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  • 1.
    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.

  • 2.
    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.

  • 3.
    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.

  • 4. 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.

  • 5.
    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.

  • 6.
    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.

  • 7. 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.

  • 8.
    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.

  • 9.
    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.

  • 10.
    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.

  • 11.
    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.

  • 12.
    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.

  • 13.
    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.

  • 14.
    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.

  • 15. Kullberg, Susanna
    et al.
    Aldskogius, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Ulfhake, Brun
    Microglial activation, emergence of ED1-expressing cells and clusterin upregulation in the aging rat CNS, with special reference to the spinal cord2001In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 899, no 1-2, p. 169-186Article in journal (Refereed)
    Abstract [en]

    With advancing age, the incidence of neuronal atrophy and dystrophy increases and, in parallel, behavioural sensorimotor impairment becomes overt. Activated microglia has been implicated in cytotoxic and inflammatory processes in neurodegenerative diseases as well as during aging. Here we have used immunohistochemistry and in situ hybridization to examine the expression of OX42, ED1, ED2, GFAP and clusterin in CNS of young adult and behaviourally tested aged rats (30-month-old), to study the occurrence of activated microglia/ED1 positive macrophages in senescence and to what extent this correlates with astrogliosis and signs of sensorimotor impairment among the individuals. The results show a massive region-specific increase in activated microglia and ED1 expressing cell profiles in aged rats. The infiltration was most prominent in the spinal cord dorsal columns, including their sensory relay nuclei, and the outer portions of the lateral and ventral columns. At such sites the occurrence of macrophages coincided with increased levels of GFAP and positive correlations were evident between the labeling for, on the one hand, OX42 and, on the other, GFAP and ED1. Also, the ventral and dorsal roots were heavily infiltrated by ED1 positive cells. The signs of gliosis were most pronounced among aged rats with advanced sensorimotor impairment. In contrast, the grey matter of aged rats showed very few activated microglia/ED1 labeled cells despite signs of focal astrogliosis. ED2 expression was confined to perivascular cells and leptominges with a similar labeling pattern in young and aged rats. In aged rats increased expression of clusterin was observed in GFAP-immunoreactive profiles of the white matter only. It is suggested that this increase may reflect a response to degenerative/inflammatory processes.

  • 16.
    Kuzmin, Alexander
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bazov, Igor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Sheedy, Donna
    The Discipline of Pathology, University of Sydney, Sydney, NSF, Australia.
    Garrick, Therese
    The Discipline of Pathology, University of Sydney, Sydney, NSF, Australia.
    Harper, Clive
    The Discipline of Pathology, University of Sydney, Sydney, NSF, Australia.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Expression of pronociceptin and its receptor is downregulated in the brain of human alcoholics2009In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1305, no Suppl. 1, p. S80-85Article in journal (Refereed)
    Abstract [en]

    Animal studies demonstrated a role of neuropeptide nociceptin (NC) and its receptor (opiate receptor like-1, OPRL1) in ethanol-induced reward; activation of the OPRL1 by natural or synthetic ligands reduced ethanol self-administration and prevented relapse to ethanol drinking. The endogenous NC may function in neuronal circuits involved in reinforcing or conditioning effects of ethanol as a "brake" to limit ethanol intake (Roberto, M., Siggins, G.R. 2006. Nociceptin/orphanin FQ presynaptically decreases GABAergic transmission and blocks the ethanol-induced increase of GABA release in central amygdala. Proc. Natl. Acad. Sci. USA 103. 9715-9720), whereas repeated ethanol intake may downregulate the endogenous NC/OPRL1 system resulting in activation of ethanol consumption. To address this hypothesis, we evaluated whether expression of the pronociceptin (PNOC) and OPRL1 genes is altered in human alcoholics. mRNAs transcribed from these genes were analyzed by quantitative RT-PCR in the prefrontal and orbitofrontal cortices, central amygdala and hippocampal dentate gyrus, structures controlling alcohol consumption. Reduction in PNOC mRNA (1.7-fold) was found in the hippocampus of alcoholics, whereas OPRL1 mRNA levels were decreased (1.4-fold) in the central amygdala. No changes in expression of these genes in other brain areas analyzed were evident. We hypothesise that chronic ethanol intake downregulates PNOC and OPRL1 gene expression in the hippocampus and amygdala, respectively. The findings may be also interpreted as inherited molecular differences between alcoholics and controls. The PNOC/OPRL1 downregulation may underlie impairment of cognitive control over alcohol seeking in alcoholics. Stimulation of the OPRL1 receptors with synthetic agonists may increase threshold for activation of ethanol-related behaviour by environmental cues, and thus may reduce cue- or stress-primed relapse to ethanol consumption.

  • 17. Latini, Francesco
    et al.
    Mårtensson, Johanna
    Larsson, Elna-Marie
    Fredrikson, Mats
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Åhs, Fredrik
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Hjortberg, Mats
    Aldskogius, Håkan
    Ryttlefors, Mats
    Segmentation of the inferior longitudinal fasciculus in the human brain: A white matter dissection and diffusion tensor tractography study2017In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240Article in journal (Refereed)
    Abstract [en]

    Abstract The inferior longitudinal fascicle (ILF) is one of the major occipital-temporal association pathways. Several studies have mapped its hierarchical segmentation to specific functions. There is, however, no consensus regarding a detailed description of ILF fibre organisation. The aim of this study was to establish whether the ILF has a constant number of subcomponents. A secondary aim was to determine the quantitative diffusion proprieties of each subcomponent and assess their anatomical trajectories and connectivity patterns. A white matter dissection of 14 post-mortem normal human hemispheres was conducted to define the course of the ILF and its subcomponents. These anatomical results were then investigated in 24 right-handed, healthy volunteers using in vivo diffusion tensor imaging (DTI) and streamline tractography. Fractional anisotropy (FA), volume, fibre length and the symmetry coefficient of each fibre group were analysed. In order to show the connectivity pattern of the ILF, we also conducted an analysis of the cortical terminations of each segment. We confirmed that the main structure of the ILF is composed of three constant components reflecting the occipital terminations: the fusiform, the lingual and the dorsolateral-occipital. ILF volume was significantly lateralised to the right. The examined indices of ILF subcomponents did not show any significant difference in lateralisation. The connectivity pattern and the quantitative distribution of ILF subcomponents suggest a pivotal role for this bundle in integrating information from highly specialised modular visual areas with activity in anterior temporal territory, which has been previously shown to be important for memory and emotions.

