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  • 1.
    Aaseth, Jan
    et al.
    Innlandet Hospital Trust, Norway; Hedmark University of Appl Science, Norway.
    Alexander, Jan
    Norwegian Institute Public Heatlh, Norway; Norwegian University of Life Science NMBU, Norway.
    Bjorklund, Geir
    Council Nutr and Environm Med, Norway.
    Hestad, Knut
    Innlandet Hospital Trust, Norway; Hedmark University of Appl Science, Norway.
    Dusek, Petr
    Charles University of Prague, Czech Republic; Charles University of Prague, Czech Republic; Gen University Hospital Prague, Czech Republic.
    Roos, Per M.
    Karolinska Institute, Sweden; St Goran Hospital, Sweden.
    Alehagen, Urban
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Treatment strategies in Alzheimers disease: a review with focus on selenium supplementation2016In: Biometals, ISSN 0966-0844, E-ISSN 1572-8773, Vol. 29, no 5, p. 827-839Article in journal (Refereed)
    Abstract [en]

    Alzheimers disease (AD) is a neurodegenerative disorder presenting one of the biggest healthcare challenges in developed countries. No effective treatment exists. In recent years the main focus of AD research has been on the amyloid hypothesis, which postulates that extracellular precipitates of beta amyloid (A beta) derived from amyloid precursor protein (APP) are responsible for the cognitive impairment seen in AD. Treatment strategies have been to reduce A beta production through inhibition of enzymes responsible for its formation, or to promote resolution of existing cerebral A beta plaques. However, these approaches have failed to demonstrate significant cognitive improvements. Intracellular rather than extracellular events may be fundamental in AD pathogenesis. Selenate is a potent inhibitor of tau hyperphosphorylation, a critical step in the formation of neurofibrillary tangles. Some selenium (Se) compounds e.g. selenoprotein P also appear to protect APP against excessive copper and iron deposition. Selenoproteins show anti-inflammatory properties, and protect microtubules in the neuronal cytoskeleton. Optimal function of these selenoenzymes requires higher Se intake than what is common in Europe and also higher intake than traditionally recommended. Supplementary treatment with N-acetylcysteine increases levels of the antioxidative cofactor glutathione and can mediate adjuvant protection. The present review discusses the role of Se in AD treatment and suggests strategies for AD prevention by optimizing selenium intake, in accordance with the metal dysregulation hypothesis. This includes in particular secondary prevention by selenium supplementation to elderly with mild cognitive impairment.

  • 2.
    Acevedo, Juan Pablo
    et al.
    Univ Los Andes, Chile; Cells Cells, Chile.
    Angelopoulos, Ioannis
    Univ Los Andes, Chile; Cells Cells, Chile.
    van Noort, Danny
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, Faculty of Science & Engineering. Univ Los Andes, Chile.
    Khoury, Maroun
    Univ Los Andes, Chile; Cells Cells, Chile; Consorcio Regenero, Chile.
    Microtechnology applied to stem cells research and development2018In: Regenerative Medicine, ISSN 1746-0751, E-ISSN 1746-076X, Vol. 13, no 2, p. 233-248Article, review/survey (Refereed)
    Abstract [en]

    Microfabrication and microfluidics contribute to the research of cellular functions of cells and their interaction with their environment. Previously, it has been shown that microfluidics can contribute to the isolation, selection, characterization and migration of cells. This review aims to provide stem cell researchers with a toolkit of microtechnology (mT) instruments for elucidating complex stem cells functions which are challenging to decipher with traditional assays and animal models. These microdevices are able to investigate about the differentiation and niche interaction, stem cells transcriptomics, therapeutic functions and the capture of their secreted microvesicles. In conclusion, microtechnology will allow a more realistic assessment of stem cells properties, driving and accelerating the translation of regenerative medicine approaches to the clinic.

  • 3.
    Agalave, Nilesh M
    et al.
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Max
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden; Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Abdelmoaty, Sally
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Su, Jie
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Baharpoor, Azar
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Lundbäck, Peter
    Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
    Palmblad, Karin
    Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden.
    Andersson, Ulf
    Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden.
    Harris, Helena
    Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
    Svensson, Camilla I
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Spinal HMGB1 induces TLR4-mediated long-lasting hypersensitivity and glial activation and regulates pain-like behavior in experimental arthritis.2014In: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 155, no 9, p. 1802-1813Article in journal (Refereed)
    Abstract [en]

    Extracellular high mobility group box-1 protein (HMGB1) plays important roles in the pathogenesis of nerve injury- and cancer-induced pain. However, the involvement of spinal HMGB1 in arthritis-induced pain has not been examined previously and is the focus of this study. Immunohistochemistry showed that HMGB1 is expressed in neurons and glial cells in the spinal cord. Subsequent to induction of collagen antibody-induced arthritis (CAIA), Hmgb1 mRNA and extranuclear protein levels were significantly increased in the lumbar spinal cord. Intrathecal (i.t.) injection of a neutralizing anti-HMGB1 monoclonal antibody or recombinant HMGB1 box A peptide (Abox), which each prevent extracellular HMGB1 activities, reversed CAIA-induced mechanical hypersensitivity. This occurred during ongoing joint inflammation as well as during the postinflammatory phase, indicating that spinal HMGB1 has an important function in nociception persisting beyond episodes of joint inflammation. Importantly, only HMGB1 in its partially oxidized isoform (disulfide HMGB1), which activates toll-like receptor 4 (TLR4), but not in its fully reduced or fully oxidized isoforms, evoked mechanical hypersensitivity upon i.t. injection. Interestingly, although both male and female mice developed mechanical hypersensitivity in response to i.t. HMGB1, female mice recovered faster. Furthermore, the pro-nociceptive effect of i.t. injection of HMGB1 persisted in Tlr2- and Rage-, but was absent in Tlr4-deficient mice. The same pattern was observed for HMGB1-induced spinal microglia and astrocyte activation and cytokine induction. These results demonstrate that spinal HMGB1 contributes to nociceptive signal transmission via activation of TLR4 and point to disulfide HMGB1 inhibition as a potential therapeutic strategy in treatment of chronic inflammatory pain.

  • 4.
    Agnvall, Beatrix
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, Faculty of Science & Engineering.
    Bélteky, Johan
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, Faculty of Science & Engineering.
    Jensen, Per
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, Faculty of Science & Engineering.
    Brain size is reduced by selectionfor tameness in Red Junglefowl–correlated effects in vital organs2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 3306Article in journal (Refereed)
    Abstract [en]

    During domestication animals have undergone changes in size of brain and other vital organs. We hypothesize that this could be a correlated effect to increased tameness. Red Junglefowl (ancestors of domestic chickens) were selected for divergent levels of fear of humans for five generations. The parental (P0) and the fifth selected generation (S5) were culled when 48–54 weeks old and the brains were weighed before being divided into telencephalon, cerebellum, mid brain and optic lobes. Each single brain part as well as the liver, spleen, heart and testicles were also weighed. Brains of S5 birds with high fear scores (S5 high) were heavier both in absolute terms and when corrected for body weight. The relative weight of telencephalon (% of brain weight) was significantly higher in S5 high and relative weight of cerebellum was lower. Heart, liver, testes and spleen were all relatively heavier (% of body weight) in S5 high. Hence, selection for tameness has changed the size of the brain and other vital organs in this population and may have driven the domesticated phenotype as a correlated response.

  • 5.
    Aho, Nikolas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Proczkowska-Björklund, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Svedin, Carl Göran
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Child and Adolescent Psychiatry in Linköping.
    Victimization, polyvictimization , and health in Swedish adolescents2016In: Adolescent Health, Medicine and Therapeutics, ISSN 1179-318X, Vol. 7, p. 89-99Article in journal (Refereed)
    Abstract [en]

    The main objective of this article was to study the relationship between the different areas of victimization (eg, sexual victimization) and psychological symptoms, taking into account the full range of victimization domains. The final aim was to contribute further evidence regarding the bias that studies that focus on just one area of victimization may be introduced into our psychological knowledge. The sample included 5,960 second-year high school students in Sweden with a mean age of 17.3 years (range =16–20 years, standard deviation =0.652), of which 49.6% were females and 50.4% males. The Juvenile Victimization Questionnaire and the Trauma Symptom Checklist for Children were used to assess victimization and psychological problems separately. The results show that a majority of adolescents have been victimized, females reported more total events and more sexual victimization and childhood maltreatment, and males were more often victims of conventional crime. The majority of victimization domains as well as the sheer number of events (polyvictimization [PV]) proved to be harmful to adolescent health, affecting females more than males. PV explained part of the health effect and had an impact on its own and in relation to each domain. This suggests the possibility that PV to a large degree explains trauma symptoms. In order to understand the psychological effects of trauma, clinicians and researchers should take into account the whole range of possible types of victimization.

  • 6.
    Andersson, Erik
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Hedman, Erik
    Karolinska Institutet, Stockholm, Sweden.
    Enander, Jesper
    Karolinska Institutet, Stockholm, Sweden.
    Radu Djurfeldt, Diana
    Karolinska Institutet, Stockholm, Sweden.
    Ljótsson, Brjánn
    Karolinska Institutet, Stockholm, Sweden.
    Cervenka, Simon
    Karolinska Institutet, Stockholm, Sweden.
    Isung, Josef
    Karolinska Institutet, Stockholm, Sweden.
    Svanborg, Cecilia
    Karolinska Institutet, Stockholm, Sweden.
    Mataix-Cols, David
    Karolinska Institutet, Stockholm, Sweden.
    Kaldo, Viktor
    Karolinska Institutet, Stockholm, Sweden.
    Andersson, Gerhard
    Linköping University, Department of Behavioural Sciences and Learning, Psychology. Linköping University, Faculty of Arts and Sciences. Karolinska Inst, Div Psychiat, Dept Clin Neurosci, Stockholm, Sweden.
    Lindefors, Nils
    Karolinska Institutet, Stockholm, Sweden.
    Rück, Christian
    Karolinska Institutet, Stockholm, Sweden.
    D-Cycloserine vs Placebo as Adjunct to Cognitive Behavioral Therapy for Obsessive-Compulsive Disorder and Interaction With Antidepressants: A Randomized Clinical Trial.2015In: JAMA psychiatry, ISSN 2168-6238, E-ISSN 2168-622X, Vol. 72, no 7, p. 659-667Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE: It is unclear whether d-cycloserine (DCS), a partial N-methyl-d-aspartate agonist that enhances fear extinction, can augment the effects of exposure-based cognitive behavioral therapy (CBT) for obsessive-compulsive disorder (OCD).

    OBJECTIVES: To examine whether DCS augments the effects of CBT for OCD and to explore (post hoc) whether concomitant antidepressant medication moderates the effects of DCS.

    DESIGN, SETTING, AND PARTICIPANTS: A 12-week, double-blind randomized clinical trial with 3-month follow-up conducted at an academic medical center between September 4, 2012, and September 26, 2013. Participants included 128 adult outpatients with a primary diagnosis of OCD and a Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score of 16 or higher. Concurrent antidepressant medication was permitted if the dose had been stable for at least 2 months prior to enrollment and remained unchanged during the trial. The main analysis was by intention-to-treat population.

    INTERVENTIONS: All participants received a previously validated Internet-based CBT protocol over 12 weeks and were randomized to receive either 50 mg of DCS or placebo, administered 1 hour before each of 5 exposure and response prevention tasks.

    MAIN OUTCOMES AND MEASURES: Clinician-administered Y-BOCS score at week 12 and at 3-month follow-up. Remission was defined as a score of 12 or lower on the Y-BOCS.

