska University Hospital, Sweden .
    Novozhilova, Ekaterina
    Karolinska University Hospital, Sweden .
    Siratirakun, Piyaporn
    Karolinska University Hospital, Sweden .
    Aquino, Jorge B.
    Karolinska Institute, Sweden .
    Thonabulsombat, Charoensri
    Mahidol University, Thailand .
    Ernfors, Patrilz
    Karolinska Institute, Sweden .
    Olivius, Petri
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Otorhinolaryngology in Linköping.
    Brain stern slice conditioned medium contains endogenous BDNF and GDNF that affect neural crest boundary cap cells in co-culture2014In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1566, p. 12-23Article in journal (Refereed)
    Abstract [en]

    Conditioned medium (CM), made by collecting medium after a few days in cell culture and then re-using it to further stimulate other cells, is a known experimental concept since the 1950s. Our group has explored this technique to stimulate the performance of cells in culture in general, and to evaluate stem- and progenitor cell aptitude for auditory nerve repair enhancement in particular. As compared to other mediums, all primary endpoints in our published experimental settings have weighed in favor of conditioned culture medium, where we have shown that conditioned culture medium has a stimulatory effect on cell survival. In order to explore the reasons for this improved survival we set out to analyze the conditioned culture medium. We utilized ELISA kits to investigate whether brain stem (BS) slice CM contains any significant amounts of brain-derived neurotrophic factor (BDNF) and glial cell derived neurotrophic factor (GDNF). We further looked for a donor cell with progenitor characteristics that would be receptive to BDNF and GDNF. We chose the well-documented boundary cap (BC) progenitor cells to be tested in our in vitro co-culture setting together with cochlear nucleus (CN) of the BS. The results show that BS CM contains BDNF and GDNF and that survival of BC cells, as well as BC cell differentiation into neurons, were enhanced when BS CM were used. Altogether, we conclude that BC cells transplanted into a BDNF and GDNF rich environment could be suitable for treatment of a traumatized or degenerated auditory nerve.

  • 42.
    Karlsson, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Lindquist, Catarina
    Malmgren, Kristina
    Asztely, Fredrik
    Altered spontaneous synaptic inhibition in an animal model of cerebral heterotopias2011In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1383, p. 54-61Article in journal (Refereed)
    Abstract [en]

    We have investigated spontaneous synaptic transmission in hippocampal nodular heterotopias in rats exposed to methylazoxymethanol (MAM) in utero. Pregnant Wistar rats were injected with MAM at E16. Acute hippocampal slices were prepared from the rat pups P14 to P40. Whole-cell voltage-clamp recordings were made from visually identified neurons using IR-DIC video microscopy. Synaptic events were recorded from either heterotopic neurons in the CA1 region or "slice-matched" normotopic CA1 pyramidal neurons. Both the spontaneous inhibitory (sIPSC) and excitatory synaptic transmission (sEPSC) to the same neurons were recorded. We found a profound reduction in the frequency of sIPSCs in the heterotopic neurons vs. normotopic neurons. No significant differences in the frequency of sEPSCs were found. We also found a profound reduction in the frequency of spontaneous IPSCs in normotopic neurons following application of the GABA reuptake blocker, NO-711, even in the presence of a GABA(B) receptor antagonist (CGP 55845). Preferentially blocking extrasynaptic GABA(A) receptors caused an increased frequency of sIPSCs in the heterotopic neurons. Our data suggest that there is a predominant change in inhibitory synaptic transmission, as measured by changes in sIPSCs, with no change in excitatory synaptic transmission to heterotopic neurons in hippocampus of rats exposed to MAM in utero. We suggest that this change is caused by an increase in the extracellular concentration of GABA but is not mediated via activation of presynaptic GABA(B) receptors. Rather, we propose that the increased extracellular GABA concentration in the heterotopias dampens the activity in inhibitory neurons via activation of extrasynaptic GABA(A) receptors. (C) 2011 Elsevier B.V. All rights reserved.

  • 43. Karlsson, Magnus
    et al.
    Hildebrand, Claes
    Invasion of the rat ventral root L5 by putative sympathetic C-fibers after neonatal sciatic nerve crush1994In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 667, no 1, p. 39-46Article in journal (Refereed)
  • 44. Karlsson, Magnus
    et al.
    Hildebrand, Claes
    Routes of putative afferent axons in rat lumbosacral ventral roots and pia mater1993In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 600, no 2, p. 298-304Article in journal (Refereed)
  • 45. Karlsson, Magnus
    et al.
    Hildebrand, Claes
    Sensory C-fibers in rat ventral roots are capsaicin-insensitive and they do not mediate extravasation from pial vessels1994In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 642, no 1-2, p. 244-250Article in journal (Refereed)
  • 46.
    Karlsson, Urban
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Haage, David
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Johansson, Staffan
    Currents evoked by GABA and glycine in acutely dissociated neurons from the rat medial preoptic nucleus1997In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 770, no 1-2, p. 256-260Article in journal (Refereed)
  • 47.
    Karlsson, Urban
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Sundgren, Anna
    Näsström, Jacques
    Johansson, Staffan
    Glutamate-evoked currents in acutely dissociated neurons from the rat medial preoptic nucleus1997In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 759, no 2, p. 270-276Article in journal (Refereed)
  • 48.
    Karlsson, Urban
    et al.
    Umeå University, Faculty of Medicine, Integrative Medical Biology.
    Sundgren-Andersson, Anna K
    Johansson, Staffan
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Physiology. Fysiologi.
    Krupp, Johannes J
    Capsaicin augments synaptic transmission in the rat medial preoptic nucleus.2005In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1043, no 1-2, p. 1-11Article in journal (Refereed)
    Abstract [en]