  • 18.
    Latini, Francesco
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Mårtensson, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Fredriksson, Mats
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology. Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.
    Åhs, Fredrik
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology. Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.
    Hjortberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Aldskogius, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Regenerative neurobiology.
    Ryttlefors, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Segmentation of the inferior longitudinal fasciculus in the human brain: A white matter dissection and diffusion tensor tractography study.2017In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, no 1675, p. 102-115, article id S0006-8993(17)30386-4Article in journal (Refereed)
    Abstract [en]

    The inferior longitudinal fascicle (ILF) is one of the major occipital-temporal association pathways. Several studies have mapped its hierarchical segmentation to specific functions. There is, however, no consensus regarding a detailed description of ILF fibre organisation. The aim of this study was to establish whether the ILF has a constant number of subcomponents. A secondary aim was to determine the quantitative diffusion proprieties of each subcomponent and assess their anatomical trajectories and connectivity patterns. A white matter dissection of 14 post-mortem normal human hemispheres was conducted to define the course of the ILF and its subcomponents. These anatomical results were then investigated in 24 right-handed, healthy volunteers using in vivo diffusion tensor imaging (DTI) and streamline tractography. Fractional anisotropy (FA), volume, fibre length and the symmetry coefficient of each fibre group were analysed. In order to show the connectivity pattern of the ILF, we also conducted an analysis of the cortical terminations of each segment. We confirmed that the main structure of the ILF is composed of three constant components reflecting the occipital terminations: the fusiform, the lingual and the dorsolateral-occipital. ILF volume was significantly lateralised to the right. The examined indices of ILF subcomponents did not show any significant difference in lateralisation. The connectivity pattern and the quantitative distribution of ILF subcomponents suggest a pivotal role for this bundle in integrating information from highly specialised modular visual areas with activity in anterior temporal territory, which has been previously shown to be important for memory and emotions.

  • 19. Li, Jimei
    et al.
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Zhang, Xiao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lu, Zhongyang
    Yu, Shan Ping
    Wei, Ling
    Expression of heparanase in vascular cells and astrocytes of the mouse brain after focal cerebral ischemia2012In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1433, p. 137-144Article in journal (Refereed)
    Abstract [en]

    Heparanase is a heparan sulfate degrading endoglycosidase. Previous work has demonstrated that heparanase plays important roles in various biological processes including angiogenesis, wound healing and metastasis. However, the role of heparanase in the post-ischemic brain is not well defined. Transient focal cerebral ischemia in adult mice was induced by ligations of the right middle cerebral artery (MCA) and both common carotid arteries (CCAs). All mice were subjected to bromodeoxyuridine (BrdU) injection and sacrificed at different time points after stroke for immunohistochemical and Western blot analyses. Heparanase expression increased after ischemia in both cell-specific and time-dependent manners. Three to 7 days after stroke, levels of the 50-kD heparanase, basic fibroblast growth factor (FGF-2), and angiopoietin-2 (Ang-2) increased in the peri-infarct region. At early time points, heparanase expression was largely confined to proliferating vascular endothelial cells. At 14 days after ischemia, this expression had shifted to astrocytes in the same region. These data show that cerebral ischemia markedly increases heparanase levels in endothelial cells and then in astrocytes. The unique features of the heparanase upregulation imply that heparanase may play specific roles in the pathological and regenerative processes during the acute and sub-acute/chronic phases in the post-stroke brain.

  • 20.
    Lindblom, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Haitina, Tatjana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Differential regulation of nuclear receptors, neuropeptides and peptide hormones in the hypothalamus and pituitary of food restricted rats2005In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 133, no 1, p. 37-46Article in journal (Refereed)
    Abstract [en]

    Food restriction is associated with a number of endocrine disturbances. We validated the experimental conditions for several house-keeping genes and determined the effects of 12 day 50% food restriction on hypothalamic and pituitary transcription of genes involved in different neuroendocrine systems, using real-time quantitative polymerase chain reaction (PCR). A total of 7 nuclear receptors and 12 neuropeptides and peptide hormones were investigated in the dorsal and ventral hypothalamus and the pituitary gland in rats. In the hypothalamus, food restriction reduced mRNA levels of estrogen receptor alpha (ERalpha), progesterone receptor, glucocorticoid receptor, thyroid hormone receptor alpha and beta, pro-opiomelanocortin (POMC), growth hormone-releasing factor (GHRF), corticotropin-releasing factor (CRF), thyrotropin-releasing factor (TRF), somatostatin, and increased that of neuropeptide Y (NPY). In the pituitary, the treatment reduced growth hormone (GH), luteinizing hormone beta (LHbeta) and thyrotropin beta, but increased ERalpha mRNA levels. The study provides a map of how food restriction affects the regulation of a number of transcripts involved in neuroendocrine control.

  • 21.
    Lindblom, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Kindlundh, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bergström, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Wikberg, Jarl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Anabolic androgenic steroid nandrolone decanoate reduces hypothalamic proopiomelanocortin mRNA levels2003In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 986, no 1-2, p. 139-147Article in journal (Refereed)
    Abstract [en]

    Supratherapeutical doses of anabolic androgenic steroids (AASs) have dramatic effects on metabolism in humans, and also inhibit feeding and reduce the rate of body weight gain in rats. In order to test the hypothesis that the AAS metabolic syndrome is accompanied by alterations in the central melanocortin system, we evaluated body weight, food intake and hypothalamic agouti-related protein (AgRP) and proopiomelanocortin (POMC) mRNA levels following administration of different doses of the anabolic androgenic steroid nandrolone decanoate. In order to distinguish changes induced by the steroid treatment per se from those resulting from the reduced food intake and growth rate, we also compared the effect of nandrolone decanoate on AgRP and POMC mRNA expression with both normally fed, and food restricted control groups. We here report that administration of nandrolone specifically reduces arcuate nucleus POMC mRNA levels while not affecting the expression level of AgRP. The effect on POMC expression was not observed in the food restricted controls, excluding the possibility that the observed effect was a mere response to the reduced food intake and body weight. These results raise the possibility that some of the metabolic and behavioural consequences of AAS abuse may be the result of alterations in the melanocortin system.

  • 22. Matsui, Toshifumi
    et al.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Fukumoto, Hiroaki
    Ramasamy, Karunya
    Kowa, Hisatomo
    Frosch, Matthew P.
    Irizarry, Michael C.
    Hyman, Bradley T.
    Expression of APP pathway mRNAs and proteins in Alzheimer's disease2007In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1161, p. 116-123Article in journal (Refereed)
    Abstract [en]