    RESULTS: In the primary intention-to-treat analyses, DCS did not augment the effects of CBT compared with placebo (mean [SD] clinician-rated Y-BOCS score, DCS: 13.86 [6.50] at week 12 and 12.35 [7.75] at 3-month follow-up; placebo: 11.77 [5.95] at week 12 and 12.37 [6.68] at 3-month follow-up) but showed a significant interaction with antidepressants (clinician-rated Y-BOCS, B = -1.08; Z = -2.79; P = .005). Post hoc analyses revealed that antidepressants significantly impaired treatment response in the DCS group but not the placebo group, at both posttreatment and follow-up (clinician-rated Y-BOCS: t62 = -3.00; P = .004; and t61 = -3.49; P < .001, respectively). In the DCS group, a significantly greater proportion of antidepressant-free patients achieved remission status at follow-up (60% [95% CI, 45%-74%]) than antidepressant-medicated patients (24% [95% CI, 9%-48%]) (P = .008). Antidepressants had no effect in the placebo group (50% [95% CI, 36%-64%] remission rate in both groups).

    CONCLUSIONS AND RELEVANCE: The findings suggest that antidepressants may interact with DCS to block its facilitating effect on fear extinction. Use of DCS may be a promising CBT augmentation strategy but only in antidepressant-free patients with OCD.

    TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01649895.

  • 7.
    Andin, Josefine
    et al.
    Linköping University, Department of Behavioural Sciences and Learning, Disability Research. Linköping University, Faculty of Arts and Sciences.
    Dahlström, Örjan
    Linköping University, Department of Behavioural Sciences and Learning, Disability Research. Linköping University, Faculty of Arts and Sciences.
    Fransson, Peter
    Karolinska institutet, Department of Clinical Neuroscience.
    Rönnberg, Jerker
    Linköping University, Department of Behavioural Sciences and Learning, Disability Research. Linköping University, Faculty of Arts and Sciences.
    Rudner, Mary
    Linköping University, Department of Behavioural Sciences and Learning, Disability Research. Linköping University, Faculty of Arts and Sciences.
    Greater reliance on magnitude manipulation during mental arithmetic in deaf signers compared to hearing non-signers: fMRI evidence2015Conference paper (Refereed)
    Abstract [en]

    Evidence suggests that the lag reported in mathematics for deaf signers derives from difficulties related to verbal processing of numbers, whereas magnitude processing seems unaffected by deafness. Neuroimaging evidence from hearing individuals suggests that verbal processing of numbers engages primarily left angular gyrus (lAG), whereas magnitude processing engages primarily the horizontal portion of the right intraparietal sulcus (rHIP). In a ROI analysis of brain imaging data from 16 adult deaf signers and 16 adult hearing non-signers, who did not differ on sex, age or education, we examined if activity in lAG and rHIP changed as a result of task (multiplication vs subtraction) and group (deaf signers and hearing non-signers). We found a significant main effect of brain region (F(1,30) = 117.00, p < .001, η_p^2 = .80) and an interaction effect between region and group (F(1,30) = 20.70, p < .001, η_p^2 = .41). Further analyses showed that there were no significant differences in average activation between groups in lAG (F(1,30) = 0.16, p = .70). However, in rHIP deaf signers showed significantly greater average activation compared to non-signers (F(1,30) = 15.20, p < .001, η_p^2 = .34). There were no significant differences in activation between subtraction and multiplication (F(1,30) = 0.66, p = .42) and no behavioural differences between groups (F(1,30) = 1.70, p = .20). These results suggest that when engaging in arithmetic tasks deaf signers successfully make use of qualitatively difference processes, compared to hearing non-signers, with stronger emphasis on brain regions relating to magnitude manipulation.

  • 8.
    Antelius, Eleonor
    et al.
    Linköping University, Department of Social and Welfare Studies, Division Ageing and Social Change. Linköping University, Faculty of Arts and Sciences.
    Kiwi, Mahin
    Linköping University, Department of Social and Welfare Studies, Division Ageing and Social Change. Linköping University, Faculty of Arts and Sciences.
    Strandroos, Lisa
    Linköping University, Department of Social and Welfare Studies, Division Ageing and Social Change. Linköping University, Faculty of Arts and Sciences.
    Ethnographic methods for understanding practices around dementia among culturally and linguistically diverse people2018In: Social research methods in dementia studies: inclusion and innovation / [ed] John Keady, Lars-Christer Hydén, Ann Johnson, Caroline Swarbrick, Abingdon, Oxon: Routledge, 2018, p. 121-139Chapter in book (Other academic)
  • 9.
    Aoun, E. G.
    et al.
    Brown Univ, RI 02912 USA.
    Jimenez, V. A.
    Oregon Hlth and Sci Univ, OR 97201 USA.
    Vendruscolo, L. F.
    Scripps Res Inst, CA 92037 USA; NIDA, MD 20892 USA.
    Walter, N. A. R.
    Oregon Hlth and Sci Univ, OR 97201 USA.
    Barbier, Estelle
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Ferrulli, A.
    Univ Cattolica Sacro Cuore, Italy.
    Haass-Koffler, C. L.
    Brown Univ, RI 02912 USA; NIAAA, MD 20892 USA; NIDA, MD 20892 USA.
    Darakjian, P.
    Oregon Hlth and Sci Univ, OR 97201 USA.
    Lee, M. R.
    NIAAA, MD 20892 USA; NIDA, MD 20892 USA.
    Addolorato, G.
    Univ Cattolica Sacro Cuore, Italy.
    Heilig, Markus
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Hitzemann, R.
    Oregon Hlth and Sci Univ, OR 97201 USA.
    Koob, G. F.
    Scripps Res Inst, CA 92037 USA; NIAAA, MD 20852 USA.
    Grant, K. A.
    Oregon Hlth and Sci Univ, OR 97201 USA.
    Leggio, L.
    Brown Univ, RI 02912 USA; NIAAA, MD 20892 USA; NIDA, MD 20892 USA.
    A relationship between the aldosterone-mineralocorticoid receptor pathway and alcohol drinking: preliminary translational findings across rats, monkeys and humans2018In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 23, no 6, p. 1466-1473Article in journal (Refereed)
    Abstract [en]

    Aldosterone regulates electrolyte and fluid homeostasis through binding to the mineralocorticoid receptors (MRs). Previous work provides evidence for a role of aldosterone in alcohol use disorders (AUDs). We tested the hypothesis that high functional activity of the mineralocorticoid endocrine pathway contributes to vulnerability for AUDs. In Study 1, we investigated the relationship between plasma aldosterone levels, ethanol self-administration and the expression of CYP11B2 and MR (NR3C2) genes in the prefrontal cortex area (PFC) and central nucleus of the amygdala (CeA) in monkeys. Aldosterone significantly increased after 6- and 12-month ethanol self-administration. NR3C2 expression in the CeA was negatively correlated to average ethanol intake during the 12 months. In Study 2, we measured Nr3c2 mRNA levels in the PFC and CeA of dependent and nondependent rats and the correlates with ethanol drinking during acute withdrawal. Low Nr3c2 expression levels in the CeA were significantly associated with increased anxiety-like behavior and compulsive-like drinking in dependent rats. In Study 3, the relationship between plasma aldosterone levels, alcohol drinking and craving was investigated in alcohol-dependent patients. Non-abstinent patients had significantly higher aldosterone levels than abstinent patients. Aldosterone levels positively correlated with the number of drinks consumed, craving and anxiety scores. These findings support a relationship between ethanol drinking and the aldosterone/MR pathway in three different species.

  • 10.
    Augier, Eric
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Dulman, Russell S.
    NIAAA, MD USA.
    Damadzic, Ruslan
    NIAAA, MD USA.
    Pilling, Andrew
    NIAAA, MD USA.
    Hamilton, Paul
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Heilig, Markus
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    The GABA(B) Positive Allosteric Modulator ADX71441 Attenuates Alcohol Self-Administration and Relapse to Alcohol Seeking in Rats2017In: Neuropsychopharmacology, ISSN 0893-133X, E-ISSN 1740-634X, Vol. 42, no 9, p. 1789-1799Article in journal (Refereed)
    Abstract [en]

    GABAergic signaling is involved in modulating the reinforcing properties of alcohol, and GABA(B) receptors have been proposed as a potential target for clinical treatment of alcoholism. The orthosteric GABA(B) receptor agonist baclofen has been shown to suppress operant self-administration of alcohol in animals and alcohol use in alcohol-dependent patients, but its utility is limited by a narrow therapeutic index. We tested the effects of ADX71441, a novel GABA(B) receptor positive allosteric modulator, on alcohol-related behaviors in rats. We first assessed the effects of ADX71441 ( 1, 3, 10 and 30 mg/kg, I.P.) on both non-dependent and dependent male Wistar rats trained to self-administer 20% alcohol. We then determined the effects of ADX71441 on stress-induced as well as cue-induced relapse-like behavior. Finally, we sought to identify the brain regions through which ADX71441 may act to prevent relapse-like behavior by mapping the neuronal activation induced by stress-induced reinstatement of alcohol-seeking using c-Fos immunohistochemistry. ADX71441 dose-dependently decreased alcohol self-administration of both dependent and non-dependent animals, but its potency was higher in alcohol-dependent rats. Furthermore, both cue-and stress-induced alcohol seeking were blocked by the GABA(B) receptor positive allosteric modulator. Finally, pretreatment with 3 mg/kg of ADX71441 before stress-induced reinstatement significantly decreased c-Fos expression in a network of brain regions implicated in stress-induced relapse, comprising the nucleus accumbens shell, the dorsal raphe nucleus and the medial prefrontal cortex. Our findings support a causal role of GABAB receptors in alcohol reinforcement and relapse to alcohol seeking. These effects are observed in the absence of significant sedative side effects. Jointly, these observations indicate that GABAB receptor positive allosteric modulators merit being tested clinically for the treatment of alcoholism. Our data also point to a potential biomarker of target engagement for early clinical studies.

  • 11.
    Azim, Kasum
    et al.
    Brain Research Institute, University of Zürich/ETHZ, Zürich, Switzerland / Adult Neurogenesis and Cellular Reprogramming, Institute of Physiological Chemistry, University Medical Centre of the Johannes Gutenberg University Mainz, Germany / Focus Program Translational Neuroscience, Johannes Gutenberg University Mainz, Germany.
    Angonin, Diane
    Univ Lyon, Université Claude Bernard Lyon 1, Inserm, Stem Cell and Brain Research Institute U1208, Bron, France.
    Marcy, Guillaume
    Univ Lyon, Université Claude Bernard Lyon 1, Inserm, Stem Cell and Brain Research Institute U1208, Bron, France.
    Pieropan, Francesca
    School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, United Kingdom.
    Rivera, Andrea
    School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, United Kingdom.
    Donega, Vanessa
    Univ Lyon, Université Claude Bernard Lyon 1, Inserm, Stem Cell and Brain Research Institute U1208, Bron, France.
    Cantù, Claudio
    IMLS, University of Zurich, Zurich, Switzerland.
    Williams, Gareth
    Wolfson Centre for Age-Related Diseases, King's College London, Guy's Campus, London, United Kingdom.
    Berninger, Benedikt
    Adult Neurogenesis and Cellular Reprogramming, Institute of Physiological Chemistry, University Medical Centre of the Johannes Gutenberg University Mainz, Germany / Focus Program Translational Neuroscience, Johannes Gutenberg University Mainz, Germany.
    Butt, Arthur M
    School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, United Kingdom.
    Raineteau, Olivier
    Brain Research Institute, University of Zürich/ETHZ, Zürich, Switzerland / Univ Lyon, Université Claude Bernard Lyon 1, Inserm, Stem Cell and Brain Research Institute U1208, Bron, France.
    Pharmacogenomic identification of small molecules for lineage specific manipulation of subventricular zone germinal activity2017In: PLoS biology, ISSN 1544-9173, E-ISSN 1545-7885, Vol. 15, no 3, article id e2000698Article in journal (Refereed)
    Abstract [en]

    Strategies for promoting neural regeneration are hindered by the difficulty of manipulating desired neural fates in the brain without complex genetic methods. The subventricular zone (SVZ) is the largest germinal zone of the forebrain and is responsible for the lifelong generation of interneuron subtypes and oligodendrocytes. Here, we have performed a bioinformatics analysis of the transcriptome of dorsal and lateral SVZ in early postnatal mice, including neural stem cells (NSCs) and their immediate progenies, which generate distinct neural lineages. We identified multiple signaling pathways that trigger distinct downstream transcriptional networks to regulate the diversity of neural cells originating from the SVZ. Next, we used a novel in silico genomic analysis, searchable platform-independent expression database/connectivity map (SPIED/CMAP), to generate a catalogue of small molecules that can be used to manipulate SVZ microdomain-specific lineages. Finally, we demonstrate that compounds identified in this analysis promote the generation of specific cell lineages from NSCs in vivo, during postnatal life and adulthood, as well as in regenerative contexts. This study unravels new strategies for using small bioactive molecules to direct germinal activity in the SVZ, which has therapeutic potential in neurodegenerative diseases.