    medial preoptic nucleus (MPN) is the major nucleus of the preoptic area (POA), a hypothalamic area involved in the regulation of body-temperature. Injection of capsaicin into this area causes hypothermia in vivo. Capsaicin also causes glutamate release from hypothalamic slices. However, no data are available on the effect of capsaicin on synaptic transmission within the MPN. Here, we have studied the effect of exogenously applied capsaicin on spontaneous synaptic activity in hypothalamic slices of the rat. Whole-cell patch-clamp recordings were made from visually identified neurons located in the MPN. In a subset of the studied neurons, capsaicin enhanced the frequency of spontaneous glutamatergic EPSCs. Remarkably, capsaicin also increased the frequency of GABAergic IPSCs, an effect that was sensitive to removal of extracellular calcium, but insensitive to tetrodotoxin. This suggests an action of capsaicin at presynaptic GABAergic terminals. In contrast to capsaicin, the TRPV4 agonist 4alpha-PDD did not affect GABAergic IPSCs. Our results show that capsaicin directly affects synaptic transmission in the MPN, likely through actions at presynaptic terminals as well as on projecting neurons. Our data add to the growing evidence that capsaicin receptors are not only expressed in primary afferent neurons, but also contribute to synaptic processing in some CNS regions.

  • 49.
    Keller, Lina
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Murphy, Charlotte
    Wang, Hui-Xin
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Fratiglioni, Laura
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Olin, Maria
    Gafvels, Mats
    Björkhem, Ingemar
    Graff, Caroline
    Meaney, Steve
    A Functional Polymorphism In The Hmgcr Promoter Affects Transcriptional Activity But Not The Risk For Alzheimer Disease In Swedish Populations2010In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1344, p. 185-91Article in journal (Refereed)
    Abstract [en]

    Variations in genes associated with cholesterol homeostasis have been reported to modify the risk of developing Alzheimer disease (AD). To date there have been few investigations into variations in genes directly involved in cholesterol biosynthesis and AD. We investigated the influence of the -911C>A polymorphism (rs3761740) in the hydroxy-methyl-glutaryl CoA reductase (HMGCR) gene promoter on basal and regulated transcription, plasma cholesterol levels and the association with AD. Under in vitro conditions the A allele was found to be significantly more responsive to SREBP-2 mediated regulation than the C allele. In an age and sex matched case-control study, the genotype distribution and allele frequency of this polymorphism were not associated with AD (OR=1.03; 95% CI=0.72-1.48). However, we did find evidence supporting an interaction between the HMGCR A allele, the APOE E4 allele and an altered risk of AD (OR=2.41; 95% CI=0.93-6.22).

  • 50.
    Kindlundh, Anna MS
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Lindblom, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Chronic administration with nandrolone decanoate induces alterations in the gene-transcript expression of dopamine D1- and D2-receptors in the rat brain2000In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 979, no 1-2, p. 37-42Article in journal (Refereed)
    Abstract [en]

    Some adolescent and young males are engaged in misuse of anabolic-androgenic steroids (AASs) in connection with multiple drug use, in order to become intoxicated and brave, apart from currently known motives connected to sports performance and physical appearance. Recent studies suggest that alterations in neurobiological circuits implicated in the regulation of reward-related learning, aggression and motoric behavior underlie the behavioral changes associated with AAS misuse. We have previously shown that AASs induce alterations in dopamine receptor densities. The aim of the present study was to investigate if these effects could be attributed to altered mRNA content for tyrosine hydroxylase, L-amino acid decarboxylase, dopamine D(1)- and dopamine D(2)-receptor as measured by in situ hybridisation. Male Sprague-Dawley rats were subjected to 2 weeks of treatment with daily intramuscular injections of the AAS nandrolone decanoate at three different doses (1, 5 and 15 mg/kg/day). Results of the in situ hybridization showed that the mRNA content of the dopamine D(1)-receptor subtype was significantly reduced at all doses in the caudate putamen and at the highest doses in the nucleus accumbens shell. The mRNA expression of the dopamine D(2)-receptor was significantly increased at the two lowest doses in the caudate putamen and the nucleus accumbens shell. In conclusion, nandrolone has been shown to affect the expression of gene transcripts of dopaminergic receptors possibly implicated in underlying mechanisms of reward-related behavioral changes among AAS misusers.

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