    In both trisomy 21 and rare cases of triplication of amyloid precursor protein (APP) Alzheimer's disease (AD) pathological changes are believed to be secondary to increased expression of APP. We hypothesized that sporadic AD may also be associated with changes in transcription of APP or its metabolic partners. To address this issue, temporal neocortex of 27 AD and 21 non-demented control brains was examined to assess mRNA levels of APP isoforms (total APP, APP containing the Kunitz protease inhibitor domain [APP-KPI] and APP770) and APP metabolic enzymatic partners (the APP cleaving enzymes beta-secretase [BACE] and presenilin-1 [PS- 1], and putative clearance molecules, low-density lipoprotein receptor protein [LRP] and apolipoprotein E [apoE]). Furthermore, we evaluated how changes in APP at the mRNA level affect the amount of Tris buffer extractable APP protein and A beta 40 and 42 peptides in AD and control brains. As assessed by quantitative PCR, APP-KPI (p=0.007), APP770 (p=0.004), PS-1 (p = 0.004), LRP (p = 0.003), apoE (p = 0.0002) and GFAP (p < 0.0001) mRNA levels all increased in AD, and there was a shift from APP695 (a neuronal isoform) towards KPI containing isoforms that are present in glia as well. APP-KPI mRNA levels correlated with soluble APP alpha -KPI protein (sAPP alpha -KPI) levels measured by ELISA (T= 0.33, p = 0.015 by Kendall's rank correlation); in turn, soluble APP alpha-KPI protein levels positively correlated with Tris -extractable, soluble A beta 40 (p=0.046) and 42 levels (p=0.007). The ratio of soluble APP alpha-KPI protein levels to total APP protein increased in AD, and also correlated with GFAP protein levels in AD. These results suggest that altered transcription of APP in AD is proportionately associated with A beta peptide, may occur in the context of gliosis, and may contribute to A beta deposition in sporadic AD.

  • 23.
    Nordquist, Niklas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Göktürk, Camilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Comasco, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Centre for Clinical Research, County of Västmanland.
    Nilsson, Kent W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Centre for Clinical Research, County of Västmanland.
    Oreland, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Hallman, Jarmila
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Transcription factor AP2 beta involved in severe female alcoholism2009In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1305, no Supplement 11, p. S20-S26Article in journal (Refereed)
    Abstract [en]

    Susceptibility to alcoholism and antisocial behavior exhibits an evident link to monoaminergic neurotransmission. The serotonin system in particular, which is associated with regulation of mood and behavior, has an influence on personality characters that are firmly connected to risk of developing alcoholism and antisocial behavior, such as impulsiveness, and aggression. The transcription factor TFAP2b has repeatedly been shown to be involved in monoaminergic transmission, likely due to a regulatory effect on genes that are fundamental to this system, e.g. monoamine oxidase type A, and the serotonin transporter. Recent research has identified a functional polymorphism in the gene encoding TFAP2B that regulates its level of expression. In the present study we have compared a sample of female alcoholics (n = 107), sentenced to institutional care for their severe addiction, contrasted against a control sample of adolescent females (n = 875). The results showed that parental alcohol misuse was significantly more common among the alcoholic females, and also that parental alcohol misuse was associated with a reduction in age of alcohol debut. We also addressed the question of whether a functional TFAP2b polymorphism was associated with alcoholism. Results showed that the high-functioning allele was significantly more common among the female alcoholics, compared to the non-alcoholic controls. Furthermore, the results also indicated that psychosocial factors, in terms of parental alcohol misuse, depression or psychiatric disorder, had an influence on the association. It was observed that the genetic association was restricted to the subset of cases that had not experienced these negative psychosocial factors.

  • 24.
    Oreland, Sadia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Pickering, Chris
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Gökturk, Camilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Oreland, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Arborelius, Lotta
    Karolinska Institutet, Avdelningen för farmakologi.
    Nylander, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Two repeated maternal separation procedures differentially affect brain 5-hydroxytryptamine transporter and receptors in young and adult male and female rats2009In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1305, no Suppl. 1, p. S37-S49Article in journal (Refereed)
    Abstract [en]

    Early environment is a known determinant for individual differences in vulnerability for adult psychopathology, e.g. ethanol addiction. One underlying mechanism could be dysfunction in serotonergic neurotransmission. This study focused on the methodological considerations regarding an animal model for studying effects of early environment, maternal separation (MS), using two different paradigms. Age- and sex-specific effects on brain stem 5-hydroxytryptamine (5-HT) transporter and receptors were examined. Male and female rat pups were assigned to either litter-wise MS for 15 or 360 minutes (MS15l or MS360l) or individual MS for 15 or 360 minutes (MS15i or MS360i) daily during postnatal days 1-21. Normal animal facility reared rats were used as controls. Analyses were performed in young and adult rats. As compared to the other males, MS15l males had lower 5-HT1A and 5-HT2C receptor mRNA expression at both ages, lower 5-HT2A receptor mRNA when young and lower 5-HTT mRNA expression when adult. In contrast, adult MS15l females had higher 5-HT2C receptor mRNA expression than the other females. The strong impact of MS15l on 5-HT-related genes was either transient or persistent depending on sex and fewer effects on gene expression were observed in females than in males. This study shows the importance of tactile contact for the consequences of short, but not long MS, as evidenced by major differences between MS15l and MS15i. The results suggest that MS15i is less suitable than MS15l to simulate a protective environment in studies of for instance ethanol addiction processes. 

  • 25.
    Oreland, Sadia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Raudkivi, Karita
    University of Tartu.
    Oreland, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Harro, Jaanus
    University of Tartu.
    Arborelius, Lotta
    Karolinska Institute.
    Nylander, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Ethanol-induced effects on the dopamine and serotonin systems in adult Wistar rats are dependent on early-life experiences2011In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1405, p. 57-68Article in journal (Refereed)
    Abstract [en]

    Some individuals control their ethanol consumption throughout life, but others escalate their intake to levels that increase the risk for addiction. The early environment influences the individual response to ethanol and affects the underlying physiological processes that lead to a transition from a voluntary to a compulsive use of ethanol. However, the neurobiological substrates for these processes are not understood. The present study aimed to test the hypothesis that early environmental experiences affect the neurobiological effects that are induced by voluntary ethanol consumption. Rat pups were subjected to three different rearing environments: conventional animal facility rearing or separation from dam and littermates for either 15 or 360 min. In adulthood, the rats were exposed to a two-bottle free choice between ethanol and water for seven weeks. Tissue levels of dopamine, 5-hydroxytryptamine (5-HT) and their metabolites were measured in brain areas that have been implicated in reward and addiction processes. Differences in ethanol-induced effects were noted in 5-HT-related measurements in the nucleus accumbens and ventral tegmental area and in dopamine-related measurements in the dorsal raphe nucleus (DRN). These results provided evidence of an early environmental impact on interactive neuronal circuits between the DRN and reward pathways. The amygdala, a key area in addiction processes, was particularly sensitive to early-life conditions. The animals that experienced the longest separation differed from the others; they had low basal 5-HT levels and responded with an increase in 5-HT after ethanol. These altered responses to initial ethanol consumption as a result of early environmental factors may affect the transition from habitual to compulsive drinking and contribute to individual vulnerability or resilience to addiction.