  • 12.
    Aziz, Abdul Maruf Asif
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Neuropeptide Receptors as Treatment Targets in Alcohol Use Disorders2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Alcohol use disorder (AUD) is a complex disorder with multiple pathophysiological processes contributing to the initiation, progression and development of the disease state. AUD is a chronic relapsing disease with escalation of alcohol-intake over time in repeated cycles of tolerance, abstinence and relapse and hence, it is very difficult to treat. There are only a few currently available treatments with narrow efficacy and variable patient response. Thus it is important to find new, more effective medications to increase the number of patients who can benefit from pharmacological treatment of AUD.

    The research presented in this thesis work focuses on the critical involvement of central neuropeptides in alcohol-related behaviors. The overall aim was to evaluate the nociceptin/orphanin FQ (NOP) receptor, the neuropeptide Y (NPY) Y2 receptor and the melanin-concentrating hormone (MCH) receptor 1 as novel and potential pharmacological treatment targets for AUD by testing the NOP receptor agonist SR-8993, the NPY-Y2 receptor antagonist CYM-9840 and the MCH1 receptor antagonist GW803430 in established animal models.

    In the first study (Paper I), the novel and selective NOP agonist SR-8993 was assessed in rat models of motivation to obtain alcohol and relapse to alcohol seeking behavior using the operant self-administration (SA) paradigm. Firstly, treatment with SR-8993 (1 mg/kg) showed a mildly anxiolytic effect and reversed acute alcohol withdrawal-induced “hangover” anxiety in the elevated plus-maze (EPM). Next, it potently attenuated alcohol SA and motivation to obtain alcohol in the progressive ratio responding (PRR) and reduced both alcohol cue-induced and yohimbine stress-induced reinstatement of alcohol seeking, without affecting the pharmacology and metabolism of alcohol nor other control behaviors. To extend these findings, SR-8993 was evaluated in escalated alcohol-intake in rats.  Treatment with SR-8993 significantly suppressed alcohol-intake and preference in rats that were trained to consume high amounts of alcohol in the two-bottle free choice intermittent access (IA) paradigm. SR-8993 also blocked operant SA of alcohol in rats that showed robust escalation in operant alcohol SA following chronic IA exposure to alcohol.

    In the second study (Paper II), SR-8993 was further evaluated in a model for escalated alcohol-intake induced by long-term IA exposure to alcohol. The effect of previous experience on operant alcohol SA on two-bottle free choice preference drinking was evaluated and sensitivity to treatment with SR-8993 was tested in rats selected for escalated and non-escalated alcohol seeking behavior. We found that rats exposed to the combined SA-IA paradigm showed greater sensitivity to SR-8993 treatment. In addition, acute escalation of alcohol SA after a three-week period of abstinence was completely abolished by pretreatment with SR-8993.

    In the third study (Paper III), the effects of the novel, small molecule NPY-Y2 antagonist CYM-9840 were tested in operant alcohol SA, PRR which is a model for motivation to work for alcohol and reinstatement of alcohol-seeking behavior. Treatment with CYM-9840 (10 mg/kg) potently attenuated alcohol SA, progressive ratio responding and stress-induced reinstatement using yohimbine as the stressor, while alcohol cue-induced reinstatement was unaffected. Moreover, a range of control behaviors including taste sensitivity, locomotor and pharmacological sensitivity to the sedative effects of alcohol remained unaffected by CYM-9840 pretreatment, indicating that its effects are specific to the rewarding and motivational aspects of alcohol-intake and related behaviors. CYM-9840 also reversed acute alcohol withdrawal-induced “hangover” anxiety measured in the EPM and reduced alcohol-intake in the 4 hour limited access two-bottle free choice preference drinking model.

    Finally, in the fourth study (Paper IV), the selective MCH1-R antagonist GW803430 was tested in rat models of escalated alcohol-intake. Pretreatment with GW803430 (effective at 10 & 30 mg/kg) dose-dependently reduced alcohol and food-intake in rats that consumed high amounts of alcohol during IA, while it only decreased food-intake in rats that consumed low amounts of alcohol during IA, likely due to a floor effect. Upon protracted abstinence following IA, GW803430 significantly reduced operant alcohol SA and this was associated with adaptations in MCH and MCH1-R gene-expression. In contrast, GW803430 did not affect escalated alcohol SA induced by chronic alcohol vapor exposure and this was accompanied by no change in MCH or MCH1-R gene expression. Overall, these results suggest that the MCH1-R antagonist affects alcohol-intake through regulation of both motivation for caloric-intake and the rewarding properties of alcohol.

    In conclusion, our results suggest critical roles for these central neuropeptides in the regulation of anxiety and of alcohol reward, making them potential pharmacological targets in the treatment of AUD.

    List of papers
    1. The nociceptin/orphanin FQ receptor agonist SR-8993 as a candidate therapeutic for alcohol use disorders: validation in rat models
    Open this publication in new window or tab >>The nociceptin/orphanin FQ receptor agonist SR-8993 as a candidate therapeutic for alcohol use disorders: validation in rat models
    Show others...
    2016 (English)In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 233, no 19-20, p. 3553-3563Article in journal (Refereed) Published
    Abstract [en]

    RATIONALE: Alcoholism is a complex disorder in which diverse pathophysiological processes contribute to initiation and progression, resulting in a high degree of heterogeneity among patients. Few pharmacotherapies are presently available, and patient responses to these are variable. The nociceptin/orphanin FQ (NOP) receptor has been suggested to play a role both in alcohol reward and in negatively reinforced alcohol seeking. Previous studies have shown that NOP-receptor activation reduces alcohol intake in genetically selected alcohol-preferring as well as alcohol-dependent rats. NOP activation also blocks stress- and cue-induced reinstatement of alcohol-seeking behavior.

    OBJECTIVES: Here, we aimed to examine a novel, potent, and brain-penetrant small-molecule NOP-receptor agonist, SR-8993, in animal models of alcohol- as well as anxiety-related behavior using male Wistar rats.

    RESULTS: SR-8993 was mildly anxiolytic when given to naïve animals and potently reversed acute alcohol withdrawal-induced ("hangover") anxiety. SR-8993 reduced both home-cage limited access drinking, operant responding for alcohol, and escalation induced through prolonged intermittent access to alcohol. SR-8993 further attenuated stress- as well as cue-induced relapse to alcohol seeking. For the effective dose (1.0 mg/kg), non-specific effects such as sedation may be limited, since a range of control behaviors were unaffected, and this dose did not interact with alcohol elimination.

    CONCLUSION: These findings provide further support for NOP-receptor agonism as a promising candidate treatment for alcoholism and establish SR-8993 or related molecules as suitable for further development as therapeutics.

    Place, publisher, year, edition, pages
    Springer, 2016
    Keywords
    Nociception/orphanin FQ, Agonist, Wistar rat, Alcohol, Operant, Reinstatement, Elevated plus-maze
    National Category
    Substance Abuse
    Identifiers
    urn:nbn:se:liu:diva-132347 (URN)10.1007/s00213-016-4385-8 (DOI)000383672500006 ()27515665 (PubMedID)
    Note

    Funding Agencies|National Institutes of Health [R01-DA035055]; Swedish Research Council [2010-3219]

    Available from: 2016-11-12 Created: 2016-11-01 Last updated: 2017-08-21Bibliographically approved
    2. Melanin-Concentrating Hormone and Its MCH-1 Receptor: Relationship Between Effects on Alcohol and Caloric Intake
    Open this publication in new window or tab >>Melanin-Concentrating Hormone and Its MCH-1 Receptor: Relationship Between Effects on Alcohol and Caloric Intake
    Show others...
    2016 (English)In: Alcoholism: Clinical and Experimental Research, ISSN 0145-6008, E-ISSN 1530-0277, Vol. 40, no 10, p. 2199-2207Article in journal (Refereed) Published
    Abstract [en]

    Background: Reward and energy homeostasis are both regulated by a network of hypothalamic neuropeptide systems. The melanin-concentrating hormone (MCH) and its MCH-1 receptor (MCH1-R) modulate alcohol intake, but it remains unknown to what extent this reflects actions on energy balance or reward. Here, we evaluated the MCH1-R in regulation of caloric intake and motivation to consume alcohol in states of escalated consumption.

    Methods: Rats had intermittent access (IA) to alcohol and were divided into high- and low-drinking groups. Food and alcohol consumption was assessed after administration of an MCH1-R antagonist, GW803430. Next, GW803430 was evaluated on alcohol self-administration in protracted abstinence induced by IA in high-drinking rats. Finally, the effect of GW803430 was assessed on alcohol self-administration in acute withdrawal in rats exposed to alcohol vapor. Gene expression of MCH and MCH1-R was measured in the hypothalamus and nucleus accumbens (NAc) in both acute and protracted abstinence.

    Results: High-drinking IA rats consumed more calories from alcohol than chow and GW803430 decreased both chow and alcohol intake. In low-drinking rats, only food intake was affected. In protracted abstinence from IA, alcohol self-administration was significantly reduced by pretreatment with GW803430 and gene expression of both MCH and the MCH1-R were dysregulated in hypothalamus and NAc. In contrast, during acute withdrawal from vapor exposure, treatment with GW803430 did not affect alcohol self-administration, and no changes in MCH or MCH1-R gene expression were observed.

    Conclusions: Our data suggest a dual role of MCH and the MCH1-R in regulation of alcohol intake, possibly through mechanisms involving caloric intake and reward motivation. A selective suppression of alcohol self-administration during protracted abstinence by GW803430 was observed and accompanied by adaptations in gene expression of MCH and MCH1-R. Selective suppression of escalated consumption renders the MCH1-R an attractive target for treatment of alcohol use disorders.

    Place, publisher, year, edition, pages
    Wiley-Blackwell, 2016
    Keywords
    Alcohol Escalation, Reward, Motivation, Calorie Intake, Melanin-Concentrating Hormone Receptor-1
    National Category
    Substance Abuse
    Identifiers
    urn:nbn:se:liu:diva-132522 (URN)10.1111/acer.13181 (DOI)000385542900017 ()27579857 (PubMedID)
    Available from: 2016-11-14 Created: 2016-11-13 Last updated: 2018-03-19Bibliographically approved
  • 13.
    Barbier, Estelle
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Heilig, Markus
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    mTORC and ProSAPiP1: How Alcohol Changes Synapses of Reward Circuitry2017In: Neuron, ISSN 0896-6273, E-ISSN 1097-4199, Vol. 96, no 1Article in journal (Other academic)
    Abstract [en]

    Alcohol addiction is characterized by broad and persistent changes in brain function, but the underlying neural adaptations remain largely unknown. In this issue of Neuron, Laguesse et al. (2017) describe a neural mechanism through which long-term alcohol exposure induces structural and synaptic adaptations that promote excessive alcohol use.

  • 14.
    Barbier, Estelle
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Johnstone, A. L.
    University of Miami, FL 33136 USA.
    Khomtchouk, B. B.
    University of Miami, FL 33136 USA.
    Tapocik, J. D.
    NIAAA, MD USA.
    Pitcairn, C.
    NIAAA, MD USA.
    Rehman, F.
    NIAAA, MD USA.
    Augier, Eric
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Borich, A.
    NIAAA, MD USA.
    Schank, J. R.
    University of Georgia, GA 30602 USA.
    Rienas, C. A.
    University of Miami, FL 33136 USA.
    Van Booven, D. J.
    University of Miami, FL 33136 USA.
    Sun, H.
    NIAAA, MD USA.
    Nätt, Daniel
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Wahlestedt, C.
    University of Miami, FL 33136 USA; University of Miami, FL 33136 USA.
    Heilig, Markus
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry. NIAAA, MD USA.
    Dependence-induced increase of alcohol self-administration and compulsive drinking mediated by the histone methyltransferase PRDM22017In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 22, no 12, p. 1746-1758Article in journal (Refereed)
    Abstract [en]

    Epigenetic processes have been implicated in the pathophysiology of alcohol dependence, but the specific molecular mechanisms mediating dependence-induced neuroadaptations remain largely unknown. Here, we found that a history of alcohol dependence persistently decreased the expression of Prdm2, a histone methyltransferase that monomethylates histone 3 at the lysine 9 residue (H3K9me1), in the rat dorsomedial prefrontal cortex (dmPFC). Downregulation of Prdm2 was associated with decreased H3K9me1, supporting that changes in Prdm2 mRNA levels affected its activity. Chromatin immunoprecipitation followed by massively parallel DNA sequencing showed that genes involved in synaptic communication are epigenetically regulated by H3K9me1 in dependent rats. In non-dependent rats, viral-vector-mediated knockdown of Prdm2 in the dmPFC resulted in expression changes similar to those observed following a history of alcohol dependence. Prdm2 knockdown resulted in increased alcohol self-administration, increased aversion-resistant alcohol intake and enhanced stress-induced relapse to alcohol seeking, a phenocopy of postdependent rats. Collectively, these results identify a novel epigenetic mechanism that contributes to the development of alcohol-seeking behavior following a history of dependence.

  • 15.
    Barde, Swapnali
    et al.
    Karolinska Institute, Sweden.
    Ruegg, Joelle
    Karolinska Institute, Sweden; Centre Molecular Med, Sweden; Swedish Toxicol Science Research Centre Swetox, Sweden.
    Prudhomme, Jose
    Douglas Mental Health University of Institute, Canada.
    Ekström, Tomas J.
    Karolinska Institute, Sweden; Centre Molecular Med, Sweden.
    Palkovits, Miklos
    Semmelweis University, Hungary.
    Turecki, Gustavo
    Douglas Mental Health University of Institute, Canada; McGill University, Canada.
    Bagdy, Gyorgy
    Semmelweis University, Hungary.
    Ihnatko, Robert
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Theodorsson, Elvar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Juhasz, Gabriella
    Semmelweis University, Hungary; University of Manchester, England.
    Diaz-Heijtz, Rochellys
    Karolinska Institute, Sweden.
    Mechawar, Naguib
    Douglas Mental Health University of Institute, Canada; McGill University, Canada.
    Hokfelt, Tomas G. M.
    Karolinska Institute, Sweden.
    Alterations in the neuropeptide galanin system in major depressive disorder involve levels of transcripts, methylation, and peptide2016In: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, ISSN 0027-8424, Vol. 113, no 52, p. E8472-E8481Article in journal (Refereed)
    Abstract [en]

    Major depressive disorder (MDD) is a substantial burden to patients, families, and society, but many patients cannot be treated adequately. Rodent experiments suggest that the neuropeptide galanin (GAL) and its three G protein-coupled receptors, GAL(1-3), are involved in mood regulation. To explore the translational potential of these results, we assessed the transcript levels (by quantitative PCR), DNA methylation status (by bisulfite pyrosequencing), and GAL peptide by RIA of the GAL system in postmortem brains from depressed persons who had committed suicide and controls. Transcripts for all four members were detected and showed marked regional variations, GAL and galanin receptor 1 (GALR1) being most abundant. Striking increases in GAL and GALR3 mRNA levels, especially in the noradrenergic locus coeruleus and the dorsal raphe nucleus, in parallel with decreased DNA methylation, were found in both male and female suicide subjects as compared with controls. In contrast, GAL and GALR3 transcript levels were decreased, GALR1 was increased, and DNA methylation was increased in the dorsolateral prefrontal cortex of male suicide subjects, however, there were no changes in the anterior cingulate cortex. Thus, GAL and its receptor GALR3 are differentially methylated and expressed in brains of MDD subjects in a region- and sex-specific manner. Such an epigenetic modification in GALR3, a hyperpolarizing receptor, might contribute to the dysregulation of noradrenergic and serotonergic neurons implicated in the pathogenesis of MDD. Thus, one may speculate that a GAL(3) antagonist could have antidepressant properties by disinhibiting the firing of these neurons, resulting in increased release of noradrenaline and serotonin in forebrain areas involved in mood regulation.

  • 16.
    Bartoszek, Krzysztof
    et al.
    Mathematical Sciences, Chalmers University of Technology and the University of Gothenburg.
    Stokowska, Anna
    University of Gothenburg.
    Performance of pseudo-likelihood estimator in modelling cells' proliferation with noisy measurements2010In: Conference proceedings from the 12th International Workshop for Young Mathematicians "Probability and Statistics", Krakow, Poland, 20th till 26th September 2009, 2010, p. 21-42Conference paper (Other academic)
    Abstract [en]

    Branching processes are widely used to describe cell development and proliferation. Currently parameter estimation is studied in mathematical models describing the dynamics of cell cultures where we can get very accurate measurements of cell counts. In vivo samples we will not have this accuracy, here the noise levels can be very significant. We will study a newly proposed pseudo-likelihood estimator of a multitype Bellman-Harris process modelling cell development and see how it performs under noisy measurements of cell counts.

  • 17.
    Berg, L K
    et al.
    Department of Anatomy, Institute of Basic Medical Sciences, Centre for Molecular, Biology and Neuroscience (CMBN), University of Oslo, Norway.
    Larsson, M
    Department of Anatomy, Institute of Basic Medical Sciences, Centre for Molecular, Biology and Neuroscience (CMBN), University of Oslo, Norway; Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Morland, C
    Department of Anatomy, Institute of Basic Medical Sciences, Centre for Molecular, Biology and Neuroscience (CMBN), University of Oslo, Norway.
    Gundersen, V
    Department of Anatomy, Institute of Basic Medical Sciences, Centre for Molecular, Biology and Neuroscience (CMBN), University of Oslo, Norway; Department of Neurology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
    Pre- and postsynaptic localization of NMDA receptor subunits at hippocampal mossy fibre synapses.2013In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 230, p. 139-150Article in journal (Refereed)
    Abstract [en]

    The N-methyl-D-aspartate (NMDA) type of glutamate receptors is involved in synaptic plasticity in hippocampal mossy fibre-CA3 pyramidal neuron synapses. The ultrastructural localization of NMDA receptor subunits at this synapse type is not known. By postembedding electron microscopic immunogold cytochemistry we show that the NMDA receptor subunits GluN1, GluN2A, GluN2B, GluN2C and GluN2D are located in postsynaptic membranes of mossy fibre as well as CA3 recurrent associational commissural synapses. In the mossy fibres the GluN1, GluN2B and GluN2D labelling patterns suggested that these subunits were located also presynaptically in nerve terminal membranes and in mossy fibre axons. GluN3B was predominantly present in mossy fibre synapses as compared to recurrent associational commissural synapses, showing a presynaptic labelling pattern. In conclusion, while the postsynaptic localization of GluN1, GluN2A, GluN2B, and GluN2D is in good agreement with the recent finding of NMDA receptor-dependent long term potentiation (LTP) at CA3 mossy fibre synapses, we propose that presynaptic GluN1, GluN2B, GluN2D and GluN3B subunits could be involved in plastic phenomena such as certain types of LTP and recurrent mossy fibre growth.

  • 18.
    Bergersen, L H
    et al.
    Department of Anatomy, Centre for Molecular Biology and Neuroscience, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
    Morland, C
    Department of Anatomy, Centre for Molecular Biology and Neuroscience, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
    Ormel, L
    Department of Anatomy, Centre for Molecular Biology and Neuroscience, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
    Rinholm, J E
    Department of Anatomy, Centre for Molecular Biology and Neuroscience, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
    Larsson, Max
    Department of Anatomy, Centre for Molecular Biology and Neuroscience, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
    Wold, J F H
    Department of Anatomy, Centre for Molecular Biology and Neuroscience, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
    Røe, A T
    Department of Anatomy, Centre for Molecular Biology and Neuroscience, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
    Stranna, A
    Department of Anatomy, Centre for Molecular Biology and Neuroscience, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
    Santello, M
    Département de Biologie Cellulaire et de Morphologie, Université de Lausanne, Lausanne, Switzerland.
    Bouvier, D
    Département de Biologie Cellulaire et de Morphologie, Université de Lausanne, Lausanne, Switzerland.
    Ottersen, O P
    Department of Anatomy, Centre for Molecular Biology and Neuroscience, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
    Volterra, A
    Département de Biologie Cellulaire et de Morphologie, Université de Lausanne, Lausanne, Switzerland.
    Gundersen, V
    Department of Anatomy, Centre for Molecular Biology and Neuroscience, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway; Department of Neurology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
    Immunogold detection of L-glutamate and D-serine in small synaptic-like microvesicles in adult hippocampal astrocytes.2012In: Cerebral Cortex, ISSN 1047-3211, E-ISSN 1460-2199, Vol. 22, no 7, p. 1690-1697Article in journal (Refereed)
    Abstract [en]

    Glutamate and the N-methyl-D-aspartate receptor ligand D-serine are putative gliotransmitters. Here, we show by immunogold cytochemistry of the adult hippocampus that glutamate and D-serine accumulate in synaptic-like microvesicles (SLMVs) in the perisynaptic processes of astrocytes. The estimated concentration of fixed glutamate in the astrocytic SLMVs is comparable to that in synaptic vesicles of excitatory nerve terminals (≈ 45 and ≈ 55 mM, respectively), whereas the D-serine level is about 6 mM. The vesicles are organized in small spaced clusters located near the astrocytic plasma membrane. Endoplasmic reticulum is regularly found in close vicinity to SLMVs, suggesting that astrocytes contain functional nanodomains, where a local Ca(2+) increase can trigger release of glutamate and/or D-serine.

  • 19.
    Bergström, Linn
    Linköping University, Department of Computer and Information Science. Gösta Ekmans Laboratorium, Psykologiska Institutionen, Stockholms Universitet.
    Is Visual Stimuli Neighboring Attended Stimuli Suppressedin High Perceptual Load?: A Steady State Evoked Potential Study2016Independent thesis Basic level (degree of Bachelor), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Perceptual load theory, together with the surround-suppression model suggest that stimulus surrounding attended stimuli is suppressed, especially if perceptual load is high. This study attempts to map surround-suppression using electroencephalography to measure neural activity related to suppression at four surrounding locations (2°, 3°, 4° and 6° from fixation). Color and orientation was used to manipulate load, and the effect of load was controlled through behavioral and neural measures using event related potentials. Our results demonstrate no statistically supported effect of load in behavioral data or SSVEP data, but unexplained increased neural amplitude of an early visual component (i.e. N1) in the (hypothesized) low load condition.