  • 26. Palmgren, Björn
    et al.
    Jin, Zhe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Jiao, Yu
    Kostyszyn, Beata
    Olivius, Petri
    Horseradish peroxidase dye tracing and embryonic statoacoustic ganglion cell transplantation in the rat auditory nerve trunk2011In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1377, p. 41-49Article in journal (Refereed)
    Abstract [en]

    At present severe damage to hair cells and sensory neurons in the inner ear results in non-treatable auditory disorders. Cell implantation is a potential treatment for various neurological disorders and has already been used in clinical practice. In the inner ear, delivery of therapeutic substances including neurotrophic factors and stem cells provide strategies that in the future may ameliorate or restore hearing impairment. In order to describe a surgical auditory nerve trunk approach, in the present paper we injected the neuronal tracer horseradish peroxidase (HRP) into the central part of the nerve by an intra cranial approach. We further evaluated the applicability of the present approach by implanting statoacoustic ganglion (SAG) cells into the same location of the auditory nerve in normal hearing rats or animals deafened by application of p-bungarotoxin to the round window niche. The HRP results illustrate labeling in the cochlear nucleus in the brain stem as well as peripherally in the spiral ganglion neurons in the cochlea. The transplanted SAGs were observed within the auditory nerve trunk but no more peripheral than the CNS-PNS transitional zone. Interestingly, the auditory nerve injection did not impair auditory function, as evidenced by the auditory brainstem response. The present findings illustrate that an auditory nerve trunk approach may well access the entire auditory nerve and does not compromise auditory function. We suggest that such an approach might compose a suitable route for cell transplantation into this sensory cranial nerve.

  • 27.
    Palmgren, Björn
    et al.
    Karolinska Institutet.
    Jin, Zhe
    Karolinska Institute.
    Jiao, Yu
    Karolinska Institute.
    Kostyszyn, Beata
    Karolinska Institute.
    Olivius, Petri
    Karolinska Institute.
    Horseradish peroxidase dye tracing and embryonic statoacoustic ganglion cell transplantation in the rat auditory nerve trunk2011In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1377, p. 41-49Article in journal (Refereed)
    Abstract [en]

    At present severe damage to hair cells and sensory neurons in the inner ear results in non-treatable auditory disorders. Cell implantation is a potential treatment for various neurological disorders and has already been used in clinical practice. In the inner ear, delivery of therapeutic substances including neurotrophic factors and stem cells provide strategies that in the future may ameliorate or restore hearing impairment. In order to describe a surgical auditory nerve trunk approach, in the present paper we injected the neuronal tracer horseradish peroxidase (HRP) into the central part of the nerve by an intra cranial approach. We further evaluated the applicability of the present approach by implanting statoacoustic ganglion (SAG) cells into the same location of the auditory nerve in normal hearing rats or animals deafened by application of β-bungarotoxin to the round window niche. The HRP results illustrate labeling in the cochlear nucleus in the brain stem as well as peripherally in the spiral ganglion neurons in the cochlea. The transplanted SAGs were observed within the auditory nerve trunk but no more peripheral than the CNS-PNS transitional zone. Interestingly, the auditory nerve injection did not impair auditory function, as evidenced by the auditory brainstem response. The present findings illustrate that an auditory nerve trunk approach may well access the entire auditory nerve and does not compromise auditory function. We suggest that such an approach might compose a suitable route for cell transplantation into this sensory cranial nerve.

  • 28. Pickering, Chris
    et al.
    Gustafsson, Lisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Cebere, Aleta
    Nylander, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Liljequist, Sture
    Repeated maternal separation of male Wistar rats alters glutamate receptor expression in the hippocampus but not the prefrontal cortex2006In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1099, no 1, p. 101-108Article in journal (Refereed)
    Abstract [en]

    Stress early in life puts the individual at a greater risk for developing mental disorders in adulthood. The animal model of maternal separation involves daily removal of pups from their mother over the early postnatal period and leads to several behavioral deficits in adults. Since this period corresponds to a time of extensive developmental changes in the glutamatergic system, glutamate receptor mRNA expression was studied in the hippocampus and prefrontal cortex. Male Wistar rats were either separated from their mother for 15 min (MS15 or 'handling') or 360 min (MS360) once a day from pnd 1-21 and glutamate receptor expression levels were measured at 25 weeks of age using real-time RTPCR analysis. A third group of animal facility reared (AFR) rats was included as a control for the handling group. In the hippocampus, mRNA expression of NMDA NR2B and AMPA GluR1 and GluR2 receptors was significantly lower in MS360 rats relative to MS15. In addition, expression of the glutamate transporter GLAST was increased in MS360 relative to MS15. No differences were observed for AFR rats relative to MS15, which indicates that the hippocampal effects were not a result of handling or maternal care. For the prefrontal cortex, no difference in mRNA expression was observed for NMDA NR2A and NR2B or AMPA GluR1 and GluR2. These findings suggest that prolonged maternal separation produces neuroadaptive changes in the hippocampus that may, at least partially, account for the behavioral deficits previously observed in this animal model.

  • 29. Puigdellívol-Sanchez, Anna
    et al.
    Prats-Galino, Alberto
    Molander, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Estimations of topographically correct regeneration to nerve branches and skin after peripheral nerve injury and repair2006In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1098, no 1, p. 49-60Article in journal (Refereed)
    Abstract [en]

    Peripheral nerve injury is typically associated with long-term disturbances in sensory localization, despite nerve repair and regeneration. Here, we investigate the extent of correct reinnervation by back-labeling neuronal soma with fluorescent tracers applied in the target area before and after sciatic nerve injury and repair in the rat. The subpopulations of sensory or motor neurons that had regenerated their axons to either the tibial branch or the skin of the third hindlimb digit were calculated from the number of cell bodies labeled by the first and/or second tracer. Compared to the normal control side, 81% of the sensory and 66% of the motor tibial nerve cells regenerated their axons back to this nerve, while 22% of the afferent cells from the third digit reinnervated this digit. Corresponding percentages based on quantification of the surviving population on the experimental side showed 91%, 87%, and 56%, respectively. The results show that nerve injury followed by nerve repair by epineurial suture results in a high but variable amount of topographically correct regeneration, and that proportionally more neurons regenerate into the correct proximal nerve branch than into the correct innervation territory in the skin.