  • 20.
    Bernardi, R. E.
    et al.
    Heidelberg University, Germany.
    Zohsel, K.
    Heidelberg University, Germany.
    Hirth, N.
    Heidelberg University, Germany.
    Treutlein, J.
    Heidelberg University, Germany.
    Heilig, Markus
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Social and Affective Neuroscience (CSAN). Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Laucht, M.
    Heidelberg University, Germany.
    Spanagel, R.
    Heidelberg University, Germany.
    Sommer, W. H.
    Heidelberg University, Germany.
    A gene-by-sex interaction for nicotine reward: evidence from humanized mice and epidemiology2016In: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 6, no e861Article in journal (Refereed)
    Abstract [en]

    It has been proposed that vulnerability to nicotine addiction is moderated by variation at the mu-opioid receptor locus (OPRM1), but results from human studies vary and prospective studies based on genotype are lacking. We have developed a humanized mouse model of the most common functional OPRM1 polymorphism rs1799971_A4G (A118G). Here we use this model system together with a cohort of German youth to examine the role of the OPRM1 A118G variation on nicotine reward. Nicotine reinforcement was examined in the humanized mouse model using i.v. self-administration. Male (n = 17) and female (n = 26) mice homozygous either for the major human A allele (AA) or the minor G allele (GG) underwent eight daily 2 h sessions of nicotine self-administration. Furthermore, male (n = 104) and female (n = 118) subjects homozygous for the A allele or carrying the G allele from the Mannheim Study of Children at Risk were evaluated for pleasurable and unpleasant experiences during their initial smoking experience. A significant sex-by-genotype effect was observed for nicotine self-administration. Male 118GG mice demonstrated higher nicotine intake than male 118AA mice, suggesting increased nicotine reinforcement. In contrast, there was no genotype effect in female mice. Human male G allele carriers reported increased pleasurable effects from their first smoking experience, as compared to male homozygous A, female G and female homozygous A allele carriers. The 118G allele appears to confer greater sensitivity to nicotine reinforcement in males, but not females.

  • 21.
    Bivik, Caroline
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Ulvklo, Carina
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Lundin, Erika
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Nilsson, Patrik
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Angel, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Thor, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    A genetic screen for genes controlling Apterous neuron identity and FMRFamide expression2010In: Journal of neurogenetics, ISSN 0167-7063, E-ISSN 1563-5260, Vol. 24, no Suppl. 1, p. 70-71Article in journal (Other academic)
    Abstract [en]

    n/a

  • 22.
    Björk, Karl
    et al.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Terasmaa, Anton
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Sun, Hui
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Thorsell, Annika
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Sommer, Wolfgang H.
    Central Institute of Mental Health, Mannheim, Germany.
    Heilig, Markus
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Ethanol-induced activation of AKT and DARPP-32 in the mouse striatum mediated by opioid receptors2010In: Addiction Biology, ISSN 1355-6215, E-ISSN 1369-1600, Vol. 15, no 3, p. 299-303Article in journal (Refereed)
    Abstract [en]

    The reinforcing properties of ethanol are in part attributed to interactions between opioid and dopaminergic signaling pathways, but intracellular mediators of such interactions are poorly understood. Here we report that an acute ethanol challenge induces a robust phosphorylation of two key signal transduction kinases, AKT and DARPP-32, in the striatum of mice. Ethanol-induced AKT phosphorylation was blocked by the opioid receptor antagonist naltrexone but unaffected by blockade of dopamine D2 receptors via sulpiride. In contrast, DARPP-32 phosphorylation was abolished by both antagonists. These data suggest that ethanol acts via two distinct but potentially synergistic striatal signaling cascades. One of these is D2-dependent, while the other is not. These findings illustrate that pharmacology of ethanol reward is likely more complex than that for other addictive drugs.

  • 23.
    Björk, Karl
    et al.
    Karolinska Institute, Stockholm, Sweden .
    Tronci, Valeria
    Psychobiology Section, NIDA, National Institutes of Health, Baltimore, MD, USA .
    Thorsell, Annika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Tanda, Gianluigi
    Psychobiology Section, NIDA, National Institutes of Health, Baltimore, MD, USA .
    Hirth, Natalie
    University of Heidelberg, Mannheim, Germany .
    Heilig, Markus
    Laboratory of Clinical and Translational Studies, NIAAA, National Institutes of Health, Bethesda, MD, USA .
    Hansson, Anita C.
    Laboratory of Clinical and Translational Studies, NIAAA, National Institutes of Health, Bethesda, MD, USA.
    Sommer, Wolfgang H
    Laboratory of Clinical and Translational Studies, NIAAA, National Institutes of Health, Bethesda, MD, USA.
    β-Arrestin 2 knockout mice exhibit sensitized dopamine release and increased reward in response to a low dose of alcohol2013In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 230, no 3, p. 439-449Article in journal (Refereed)
    Abstract [en]

    Rationale

    The rewarding effects of alcohol have been attributed to interactions between opioid and dopaminergic system within the mesolimbic reward pathway. We have previously shown that ablation of β-arrestin 2 (Arrb2), a crucial regulator of μ-opioid receptor function, attenuates alcohol-induced hyperlocomotion and c-fos activation in the nucleus accumbens.

    Objectives

    Here, we further investigated the role of Arrb2 in modulating alcohol-induced dopamine (DA) release and conditioned place preference (CPP). We also assessed the functional importance of Arrb2 for μ-opioid receptor surface expression and signaling following an acute alcohol challenge.

    Methods

    Alcohol-evoked (0.375, 0.75, and 1.5 g/kg intraperitoneally) DA release was measured by in vivo microdialysis in the shell of nucleus accumbens. Reward was assessed by the CPP paradigm. Receptor function was assessed by μ-receptor binding and [35S]GTP-γ-S autoradiography.

    Results

    In Arrb2 knockout mice accumbal DA levels reach maximum response at a lower dose compared to wild-type (wt) animals. In line with these results, Arrb2 knockout mice display increased CPP for alcohol as compared to wt mice. Finally, Arrb2 mutant mice display increased μ-opioid receptor signaling in the ventral and dorsal striatum and amygdala in response to a low dose of alcohol, indicating impaired desensitization mechanisms in these mice.

    Conclusions

    Our results show that Arrb2 modulates the response to low doses of alcohol on various levels including μ-opioid receptor signaling, DA release, and reward. They also reveal a clear dissociation between the effects of Arrb2 on psychomotor and reward behaviors.

  • 24.
    Björnsdotter, Malin
    et al.
    Department of Physiology, Institute for Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
    Gordon, Ilanit
    Child Study Center, Yale University, New Haven, CT, USA.
    Pelphrey, Kevin A
    Child Study Center, Yale University, New Haven, CT, USA.
    Olausson, Håkan
    Department of Physiology, Institute for Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
    Kaiser, Martha D
    Child Study Center, Yale University, New Haven, CT, USA.
    Development of brain mechanisms for processing affective touch2014In: Frontiers in Behavioral Neuroscience, ISSN 1662-5153, E-ISSN 1662-5153, Vol. 8, no 24Article in journal (Refereed)
    Abstract [en]

    Affective tactile stimulation plays a key role in the maturation of neural circuits, but the development of brain mechanisms processing touch is poorly understood. We therefore used functional magnetic resonance imaging (fMRI) to study brain responses to soft brush stroking of both glabrous (palm) and hairy (forearm) skin in healthy children (5-13 years), adolescents (14-17 years), and adults (25-35 years). Adult-defined regions-of-interests in the primary somatosensory cortex (SI), secondary somatosensory cortex (SII), insular cortex and right posterior superior temporal sulcus (pSTS) were significantly and similarly activated in all age groups. Whole-brain analyses revealed that responses in the ipsilateral SII were positively correlated with age in both genders, and that responses in bilateral regions near the pSTS correlated significantly and strongly with age in females but not in males. These results suggest that brain mechanisms associated with both sensory-discriminative and affective-motivational aspects of touch are largely established in school-aged children, and that there is a general continuing maturation of SII and a female-specific increase in pSTS sensitivity with age. Our work establishes a groundwork for future comparative studies of tactile processing in developmental disorders characterized by disrupted social perception such as autism.

  • 25.
    Björnsdotter, Malin
    et al.
    Institute for Neuroscience and Physiology, University of Gothenburg, Göteborg, Sweden.
    Morrison, India
    Institute for Neuroscience and Physiology, University of Gothenburg, Göteborg, Sweden.
    Olausson, Håkan
    Institute for Neuroscience and Physiology, University of Gothenburg, Göteborg, Sweden.
    Feeling good: on the role of C fiber mediated touch in interoception.2010In: Experimental Brain Research, ISSN 0014-4819, E-ISSN 1432-1106, Vol. 207, no 3, p. 149-155Article in journal (Refereed)
    Abstract [en]

    The human skin is innervated by a network of thin, slow-conducting afferent (C and Aδ) fibers, transmitting a diverse range of information. Classically, these fibers are described as thermo-, noci- or chemoreceptive, whereas mechanoreception is attributed exclusively to thick, fast-conducting (Aβ) afferents. A growing body of evidence, however, supports the notion that C tactile afferents comprise a second anatomically and functionally distinct system signaling touch in humans. This review discusses established as well as recent findings which highlight fundamental differences in peripheral and central information coding and processing between Aβ and C mechanoreception. We conclude that from the skin through the brain, C touch shares more characteristics with interoceptive modalities (e.g. pain, temperature, and itch) than exteroceptive Aβ touch, vision or hearing. In this light, we discuss the motivational-affective role of C touch as an integral part of a thin-fiber afferent homeostatic network for the maintenance of physical and social well-being.

  • 26.
    Blomberg, Rina
    Linköping University, Department of Computer and Information Science.
    CORTICAL PHASE SYNCHRONISATION MEDIATES NATURAL FACE-SPEECH PERCEPTION2015Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    It is a challenging task for researchers to determine how the brain solves multisensory perception, and the neural mechanisms involved remain subject to theoretical conjecture.  According to a hypothesised cortical model for natural audiovisual stimulation, phase synchronised communications between participating brain regions play a mechanistic role in natural audiovisual perception.  The purpose of this study was to test the hypothesis by investigating oscillatory dynamics from ongoing EEG recordings whilst participants passively viewed ecologically realistic face-speech interactions in film.  Lagged-phase synchronisation measures were computed for conditions of eye-closed rest (REST), speech-only (auditory-only, A), face-only (visual-only, V) and face-speech (audio-visual, AV) stimulation. Statistical contrasts examined AV > REST, AV > A, AV > V and AV-REST > sum(A,V)-REST effects.  Results indicated that cross-communications between the frontal lobes, intraparietal associative areas and primary auditory and occipital cortices are specifically enhanced during natural face-speech perception and that phase synchronisation mediates the functional exchange of information associated with face-speech processing between both sensory and associative regions in both hemispheres.  Furthermore, phase synchronisation between cortical regions was modulated in parallel within multiple frequency bands.  

  • 27.
    Blomqvist, Anders
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Engblom, David
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Neural Mechanisms of Inflammation-Induced Fever2018In: The Neuroscientist, ISSN 1073-8584, E-ISSN 1089-4098, Vol. 24, no 4, p. 381-399Article, review/survey (Refereed)
    Abstract [en]

    Fever is a common symptom of infectious and inflammatory disease. It is well-established that prostaglandin E-2 is the final mediator of fever, which by binding to its EP3 receptor subtype in the preoptic hypothalamus initiates thermogenesis. Here, we review the different hypotheses on how the presence of peripherally released pyrogenic substances can be signaled to the brain to elicit fever. We conclude that there is unequivocal evidence for a humoral signaling pathway by which proinflammatory cytokines, through their binding to receptors on brain endothelial cells, evoke fever by eliciting prostaglandin E-2 synthesis in these cells. The evidence for a role for other signaling routes for fever, such as signaling via circumventricular organs and peripheral nerves, as well as transfer into the brain of peripherally synthesized prostaglandin E-2 are yet far from conclusive. We also review the efferent limb of the pyrogenic pathways. We conclude that it is well established that prostaglandin E-2 binding in the preoptic hypothalamus produces fever by disinhibition of presympathetic neurons in the brain stem, but there is yet little understanding of the mechanisms by which factors such as nutritional status and ambient temperature shape the response to the peripheral immune challenge.

  • 28.
    Boenitz, Hanna
    et al.
    Hannover Medical Sch, Germany.
    Kopp, Bruno
    Hannover Medical Sch, Germany.
    Buechner, Andreas
    Hannover Medical Sch, Germany; Cluster Excellence Hearing4all, Germany.
    Lunner, Thomas
    Linköping University, Department of Behavioural Sciences and Learning, Disability Research. Linköping University, Faculty of Arts and Sciences. Linköping University, The Swedish Institute for Disability Research. Oticon AS, Denmark.
    Lyxell, Björn
    Linköping University, Department of Behavioural Sciences and Learning, Disability Research. Linköping University, Faculty of Arts and Sciences. Linköping University, The Swedish Institute for Disability Research.
    Finke, Mareike
    Hannover Medical Sch, Germany; Cluster Excellence Hearing4all, Germany.
    Event-related neuronal responses to acoustic novelty in single-sided deaf cochlear implant users: Initial findings2018In: Clinical Neurophysiology, ISSN 1388-2457, E-ISSN 1872-8952, Vol. 129, no 1, p. 133-142Article in journal (Refereed)
    Abstract [en]

    Objective: A cochlear implant (CI) is an auditory prosthesis restoring profound hearing loss. However, CItransmitted sounds are degraded compared to normal acoustic hearing. We investigated cortical responses related to CI-degraded against acoustic listening. Methods: Event-related potentials (ERPs) were recorded from eight single-sided deaf CI users who performed a three-stimulus oddball task, separatelywith their normal hearing ear and CI ear. The oddball tones were occasionally intermitted by novel sounds. ERP responses were compared between electric and acoustic listening for the auditory (N1) and auditory-cognitive (Novelty P3, Target-P3) ERP components. Results: CI-degraded listening was associated with attenuated sensory processing (N1) and with attenuated early cortical responses to acoustic novelty whereas the late cortical responses to acoustic novelty and the target-P3 did not differ between NH and CI ears. Conclusion: The present study replicates the CI-attenuation of Novelty-P3 amplitudes in a within-subject comparison. Further, we show that the CI-attenuation of Novelty-P3 amplitudes extends to early cortical responses to acoustic novelty, but not to late novelty responses. Significance: The dissociation into CI-attenuated P3 early Novelty-P3 amplitudes and CI-unaffected late Novelty-P3 amplitudes represents a cortical fingerprint of CI-degraded listening. It further contributes to general claims of distinct auditory Novelty-P3 sub-components. (C) 2017 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

  • 29.
    Boij, Roland
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Aspects of inflammation, angiogenesis and coagulation in preeclampsia2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Preeclampsia is a major challenge to obstetricians, due to its impact on maternal and fetal morbidity and mortality and the lack of preventive and treatment strategies. The overall aim of this thesis is to increase the knowledge of the pathogenesis of preeclampsia including the role of inflammation, angiogenesis and coagulation, both locally at the fetomaternal interface and in the maternal circulation. Uncompensated maternal endothelial inflammatory responses to factors from stressed trophoblasts seem to be a major contributor to the syndrome, together with an imbalance in angiogenesis and an activated coagulation system. An increasing amount of data indicates an involvement of the immune system with defect tolerance to the conceptus as an integral part of the pathogenesis, at least in early-onset preeclampsia (EOP).

    We showed that a single administration of human preeclampsia serum in pregnant IL-10−/− mice induced the full spectrum of preeclampsia-like symptoms including hypoxic injury in uteroplacental tissues and endotheliosis in maternal kidneys. Importantly, preeclampsia serum, as early as 12 to 14 weeks of gestation, disrupted cross talk between trophoblasts and endothelial cells in an in vitro model of endovascular activity (Tube formation test). These results indicate that preeclamptic sera can be used to better understand the pathophysiology and to predict the disorder. Preeclampsia has been associated with increased inflammation, aberrant angiogenesis and activated coagulation, but their correlation and relative contribution are unknown. We found that markers for all these mechanisms were independently associated with preeclampsia. Cytokines, chemokines, and complement factors seem all to be part of a Th1-associated inflammatory reaction in preeclampsia, more pronounced in EOP than in late-onset preeclampsia (LOP), in line with a more homogeneous pathogenesis in EOP as based on placental pathology. In women with intrauterine growth restriction (IUGR), with an anticipated pathologic placentation, only differences in levels for sFlt-1 and PlGF were found in comparison with mothers without IUGR. Thus, sFlt-1 and PlGF seem to be indicators of placental pathology, while other biomarkers might also reflect maternal endothelial pathology. Chemokines, in contrast to cytokines, may prove to be useful markers in preeclampsia.

    A deficiency in regulatory T (Treg) cells causing reduced immune regulatory capacity has been proposed in preeclampsia. Utilizing recent advances in flow cytometry phenotyping, we found no major alterations in circulating Treg numbers in preeclamptic women compared with normal pregnant and non-pregnant women. However, preeclampsia was associated with increased fractions of CTLA-4+ and CCR4+ cells within Treg subpopulations, which is in line with a migratory defect of Treg cells, and potentially associated with a reduced number of suppressive Treg cells at the fetomaternal interface. As we found that corticosteroid treatment affected the results, it should be accounted for in studies of EOP. Chemokines are supposed to be part of the immune adaptation in pregnancy. We found a decreased expression of CCL18  (Th2/Tregassociated), in trophoblasts from preeclamptic compared to normal pregnant women, indicating a local regulatory defect in preeclampsia, in line with our finding of a possible migratory defect of circulating Treg cells. Due to increased expression of CCL20 (Th17) and CCL22 (Th2) in first trimester placenta and increased circulating levels of CXCL10 (Th1) and CCL20 (Th17) in third trimester preeclamptic women, we suggest that CCL20 and CCL22 may be important for implantation and early placentation while in third trimester of a preeclamptic pregnancy CXCL10 and CCL20 mainly mirror maternal increased endothelial inflammation and aberrant angiogenesis. In summary, we found that preeclampsia is associated with increased inflammation, aberrant angiogenesis and activated coagulation, caused by placental factors in maternal peripheral circulation, more pronounced in the early-onset form of preeclampsia. It also appears that there is a defective modulation of the immune system in preeclamptic pregnancies. The results provide a better understanding of the pathogenesis of preeclampsia and have given suggestions to predictive markers for preeclampsia in the future.

    List of papers
    1. Sera from Preeclampsia Patients Elicit Symptoms of Human Disease in Mice and Provide a Basis for an in Vitro Predictive Assay
    Open this publication in new window or tab >>Sera from Preeclampsia Patients Elicit Symptoms of Human Disease in Mice and Provide a Basis for an in Vitro Predictive Assay
    Show others...
    2010 (English)In: AMERICAN JOURNAL OF PATHOLOGY, ISSN 0002-9440, Vol. 177, no 5, p. 2387-2398Article in journal (Refereed) Published
    Abstract [en]

    Early diagnosis and treatment of preeclampsia would significantly reduce maternal and fetal morbidity and mortality. However, its etiology and prediction have remained elusive. Based on the hypothesis that sera from patients with preeclampsia could function as a "blueprint" of causative factors, we describe a serum-based pregnancy-specific mouse model that closely mirrors the human condition as well as an in vitro predictive assay. We show that a single administration of human preeclampsia serum in pregnant IL-10(-/-) mice induced the full spectrum of preeclampsia-like symptoms, caused hypoxic injury in uteroplacental tissues, and elevated soluble fins-like tyrosine kinase 1 and soluble endoglin, markers thought to be related to the disease. The same serum sample(s) induced a partial preeclampsia phenotype in wild-type mice. Importantly, preeclampsia serum disrupted cross talk between trophoblasts and endothelial cells in an in vitro model of endovascular activity. Disruption of endovascular activity could be documented in serum samples as early as 12 to 14 weeks of gestation from patients who subsequently developed preeclampsia. These results indicate that preeclampsia patient sera can be used to understand the pregnancy-specific disease pathology in mice and can predict the disorder.

    Place, publisher, year, edition, pages
    American Society for Investigative Pathology (ASIP), 2010
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-62755 (URN)10.2353/ajpath.2010.100475 (DOI)000284182900026 ()
    Available from: 2010-12-03 Created: 2010-12-03 Last updated: 2016-11-11
    2. Biomarkers of Coagulation, Inflammation, and Angiogenesis are Independently Associated with Preeclampsia
    Open this publication in new window or tab >>Biomarkers of Coagulation, Inflammation, and Angiogenesis are Independently Associated with Preeclampsia
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    2012 (English)In: AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, ISSN 1046-7408, Vol. 68, no 3, p. 258-270Article in journal (Refereed) Published
    Abstract [en]

    Problem Although preeclampsia has been associated with inflammation, coagulation, and angiogenesis, their correlation and relative contribution are unknown. Method of Study About 114 women with preeclampsia, 31 with early onset (EOP) and 83 with late onset preeclampsia (LOP), and 100 normal pregnant controls were included. A broad panel of 32 biomarkers reflecting coagulation, inflammation, and angiogenesis was analyzed. Results Preeclampsia was associated with decreased antithrombin, IL-4 and placental growth factor levels and with increased C3a, pentraxin-3, and sFlt-1 levels, with more marked differences in the EOP group. The Th1-associated chemokines CXCL10 and CXCL11 were significantly higher in the preeclampsia and EOP group than in controls, respectively. No correlations between the biomarkers were found in preeclampsia. Multivariate logistic regression tests confirmed the results. Conclusions Cytokines, chemokines and complement activation seem to be part of a Th1-like inflammatory reaction in preeclampsia, most pronounced in EOP, where chemokines may be more useful than cytokines as biomarkers. Biomarkers were not correlated suggesting partly independent or in time separated mechanisms.

    Place, publisher, year, edition, pages
    John Wiley and Sons, 2012
    Keywords
    preeclampsia, coagulation, inflammation, angiogenesis, chemokines, cytokines and early onset preeclampsia
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-81815 (URN)10.1111/j.1600-0897.2012.01158.x (DOI)000307440300012 ()
    Note

    Funding Agencies|FORSS (Medical Research Council of Southeast Sweden)||Futurum (the Research department of County of Jonkoping)||Swedish Research Council|2007-15809-48800-58|Linneaus University (Sweden)||

    Available from: 2012-09-26 Created: 2012-09-24 Last updated: 2016-11-11
    3. Regulatory T-cell Subpopulations in Severe or Early-onset Preeclampsia
    Open this publication in new window or tab >>Regulatory T-cell Subpopulations in Severe or Early-onset Preeclampsia
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    2015 (English)In: American Journal of Reproductive Immunology, ISSN 1046-7408, E-ISSN 1600-0897, Vol. 74, no 4, p. 368-378Article in journal (Refereed) Published
    Abstract [en]

    Problem A deficiency in regulatory T (Treg) cells causing reduced immune regulatory capacity has been proposed in preeclampsia. Objective Utilizing recent advances in flow cytometry phenotyping, we aimed to assess whether a deficiency of Treg subpopulations occurs in preeclampsia. Method of study Six-color flow cytometry was used for Treg phenotyping in 18 preeclamptic women (one early-onset, one severe and 16 both), 20 women with normal pregnancy, and 20 non-pregnant controls. Results No differences were found in major Treg populations including CD127(low)CD25(+)/CD127(ow)FOXP3(+), resting (FOXP3(dim)CD45RA(+)), and activated (FOXP3(bright)CD45RA(-)) Treg cells, whereas preeclamptic women showed increased CTLA-4(+) and CCR4(+) proportions within resting/activated Treg populations. Corticosteroid treatment prior to blood sampling (n = 10) affected the distribution of Treg populations. Conclusions Although we found no major alterations in circulating Treg frequencies, differences in CTLA-4(+) and CCR4(+) frequencies suggest a migratory defect of Treg cells in preeclampsia. Corticosteroid treatment should be taken into account when evaluating Treg cells.