  • 30. Radu, Diana
    et al.
    Tomkinson, Birgitta
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Zachrisson, Olof
    Weber, Günther
    de Belleroche, Jacqueline
    Hirsch, Steven
    Lindefors, Nils
    Overlapping regional distribution of CCK and TPPII mRNAs in Cynomolgus monkey brain and correlated levels in human cerebral cortex (BA 10)2006In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1104, no 1, p. 175-182Article in journal (Refereed)
    Abstract [en]

    Tripeptidyl peptidase II (TPPII) is a high molecular weight exopeptidase important in inactivating extracellular cholecystokinin (CCK). Our aims were to study the anatomical localization of TPPII and CCK mRNA in the Cynomolgus monkey brain as a basis for a possible functional anatomical connection between enzyme (TPPII) and substrate (CCK) and examine if indications of changes in substrate availability in the human brain might be reflected in changes of levels of TPPII mRNA. Methods: mRNA in situ hybridization on postmortem brain from patients having had a schizophrenia diagnosis as compared to controls and on monkey and rat brain slices. Results: overlapping distribution patterns of mRNAs for TPPII and CCK in rat and monkey. High amounts of TPPII mRNA are seen in the neocortex, especially in the frontal region and the hippocampus. TPPII mRNA is also present in the basal ganglia and cerebellum where CCK immunoreactivity and/or CCK B receptors have been found in earlier studies, suggesting presence of CCK-ergic afferents from other brain regions. Levels of mRNAs for CCK and TPPII show a positive correlation in postmortem human cerebral cortex Brodmann area (BA) 10. TPPII mRNA might be affected following schizophrenia. Discussion: overall TPPII and CCK mRNA show a similar distribution in rat and monkey brain, confirming and extending earlier studies in rodents, In addition, correlated levels of TPPII and CCK mRNA in human BA 10 corroborate a functional link between CCK and TPPII in the human brain.

  • 31.
    Roos, Magnus W.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Ericsson, Anders
    Berg, Marita
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Sperber, Göran O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Sjöquist, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Meyerson, Bengt J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Functional evaluation of cerebral microembolization in the rat2003In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 961, no 1, p. 15-21Article in journal (Refereed)
    Abstract [en]

    This study investigates the effects of cerebral microembolism on motor performance and risk assessment behavior in the rat. Cerebral infarcts were produced in rats by injecting small plastic beads into the left heart ventricle under short-acting anesthesia. The functional outcome was tested 24 h later by subjecting the animals to a series of consecutive behavioral tests. Thereafter, the rats were anesthetized and underwent magnetic resonance imaging. On average about seven infarcts per brain were found. The volume of the individual infarcts was largest in the hippocampus (mean=4.26 mm(3)) and smallest in the white matter (mean=0.83 mm(3)). Embolized animals performed spontaneous and evident locomotion. The activity was, however, significantly decreased compared to rats treated with vehicle. More specific tests for motor ability revealed reduced gait capacity and muscular strength. A significant relationship was found between behaviors reflecting motor ability and the total volume of infarcted tissue in the brain stem, cortex and cerebellum. Also the behavioral profile of risk and benefit assessment was found to be altered by the microembolization. It is concluded that the combination of the microembolization method and behavioral tests provides a valuable tool for further studies of the pathophysiology of, and potential treatment for, cerebral infarction.

  • 32.
    Roshanbin, Sahar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Hellsten, Sofie V
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Tafreshiha, Atieh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Zhu, Yinan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Raine, Amanda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    PAT4 is abundantly expressed in excitatory and inhibitory neurons as well as epithelial cells2014In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1557, p. 12-25Article in journal (Refereed)
    Abstract [en]

    PAT4, the fourth member of the SLC36/proton dependent amino acid transporter (PAT) family, is a high-affinity, low capacity electroneutral transporter of neutral amino acids like proline and tryptophan. It has also been associated with the function of mTORC1, a complex in the mammalian target of rapamycin (mTOR) pathway. We performed in situ hybridization and immunohistological analysis to determine the expression profile of PAT4, as well as an RT-PCR study on tissue from mice exposed to leucine. We performed a phylogenetic analysis to determine the evolutionary origin of PAT4. The in situ hybridization and the immunohistochemistry on mouse brain sections and hypothalamic cells showed abundant PAT4 expression in the mouse brain intracellularly in both inhibitory and excitatory neurons, partially co-localizing with lysosomal markers and epithelial cells lining the ventricles. Its location in epithelial cells around the ventricles indicates a transport of substrates across the blood brain barrier. Phylogenetic analysis showed that PAT4 belongs to an evolutionary old family most likely predating animals, and PAT4 is the oldest member of that family.

  • 33.
    Rostami, Elham
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Krueger, Frank
    Plantman, Stefan
    Davidsson, Johan
    Agoston, Denes
    Grafman, Jordan
    Risling, Mårten
    Alteration in BDNF and its receptors, full-length and truncated TrkB and p75NTR following penetrating traumatic brain injury2014In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1542, p. 195-205Article in journal (Refereed)
    Abstract [en]

    The evidence that BDNF is involved in neuroprotection, neuronal repair and recovery after traumatic brain injury (TBI) is substantial. We have previously shown that the polymorphism of the human BDNF gene predicts cognitive recovery and outcome following penetrating TBI. The distribution of expression of BDNF and its receptors after penetrating TBI has not been investigated. In this study we examined the expression of these genes in a rat model of penetrating TBI. The injury is produced by a controlled penetration of a 2 mm thick needle-shaped object, which is accelerated with a pellet from an air gun. We used in situ hybridization and investigated the mRNA expression of BDNF and its receptors: the full-length and the truncated TrkB and p75NTR, from 1 day to 8 weeks following penetrating TBI. In addition, the protein level of BDNF in frontal cortex and hippocampus was measured by reverse phase protein microarray (RPPM). The mRNA expression of BDNF and its receptors decreased in the hippocampus in the border zone ipsilateral to the injury while there was an increase in mRNA expression at the contralateral side. The increase in BDNF mRNA expression in the hippocampus was sustained for 2 weeks following injury, with the highest expression noted in the CA3 cell layer. Furthermore, the protein analysis by RPPM showed increased levels of BDNF in the frontal cortex and the hippocampus up to 2 weeks after TBI. At 8 weeks following injury there was an intense labeling of the truncated TrkB receptor and the p75NTR in the area surrounding the cavity. Our study is the first report on the expression of BDNF and its receptors following penetrating TBI and suggests that their expression is altered long after the acute phase of injury. Further studies are needed to investigate if the late expressions of these receptors are beneficial or deleterious. In either case it indicates the possibility to influence the recovery after brain injury during the chronic phase and the development of treatments that may improve the outcome of TBI patients.

  • 34. Rosén, Annika
    et al.
    Lundeberg, Thomas
    Bytner, Beata
    Nylander, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Central changes in nociceptin, dynorphin and met-enkephalin-Arg-Phe in different models of nociception2000In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 857, no 1-2, p. 212-218Article in journal (Refereed)
    Abstract [en]

    The newly identified neuropeptide nociceptin/orphanin FQ (NOC) was measured in different rat brain areas related to the descending anti-nociceptive pathways and compared to two opioid peptides, dynorphin B (DYN B) and Met-enkephalinArgPhe (MEAP). Two experimental models of chronic nociception, one neurogenic and one inflammatory, used in this study, reveal how different pathological conditions may influence these endogenous systems. Nerve injury is induced by ligation of the sciatic nerve and inflammation by a carrageenan injection in the gluteal muscle, 2 weeks prior to decapitation. Selected brain areas were dissected out and frozen. NOC-, DYN B- and MEAP-like immunoreactivity (LI) is determined by radioimmunoassay. Nerve injury increased the NOC-LI levels in the cortex cinguli, DYN B-LI levels in the dorsal and the ventral part of the spinal cord, whereas a decrease in the MEAP-LI levels is seen in the dorsal part of the periaqueductal grey (PAG). After inflammation, the NOC-LI levels increased in cortex cinguli, hypothalamus and in the dorsal spinal cord, whereas DYN B-LI levels increased in the dorsal part of the PAG. A general increase in MEAP-LI levels is found after inflammation in all analyzed brain areas except in hippocampus. In conclusion, increased levels of NOC-LI were found in cortex cinguli in both treatment groups and in hypothalamus and spinal cord following carrageenan treatment. The changes in the NOC-LI concentrations were not parallelled by changes in DYN B-LI and MEAP-LI, suggesting that NOC and opioid peptides elicit different reactions in the systems of nociception/antinociception.

  • 35. Ryan, Allen F.
    et al.
    Ebmeyer, Jörg
    Furukawa, Masayuki
    Pak, Kwang
    Melhus, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Wasserman, Stephen I.
    Chung, Won-Ho
    Mouse models of induced otitis media2006In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1091, no 1, p. 3-8Article in journal (Refereed)
    Abstract [en]

    The mouse has seen limited use as a model for experimental otitis media, due primarily to the small size of its middle ear. However, the genetic resources of this species offer substantial potential benefits. These include detailed genomic information, a wealth of genetic models, and gene arrays that represent virtually all mouse genes. This has led to the development of methods for inducing otitis in mice. These include surgical approaches to the middle ear, documentation of the murine middle ear response to various pathogens and inflammatory factors, as well as characterization of induced otitis media in several mouse strains. The results indicate that induced otitis media in the normal mouse is in most respects comparable to that observed in other animal models and in humans. They further suggest that the considerable genetic resources of this species can be harnessed to increase our understanding of this disease.

  • 36. Sakurai, Eiichi
    et al.
    Sakurai, Eiko
    Tanaka, Yorihisa
    Watanabe, Takehiko
    Jossan, Sukhwinder Singh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Oreland, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Effects of histamine H3-receptor ligands on brain monoamine oxidase in various mammalian species2001In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 906, no 1-2, p. 180-183Article in journal (Refereed)
  • 37. Seppänen, Allan
    et al.
    Pikkarainen, Maria
    Hartikainen, Päivi
    Hofmann, Silke C.
    Majamaa, Kari
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Expression of collagen XVII and ubiquitin-binding protein p62 in motor neuron disease2009In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1247, p. 171-177Article in journal (Refereed)
    Abstract [en]

    Collagen involvement in motor neuron disease has been suggested by several earlier studies. Recently, we found collagen XVII to be expressed in locations in the human brain that include those damaged in motor neuron disease. In this study, we examined the extent of motor neuron disease-related changes in the brain of 9 subjects using ubiquitin-binding protein p62/sequestosome 1 (p62) immunohistochemistry. We then assessed whether or not the expression of collagen XVII was altered in relation to the p62 immunoreactive lesions. We found that neuronal collagen XVII expression in motor neuron disease remains similar to that seen in the normal human brain and thus a change in collagen XVII expression is not an immunohistochemically detectable feature of motor neuron disease. We also found that the regional distribution of p62 varied according to clinical presentation: p62 immunoreactive inclusions were found in the frontal cortex, hippocampus and cerebellum only in subjects with a history of psychiatric morbidity. Our study supports the re-definition of motor neuron disease as a multisystem disorder with a wide clinicopathological spectrum, and we advocate addressing psychiatric symptomology in future studies of motor neuron disease.

  • 38. Seppänen, Allan
    et al.
    Suuronen, Tiina
    Hofmann, Silke C
    Majamaa, Kari
    Alafuzoff, Irina
    Department of Neuroscience and Neurology, University of Kuopio Finland .
    Distribution of collagen XVII in the human brain.2007In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1158, p. 50-6Article in journal (Refereed)
    Abstract [en]

    We have recently discovered collagen XVII to be present in neurons of the human central nervous system. Collagen XVII has previously been primarily studied in the field of dermatopathology since it is abundantly expressed in the skin, which, like the nervous system, is ectodermal in origin. A link between dermatopathological and neurological entities has been implied due to clinical case studies revealing an association between bullous pemphigoid and age-related neurodegenerative disorders. The objective of this study was to assess the distribution of collagen XVII in the human brain in relation to normal ageing. Post-mortem brain tissue was obtained from 11 neurologically unimpaired subjects who had died from cardiovascular causes at the age of 17 to 78 years. Collagen XVII expression in various neuroanatomical regions, representing essentially the entire human brain, was then assessed using immunohistochemistry. We found collagen XVII to be expressed widely in the brain and to be located primarily in the soma and proximal axons of neurons. In contrast, glial cells did not express collagen XVII. The expression varied strikingly between different neuroanatomical regions, being most notable in motor nuclei and Betz cells followed by pyramidal neurons. There was no correlation between collagen XVII expression and variables such as gender, age at death, post-mortem delay and fixation time whereas a mode of death leading to notable neuronal ischemia depleted the protein expression. Many neurodegenerative disorders display a specific pattern of neuroanatomical involvement, thus the regionally variable expression of collagen XVII offers new prospects for research.

  • 39.
    Spencer, Nick J.
    et al.
    Flinders Univ S Australia, Coll Med & Publ Hlth, Ctr Neurosci, Bedford Pk, SA, Australia.
    Hibberd, Tim J.
    Flinders Univ S Australia, Coll Med & Publ Hlth, Ctr Neurosci, Bedford Pk, SA, Australia.
    Lagerström, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Otsuka, Yoichiro
    Flinders Univ S Australia, Coll Med & Publ Hlth, Ctr Neurosci, Bedford Pk, SA, Australia.
    Kelley, Nigel
    Govt South Australia, SA Hlth, SA Biomed Engn, Adelaide, SA, Australia.
    Visceral pain: Novel approaches for optogenetic control of spinal afferents2018In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1693, no part B, p. 159-164Article in journal (Refereed)
    Abstract [en]

    Painful stimuli arising within visceral organs are detected by peripheral nerve endings of spinal afferents, whose cell bodies are located in dorsal root ganglia (DRG). Recent technical advances have made it possible to reliably expose and inject single DRG with neuronal tracers or viruses in vivo. This has facilitated, for the first time, unequivocal identification of different types of spinal afferent endings in visceral organs. These technical advances paved the way for a very exciting series of in vivo experiments where individual DRG are injected to facilitate opsin expression (e.g. Archaerhodopsin). Organ-specific expression of opsins in sensory neurons may be achieved by retrograde viral transduction. This means activity of target specific populations of sensory neurons, within single DRG, can be modulated by optogenetic photo stimulation. Using this approach we implanted micro light-emitting diodes (micro-LEDs) adjacent to DRG of interest, thereby allowing focal DRG-specific control of visceral and/or somatic afferents in conscious mice. This is vastly different from broad photo-illumination of peripheral nerve endings, which are dispersed over much larger surface areas across an entire visceral organ; and embedded deep within multiple anatomical layers. Focal DRG photo-stimulation also avoids the potential that wide-field illumination of the periphery could inadvertently activate other closely apposed organs, or co-activate different classes of axons in the same organ (e.g. enteric and spinal afferent endings in the gut). It is now possible to selectively control nociceptive and/or non-nociceptive pathways to specific visceral organs in vivo, using wireless optogenetics and micro-LEDs implanted adjacent to DRG, for targeted photo-stimulation.