    Place, publisher, year, edition, pages
    WILEY-BLACKWELL, 2015
    Keywords
    Early-onset preeclampsia; preeclampsia; pregnancy; regulatory T cells
    National Category
    Obstetrics, Gynecology and Reproductive Medicine
    Identifiers
    urn:nbn:se:liu:diva-122528 (URN)10.1111/aji.12410 (DOI)000362664200009 ()26118401 (PubMedID)
    Note

    Funding Agencies|FORSS (Medical Research Council of Southeast Sweden); Futurum, academy for Health and Care Jonkoping County Council, Sweden

    Available from: 2015-11-09 Created: 2015-11-06 Last updated: 2017-12-01
  • 30.
    Bolic Baric, Vedrana
    Linköping University, Department of Social and Welfare Studies, Division of Health, Activity and Care. Linköping University, Faculty of Medicine and Health Sciences.
    Support in school and the occupational transition process: Adolescents and young adults with neuropsychiatric disabilities2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The overall aim of this thesis was to describe and explore the experiences of support in school of adolescents and young adults with neuropsychiatric disabilities. Furthermore, the aim was to explore support that influences the occupational transition to upper secondary school, further education and work. The two first studies investigated computer use in educational activities and during leisure activities by adolescents with attention deficit hyperactivity disorder (ADHD). Study II also aimed to explore how traditional leisure activities and Internet activities interrelate among adolescents with ADHD. In Studies I and II data was collected using a questionnaire focusing on information and communication technology (ICT) use in school and leisure. Adolescents with ADHD (n = 102) aged 12-18 years were compared with adolescents with physical disabilities (Study I) and adolescents from the general population (Studies I and II). In Study III the aim was to describe the experiences of support at school among young adults with AS and ADHD, and to explore what support they, in retrospect, described as influencing learning. Study IV aimed to describe the occupational transition process to upper secondary school, further education and/or work and to explore what support influenced the process from the perspectives of young adults with AS or ADHD. Studies III (n=13) and IV (n=15) used qualitative semi-structured interviews with young adults with AS or ADHD, aged 18-30 years and were analysed using hermeneutics according to Gadamer.

    The findings of Study I showed that students with ADHD reported significantly less frequent use of computers for almost all educational activities compared with students with physical disabilities and students from the general population. They reported low satisfaction with computer use in school and a desire to use computers more often and for more activities in school compared with students with physical disabilities. Study II showed that Internet activities among adolescents with ADHD during leisure, tended to focus on online games. Furthermore, analysis demonstrated that Internet activities were broadening leisure activities among adolescents with ADHD, rather than being a substitute for traditional leisure activities. Study III found that young adults with AS or ADHD experienced difficulties at school that included academic, social, and emotional aspects, all of which influenced learning. Support addressing difficulties with academic performance was described as insufficient and only occasionally provided in school. In conclusion, support for learning among students with AS or ADHD needs to combine academic and psychosicial support. The findings of Study IV identified three different pathways following compulsory school. Support influencing the occupational transition process included: occupational transition preparation in compulsory school, practical work experience in a safe environment, and support beyond the workplace. Support from community-based day centres was described both as an important step towards work in the regular labour market, as well as being too far away from the regular labour market.

    In conclusion, this thesis revealed that support in school among students with AS or ADHD needs to combine academic and psychosocial support. Despite being regarded as facilitating learning, individuals with ADHD or AS reported limited computer and Internet use in school. Based on the results it is suggested that Internet activities may provide adolescents with neuropsychiatric disabilities with new opportunities for social interaction and educational activities. On the basis of the results it is suggested that the occupational transition process should be viewed as a longitudinal one, starting in compulsory school and continuing on until young adults obtain and are able to remain in work or further education. This thesis revealed that extended transition planning, inter-service collaboration and support from communitybased day centres were aspects of the environment that influenced the occupational transition process.

    List of papers
    1. Computer use in educational activities by students with ADHD
    Open this publication in new window or tab >>Computer use in educational activities by students with ADHD
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    2013 (English)In: Scandinavian Journal of Occupational Therapy, ISSN 1103-8128, E-ISSN 1651-2014, Vol. 20, no 5, p. 357-364Article in journal (Refereed) Published
    Abstract [en]

    Aim: The aim of this study was to investigate computer use in educational activities by students with attention deficit hyperactivity disorder (ADHD) in comparison with that of students with physical disabilities and students from the general population.

    Methods: The design of the study was cross-sectional with group comparison. Students with ADHD (n = 102) were pair-matched in terms of age and sex with students with physical disabilities and students from the general population (n = 940) were used as a reference group.

    Results: The study showed that less than half of the students with ADHD had access to a computer in the classroom. Students with ADHD reported significantly less frequent use of computers for almost all educational activities compared with students with physical disabilities and students from the general population. Students with ADHD reported low satisfaction with computer use in school. In addition, students with ADHD reported a desire to use computers more often and for more activities in school compared with students with physical disabilities.

    Conclusions: These results indicate that occupational therapists should place more emphasize on how to enable students with ADHD to use computers in educational activities in school.

    Place, publisher, year, edition, pages
    Informa Healthcare, 2013
    Keywords
    Information and communication technology (ICT), computer access, school-based practice, physical disabilities
    National Category
    Occupational Therapy
    Identifiers
    urn:nbn:se:liu:diva-86782 (URN)10.3109/11038128.2012.758777 (DOI)000323943600006 ()
    Available from: 2013-01-04 Created: 2013-01-04 Last updated: 2017-12-06Bibliographically approved
    2. Internet Activities During Leisure: A Comparison Between Adolescents With ADHD and Adolescents From the General Population
    Open this publication in new window or tab >>Internet Activities During Leisure: A Comparison Between Adolescents With ADHD and Adolescents From the General Population
    2018 (English)In: Journal of Attention Disorders, ISSN 1087-0547, E-ISSN 1557-1246, Vol. 22, no 12, p. 1131-1139Article in journal (Refereed) Published
    Abstract [en]

    Objective: Adolescents’ leisure activities are increasingly focusing on Internet activities, and today, these coexist with traditional leisure activities such as sport and meeting friends. The purpose of the present study was to investigate leisure activities, particularly Internet activities, among boys and girls with ADHD, and compare these with boys and girls from the general population. The objective was also to explore how traditional leisure activities and Internet activities interrelate among adolescents with ADHD. 

    Method: Adolescents with ADHD (n = 102) were compared with adolescents from the general population on leisure activities and Internet use. 

    Results: Leisure activities among adolescents with ADHD tended to focus on Internet activities, particularly online games. Internet activities were broadening leisure activities among adolescents with ADHD, rather than being a substitute for traditional leisure activities. 

    Conclusion: Internet activities may provide adolescents with ADHD accessible means of social interaction.

    Place, publisher, year, edition, pages
    Sage Publications, 2018
    Keywords
    adolescent ADHD, computer games, principal components analysis, peer relationships
    National Category
    Public Health, Global Health, Social Medicine and Epidemiology Social Sciences Interdisciplinary
    Identifiers
    urn:nbn:se:liu:diva-123871 (URN)10.1177/1087054715613436 (DOI)000444488700005 ()26610742 (PubMedID)
    Available from: 2016-01-12 Created: 2016-01-12 Last updated: 2018-09-27Bibliographically approved
    3. Support for learning- goes beyond academic support: voices of students with Asperger’s disorder and ADHD
    Open this publication in new window or tab >>Support for learning- goes beyond academic support: voices of students with Asperger’s disorder and ADHD
    2016 (English)In: Autism, ISSN 1362-3613, E-ISSN 1461-7005, Vol. 20, no 2, p. 183-195Article in journal (Refereed) Published
    Abstract [en]

    The purpose of this study was to describe and explore the experiences of support at school among young adults with Asperger’s disorder (AS) and attention-deficit/hyperactivity disorder (ADHD), and also to examine what support they, in retrospect, described as influencing learning. Purposive sampling was used to enroll participants. Data were collected through semi-structured interviews with thirteen young adults aged between 20-29 years. A qualitative analysis, based on interpreting people’s experiences was conducted by grouping and searching for patterns in data. The findings indicate that the participants experienced difficulties at school that included academic, social and emotional conditions, all of which could influence learning. Support for learning included small groups, individualized teaching methods, teachers who cared, and practical and emotional support. These clusters together confirm the overall understanding that support for learning aligns academic and psychosocial support. In conclusion, academic support combined with psychosocial support at school seems to be crucial for learning among students with AS and ADHD.

    Place, publisher, year, edition, pages
    Sage Publications, 2016
    Keywords
    Autism Spectrum Disorders, ADHD/ADD, psychosocial support, education, educational provision, services, qualitative research, special needs students
    National Category
    Other Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-115117 (URN)10.1177/1362361315574582 (DOI)000372880100007 ()
    Available from: 2015-03-10 Created: 2015-03-09 Last updated: 2017-04-21Bibliographically approved
    4. The Occupational Transition Process to Upper Secondary School, Further Education and/or Work in Sweden: As Described by Young Adults with Asperger Syndrome and Attention Deficit Hyperactivity Disorder
    Open this publication in new window or tab >>The Occupational Transition Process to Upper Secondary School, Further Education and/or Work in Sweden: As Described by Young Adults with Asperger Syndrome and Attention Deficit Hyperactivity Disorder
    2017 (English)In: Journal of autism and developmental disorders, ISSN 0162-3257, E-ISSN 1573-3432, Vol. 47, no 3, p. 667-679Article in journal (Refereed) Published
    Abstract [en]

    The aim of the study was to describe the occupational transition process to upper secondary school, further education and/or work, and to discover what support influences the process from the perspectives of young adults with Asperger’s disorder (AS) or attention deficit/hyperactivity disorder (ADHD). This qualitative study comprised semi-structured interviews with 15 young adults with AS or ADHD, eight men and seven women (aged 20 to 29 years). Most of the participants were attending community-based day centres at local businesses. Analysis identified three different occupational transition pathways following compulsory school. Support influencing the occupational transition process included: occupational transition preparation in compulsory school, practical work experience in a safe environment, and support beyond the workplace. The overall understanding shows that the occupational transition process was a longitudinal one starting as early as in middle school, and continuing until the young adults with AS and ADHD obtained and were able to remain in employment or further education. Support from community-based day centres was described both as an important step towards finding employment in the regular labour market in which participants could develop practical work experience, and as being too far away from the regular labour market.