  • 40. Tan-No, Koichi
    et al.
    Ohshima, Kiyoshi
    Taira, Aki
    Inoue, Makoto
    Niijima, Fukie
    Nakagawasai, Osamu
    Tadano, Takeshi
    Nylander, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Silberring, Jerzy
    Terenius, Lars
    Kisara, Kensuke
    Antinociceptive effect produced by intracerebroventricularly administered dynorphin A is potentiated by p-hydroxymercuribenzoate or phosphoramidon in the mouse formalin test2001In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 891, no 1-2, p. 274-280Article in journal (Refereed)
    Abstract [en]

    The antinociceptive effects of intracerebroventricularly (i.c.v.) administered dynorphin A, an endogenous agonist for kappa-opioid receptors, in combination with various protease inhibitors were examined using the mouse formalin test in order to clarify the nature of the proteases involved in the degradation of dynorphin A in the mouse brain. When administered i.c.v. 15 min before the injection of 2% formalin solution into the dorsal surface of a hindpaw, 1-4 nmol dynorphin A produced a dose-dependent reduction of the nociceptive behavioral response consisting of licking and biting of the injected paw during both the first (0-5 min) and second (10-30 min) phases. When co-administered with p-hydroxymercuribenzoate (PHMB), a cysteine protease inhibitor, dynorphin A at the subthreshold dose of 0.5 nmol significantly produced an antinociceptive effect during the second phase. This effect was significantly antagonized by nor-binaltorphimine, a selective kappa-opioid receptor antagonist, but not by naltrindole, a selective delta-opioid receptor antagonist. At the same dose of 0.5 nmol, dynorphin A in combination with phosphoramidon, an endopeptidase 24.11 inhibitor, produced a significant antinociceptive effect during both phases. The antinociceptive effect was significantly antagonized by naltrindole, but not by nor-binaltorphimine. Phenylmethanesulfonyl fluoride (PMSF), a serine protease inhibitor, bestatin, a general aminopeptidase inhibitor, and captopril, an angiotensin-converting enzyme inhibitor, were all inactive. The degradation of dynorphin A by mouse brain extracts in vitro was significantly inhibited only by the cysteine protease inhibitors PHMB and N-ethylmaleimide, but not by PMSF, phosphoramidon, bestatin or captopril. The present results indicate that cysteine proteases as well as endopeptidase 24.11 are involved in two steps in the degradation of dynorphin A in the mouse brain, and that phosphoramidon inhibits the degradation of intermediary delta-opioid receptor active fragments enkephalins which are formed from dynorphin A.

  • 41.
    Taqi, Malik Mumtaz
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bazov, Igor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Watanabe, Hiroyuki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Yakovleva, Tatjana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Prodynorphin promoter SNP associated with alcohol dependence forms noncanonical AP-1 binding site that may influence gene expression in human brain2011In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1385, p. 18-25Article in journal (Refereed)
    Abstract [en]

    Single nucleotide polymorphism (rs1997794) in promoter of the prodynorphin gene (PDYN) associated with alcohol-dependence may impact PDYN transcription in human brain. To address this hypothesis we analyzed PDYN mRNA levels in the dorsolateral prefrontal cortex (dl-PFC) and hippocampus, both involved in cognitive control of addictive behavior and PDYN promoter SNP genotype in alcohol-dependent and control human subjects. The principal component analysis suggested that PDYN expression in the dl-PFC may be related to alcoholism, while in the hippocampus may depend on the genotype. We also demonstrated that the T, low risk SNP allele resides within noncanonical AP-1-binding element that may be targeted by JUND and FOSS proteins, the dominant AP-1 constituents in the human brain. The T to C transition abrogated AP-1 binding. The impact of genetic variations on PDYN transcription may be relevant for diverse adaptive responses of this gene to alcohol.

  • 42. Tingsborg, S
    et al.
    Zetterström, M
    Alheim, K
    Hasanvan, H
    Schultzberg, M
    Bartfai, T
    Regionally specific induction of ICE mRNA and enzyme activity in the rat brain and adrenal gland by LPS.1996In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 712, no 1, p. 153-8Article in journal (Refereed)
    Abstract [en]

    Pro interleukin-1 beta converting enzyme (ICE) activity in the pituitary was found to be significantly increased 4 h after intraperitoneal injection of E. coli lipopolysaccharides, when distribution and inducibility of the enzyme was studied in the adult rat brain and the adrenal gland, using an artificial fluorescence peptide substrate. The same lipopolysaccharide treatment induced ICE mRNA levels in the pituitary, adrenal gland and hypothalamus as studied by reverse transcript-polymerase chain reaction.

  • 43. Vlaskovska, Mila
    et al.
    Nylander, Ingrid
    Department of Clinical Neuroscience, Experimental Alcohol and Drug Addiction Research Section, Karolinska Institute.
    Schramm, Michael
    Hahne, Solveig
    Kasakov, Lubomir
    Silberring, Jerzy
    Terenius, Lars
    Opiate modulation of dynorphin conversion in primary cultures of rat cerebral cortex1997In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 760, no 1-2, p. 85-93Article in journal (Refereed)
    Abstract [en]

    Rat brain cortical cells in primary culture were used to investigate long-term effects of opiates on endopeptidases acting on dynorphin peptides. Enzyme activity in the soluble fraction of the cells converted dynorphin B to Leu-enkephalin-Arg6 and to a lesser extent to Leu-enkephalin. Five day treatment with 10 microM morphine increased the conversion to Leu-enkephalin-Arg6 by 370%. This effect was prevented by the presence of naloxone in the culture medium. The opiate-inducible activity was directed to the Arg-Arg bond in dynorphins with preference for dynorphin B > alpha-neoendorphin > > dynorphin A. The Km for the generation of Leu-enkephalin-Arg6 from dynorphin B was 40 microM. Enzyme activity was inhibited by dynorphin fragments, in the following order of potency: dynorphin A(1-13) > A(2-13) > A(1-17) > A(2-17) and by SH-reagents, suggesting the presence of a cysteine-protease. The opiate-stimulated dynorphin-converting enzyme (DCE)-activity affects the balance between dynorphin peptides (selective for kappa-opioid receptors) and enkephalin peptides (selective for delta-opioid receptors). Since both types of opioid peptides can influence the development of opiate tolerance, the change in the extent of this transformation may be functionally important.

  • 44.
    Wentzel, Parri
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Eriksson, Ulf J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Altered gene expression in neural crest cells exposed to ethanol in vitro2009In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1305, p. S50-S60Article in journal (Refereed)
    Abstract [en]

    Aim: to characterize and compare ethanol-induced changes of gene expression in cells from the cranial (cNCC) and trunk (tNCC) portion of the neural crest cell (NCC) population of day-10 rat embryos. Background: previous work has suggested that ethanol-induced embryonic maldevelopment is associated with oxidative stress, and, in particular, that ethanol-induced anomalies of the facial skeleton and heart are associated with disturbed development of the cNCC. We studied alterations of mRNA levels of genes involved in apoptosis, oxidative defense, cellular metabolism, NCC development or inflammation in cNCC and tNCC from rat embryos exposed to ethanol in vitro. We specifically evaluated expression differences between cNCC and tNCC genes, possibly reflecting the different teratological susceptibilities of the two cell populations. Methods: neural tube explants; from rat embryos were divided in cranial and trunk portions and used for NCC isolation in vitro on gestational day 10. The migrating cells from the cranial or trunk explants; of the neural tube were subsequently exposed to 0 or 88 mmol/l ethanol concentration with or without addition of 0.5 mM N-acetylcysteine (NAC) for 48 h, harvested, and prepared for gene expression measurement by RT-PCR or immunostaining with either distal-less (DLX) or AP 2-alpha antibodies. Results: evaluation of the immunostained slides showed that approximately 75% of the cNCC and tNCC preparations were of neural crest origin. Exposure to 88 mM ethanol increased the Bax/Bcl-2 ratio in the NCC, and NAC addition diminished this increase. Both cNCC and tNCC upregulated MnSOD and Gpx-1 in response to ethanol, whereas tNCC increased CuZnSOD and EC-SOD after ethanol exposure (cNCC unchanged). Expression of glyceraldehyde-3-phosphate dehydrogenase was downregulated by ethanol in cNCC only. In addition, ethanol exposure caused increased mRNA levels of Pax-3, p53, Vegf-A and decreased expression of Pax-6, Nfe2 in both cNCC and tNCC. Ethanol increased Shh and Bmp-4 and decreased Parp only in cNCC (tNCC unchanged), whereas ethanol exposure increased T box-2 and decreased Gdnf and Ret only in tNCC (cNCC unchanged). In addition, ethanol exposure almost abolished expression of Hox a(1), a(4) and a(5), and left Hox a(2) unchanged in cNCC, whereas all four of these Hox genes were upregulated in tNCC. Conclusions: ethanol causes a shift towards apoptosis in both cNCC and tNCC, a shift, which is diminished by NAC treatment. Oxidative defense genes, and genes involved in neural crest cell development are affected differently in cNCC compared to tNCC upon ethanol exposure. Moreover, ethanol downregulates cNCC Hox genes, whereas tNCC Hox genes are upregulated. These patterns of ethanol-altered gene expression may be of etiological importance for NCC-associated maldevelopment in ethanol-exposed pregnancy. (C) 2009 Elsevier B.V. All rights reserved.

  • 45. You, Zhi-Bing
    et al.
    Herrera-Marschitz, Mario
    Nylander, Ingrid
    Department of Clinical Neuroscience, Karolinska Institute.
    Goiny, Michel
    Kehr, Jan
    Ungerstedt, Urban
    Terenius, Lars
    Effect of morphine on dynorphin B and GABA release in the basal ganglia of rat1996In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 710, no 1-2, p. 241-248Article in journal (Refereed)
    Abstract [en]

    In vivo microdialysis was used to study the effects of systemic, as well as intracerebral administration of morphine and naloxone on dynorphin B release in neostriatum and substantia nigra of rats. The release of dopamine (DA), gamma-aminobutyric acid (GABA), glutamate (Glu) and aspartate (Asp) was also investigated. Systemic injection of morphine (1 mg/kg s.c.) induced long-lasting increases in extracellular dynorphin B and GABA levels in the substantia nigra, whereas DA, Glu and Asp levels, measured in the same region, were not significantly affected. No effect on striatal neurotransmitter levels was observed following systemic morphine administration. Local perfusion of the substantia nigra with morphine (100 microM) through the microdialysis probe also increased nigral dynorphin B and GABA levels. Perfusion of the neostriatum with morphine (100 microM) significantly increased GABA and dynorphin B levels in the ipsilateral substantia nigra, but no effect was observed locally. Naloxone blocked the effect of systemic morphine administration on nigral dynorphin B and GABA release, already at a dose of 0.2 mg/kg s.c. Naloxone alone, given either systemically (0.2-4 mg/kg s.c.) or intracerebrally (1-100 microM), did not affect dynorphin B or amino acid levels, either in neostriatum or in substantia nigra. However, naloxone produced a concentration-dependent increase in DA levels. The present results indicate that systemic morphine administration stimulates the release of dynorphin B in the substantia nigra, probably by activating the mu-subtype of opioid receptor, since the effect of morphine on nigral dynorphin B and GABA was antagonized by a low dose of naloxone. The increase in extracellular DA levels produced by high concentrations of naloxone, both in neostriatum and substantia nigra, indicates a disinhibitory effect of this drug on DA release, probably via a non-mu subtype of opioid receptors located on nigro-striatal DA neurones.

  • 46.
    Zhang, Xiaoqun
    et al.
    Karolinska Institutet, Institutionen för fysiologi och farmakologi .
    Andrén, Per E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, MMS, Medical Mass Spectrometry.
    Svenningsson, Per
    Karolinska Institutet, Institutionen för fysiologi och farmakologi.
    Repeated l-DOPA treatment increases c-fos and BDNF mRNAs in the subthalamic nucleus in the 6-OHDA rat model of Parkinson's disease2006In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1095, p. 207-210Article in journal (Refereed)
    Abstract [en]

    The subthalamic nucleus and the striatum are input regions of the basal ganglia. This study used the unilateral 6-OHDA rat model of Parkinson's disease to examine effects of l-DOPA on the expression of c-fos and BDNF mRNAs in these nuclei. Dopamine depletion per se did not affect c-fos or BDNF. Both a single and repeated injections of l-DOPA induced c-fos, but not BDNF, in the dopamine-depleted striatum. However, repeated l-DOPA treatment increased c-fos and BDNF in the dopamine-depleted subthalamic nucleus. These molecular adaptations may reflect changes in neuronal plasticity that underlie some therapeutic actions and/or side effects of l-DOPA in Parkinson's disease.

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