    Place, publisher, year, edition, pages
    Springer, 2017
    Keywords
    Attention deficit hyperactivity disorder/attention deficit disorder, autism spectrum disorders, employment, education, qualitative research, services
    National Category
    Other Health Sciences Neurosciences
    Identifiers
    urn:nbn:se:liu:diva-123872 (URN)10.1007/s10803-016-2986-z (DOI)000396815400014 ()
    Available from: 2016-01-12 Created: 2016-01-12 Last updated: 2018-01-15Bibliographically approved
  • 31.
    Bolic Baric, Vedrana
    et al.
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Social and Welfare Studies, Division of Occupational Therapy.
    Hemmingsson, Helena
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Social and Welfare Studies, Division of Occupational Therapy.
    Hellberg, Kristina
    Linnaeus University, Växjö, Sweden .
    Kjellberg, Anette
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Social and Welfare Studies, Division of Occupational Therapy.
    The Occupational Transition Process to Upper Secondary School, Further Education and/or Work in Sweden: As Described by Young Adults with Asperger Syndrome and Attention Deficit Hyperactivity Disorder2017In: Journal of autism and developmental disorders, ISSN 0162-3257, E-ISSN 1573-3432, Vol. 47, no 3, p. 667-679Article in journal (Refereed)
    Abstract [en]

    The aim of the study was to describe the occupational transition process to upper secondary school, further education and/or work, and to discover what support influences the process from the perspectives of young adults with Asperger’s disorder (AS) or attention deficit/hyperactivity disorder (ADHD). This qualitative study comprised semi-structured interviews with 15 young adults with AS or ADHD, eight men and seven women (aged 20 to 29 years). Most of the participants were attending community-based day centres at local businesses. Analysis identified three different occupational transition pathways following compulsory school. Support influencing the occupational transition process included: occupational transition preparation in compulsory school, practical work experience in a safe environment, and support beyond the workplace. The overall understanding shows that the occupational transition process was a longitudinal one starting as early as in middle school, and continuing until the young adults with AS and ADHD obtained and were able to remain in employment or further education. Support from community-based day centres was described both as an important step towards finding employment in the regular labour market in which participants could develop practical work experience, and as being too far away from the regular labour market.

  • 32.
    Boman, Andrea
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Lysosomal network proteins as biomarkers and therapeutic targets in neurodegenerative disease2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The pre-symptomatic stage of neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) occurs several decades before the clinical onset. Changes in the lysosomal network, i.e. the autophagosomal, endosomal and lysosomal vesicular system, are among the first alterations observed. There are currently no treatments to slow or cure neurodegenerative diseases, and there is a great need for discovery of treatment targets in cellular pathways where pathology pre-dates the neuronal death. It is also crucial to be able to diagnose neurodegenerative diseases earlier, both to enable early intervention treatment and aid in selecting clinical trial populations before the patient has widespread pathology.

    This thesis aims at investigating the potential of lysosomal network proteins as biomarkers and therapeutic targets in neurodegenerative disease.

    A targeted search for lysosomal network proteins was performed in cerebrospinal fluid (CSF) from AD patients, and seven proteins: early endosomal antigen 1 (EEA1), lysosomal-associated membrane proteins 1 and 2 (LAMP-1, LAMP-2), lysozyme, microtubule-associated protein 1 light chain 3 (LC3), Rab3 and Rab7, were elevated. The levels of EEA1, LAMP-1, LAMP-2, LC3, lysozyme and Rab3 were also measured in CSF from parkinsonian syndrome patients: PD, clinically diagnosed 4-repeat tauopathy, pathologically confirmed corticobasal degeneration (CBD) and pathologically confirmed progressive supranuclear palsy (PSP) patients. LAMP-1 and LAMP-2 were decreased in PD. LC3 and lysozyme levels were increased in 4-repeat tauopathy patients. EEA1 was decreased and lysozyme increased in PSP, and LAMP-1, LAMP-2, LC3 and lysozyme were increased in CBD. The lysosomal network proteins had different CSF protein profiles in all the parkinsonian syndromes, as well as in AD. It should be emphasized that only a select few of the lysosomal network proteins were observed to be changed, rather than a general change in lysosomal network proteins, which implicates the involvement of these seven proteins in specific pathological processes. The most interesting candidates, LAMP-2 and lysozyme, were selected for further study for their involvement in the pathology of AD.

    Lysozyme was found to co-localise with Aβ plaques in AD patients and overexpression prolonged survival and improved the activity in a Drosophila model of AD. Lysozyme was found to alter the aggregation pathway of Aβ1-42, to counteract the formation of toxic Aβ species and to protect from Aβ1-42 induced cell toxicity. Aβ1-42 in turn was found to increase the expression of lysozyme in both neuronal and glial cells. These data suggest that lysozyme levels rise in AD as a compensatory response which is protective against Aβ associated toxicity.

    LAMP-2 mRNA and protein were found increased in brain areas relevant for AD pathology and various cellular models showed complex involvement of LAMP-2 in Aβ related pathology, with extensive crosstalk between LAMP-2 and Aβ. Exposure to oligomeric Aβ1-42 caused an upregulation of LAMP-2 and in turn, overexpression of LAMP-2 caused a reduction in secreted levels of Aβ1-42, as well as changing the generation pattern of Aβ and affecting clearance and secretion of Aβ1-42. These data indicate that the increased levels of LAMP-2 in AD could be an attempt to regulate Aβ generation and secretion.

    In summary, this thesis reports that utilising lysosomal network proteins as biomarkers and novel therapeutic targets for neurodegenerative diseases holds great promise.

    List of papers
    1. Lysosomal Network Proteins as Potential Novel CSF Biomarkers for Alzheimers Disease
    Open this publication in new window or tab >>Lysosomal Network Proteins as Potential Novel CSF Biomarkers for Alzheimers Disease
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    2014 (English)In: Neuromolecular medicine, ISSN 1535-1084, E-ISSN 1559-1174, Vol. 16, no 1, p. 150-160Article in journal (Refereed) Published
    Abstract [en]

    The success of future intervention strategies for Alzheimers disease (AD) will likely rely on the development of treatments starting early in the disease course, before irreversible brain damage occurs. The pre-symptomatic stage of AD occurs at least one decade before the clinical onset, highlighting the need for validated biomarkers that reflect this early period. Reliable biomarkers for AD are also needed in research and clinics for diagnosis, patient stratification, clinical trials, monitoring of disease progression and the development of new treatments. Changes in the lysosomal network, i.e., the endosomal, lysosomal and autophagy systems, are among the first alterations observed in an AD brain. In this study, we performed a targeted search for lysosomal network proteins in human cerebrospinal fluid (CSF). Thirty-four proteins were investigated, and six of them, early endosomal antigen 1 (EEA1), lysosomal-associated membrane proteins 1 and 2 (LAMP-1, LAMP-2), microtubule-associated protein 1 light chain 3 (LC3), Rab3 and Rab7, were significantly increased in the CSF from AD patients compared with neurological controls. These results were confirmed in a validation cohort of CSF samples, and patients with no neurochemical evidence of AD, apart from increased total-tau, were found to have EEA1 levels corresponding to the increased total-tau levels. These findings indicate that increased levels of LAMP-1, LAMP-2, LC3, Rab3 and Rab7 in the CSF might be specific for AD, and increased EEA1 levels may be a sign of general neurodegeneration. These six lysosomal network proteins are potential AD biomarkers and may be used to investigate lysosomal involvement in AD pathogenesis.

    Place, publisher, year, edition, pages
    Humana Press, 2014
    Keywords
    PICALM; DRAM; TFEB; Cathepsins; Proteasome; hsc70
    National Category
    Cell and Molecular Biology
    Identifiers
    urn:nbn:se:liu:diva-105235 (URN)10.1007/s12017-013-8269-3 (DOI)000331101900015 ()
    Available from: 2014-03-14 Created: 2014-03-14 Last updated: 2018-01-11
    2. Protective properties of lysozyme on β-amyloid pathology: implications for Alzheimer disease
    Open this publication in new window or tab >>Protective properties of lysozyme on β-amyloid pathology: implications for Alzheimer disease
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    2015 (English)In: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 83, p. 122-133Article in journal (Refereed) Published
    Abstract [en]

    The hallmarks of Alzheimer disease are amyloid-β plaques and neurofibrillary tangles accompanied by signs of neuroinflammation. Lysozyme is a major player in the innate immune system and has recently been shown to prevent the aggregation of amyloid-β1-40 in vitro. In this study we found that patients with Alzheimer disease have increased lysozyme levels in the cerebrospinal fluid and lysozyme co-localized with amyloid-β in plaques. In Drosophila neuronal co-expression of lysozyme and amyloid-β1-42 reduced the formation of soluble and insoluble amyloid-β species, prolonged survival and improved the activity of amyloid-β1-42 transgenic flies. This suggests that lysozyme levels rise in Alzheimer disease as a compensatory response to amyloid-β increases and aggregation. In support of this, in vitro aggregation assays revealed that lysozyme associates with amyloid-β1-42 and alters its aggregation pathway to counteract the formation of toxic amyloid-β species. Overall, these studies establish a protective role for lysozyme against amyloid-β associated toxicities and identify increased lysozyme in patients with Alzheimer disease. Therefore, lysozyme has potential as a new biomarker as well as a therapeutic target for Alzheimer disease.

    Place, publisher, year, edition, pages
    Elsevier, 2015
    Keywords
    Lysozyme, Biomarker, Alzheimer disease, Drosophila, Aβ aggregation
    National Category
    Cell and Molecular Biology Chemical Sciences
    Identifiers
    urn:nbn:se:liu:diva-122341 (URN)10.1016/j.nbd.2015.08.024 (DOI)000366230000012 ()26334479 (PubMedID)
    Available from: 2015-10-29 Created: 2015-10-29 Last updated: 2018-01-10Bibliographically approved
    3. Distinct lysosomal network protein profiles in parkinsonian syndrome cerebrospinal fluid
    Open this publication in new window or tab >>Distinct lysosomal network protein profiles in parkinsonian syndrome cerebrospinal fluid
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    2016 (English)In: Journal of Parkinson's Disease, ISSN 1877-7171, E-ISSN 1877-718X, Vol. 6, no 2, p. 307-315Article in journal (Refereed) Published
    Abstract [en]

    Introduction: Clinical diagnosis of parkinsonian syndromes like Parkinson’s disease, corticobasal degeneration and progressive supranuclear palsy is hampered by overlapping symptomatology and lack of biomarkers for diagnosis, and definitive diagnosis is only possible post-mortem. Since impaired protein degradation plays an important role in many neurodegenerative disorders, we hypothesized that levels and profiles of lysosomal network proteins in cerebrospinal fluid could be changed in these parkinsonian syndromes.

    Methods: Cerebrospinal fluid samples were collected from Parkinson’s disease patients (n=18), clinically diagnosed 4-repeat tauopathy patients, corticobasal syndrome (n=6) and progressive supranuclear palsy (n=5), pathologically diagnosed progressive supranuclear palsy (n=8) and corticobasal degeneration patients (n=7). Each patient set was compared to its appropriate control group consisting of the same number of age and gender matched individuals. Lysosomal network protein levels were detected via Western blotting.

    Results: Lysosomal network proteins have markedly different cerebrospinal fluid protein levels and profiles in Parkinson’s disease, corticobasal degeneration and progressive supranuclear palsy. Lysosomal-associated membrane proteins 1 and 2 were significantly decreased in Parkinson´s disease; early endosomal antigen 1 was decreased and lysozyme increased in progressive supranuclear palsy; and lysosomal-associated membrane proteins 1 and 2, microtubule-associated protein 1 light chain 3 and lysozyme were increased in corticobasal degeneration.

    Conclusions: Lysosomal network proteins hold promise of being interesting novel candidates for biomarker studies and for elucidating disease mechanisms of Parkinson’s disease, corticobasal degeneration and progressive supranuclear palsy, but further validation studies will be needed to assess the specificity and the predictive value of these proteins in CSF.

    Place, publisher, year, edition, pages
    IOS Press, 2016
    National Category
    Cell and Molecular Biology Chemical Sciences
    Identifiers
    urn:nbn:se:liu:diva-122342 (URN)10.3233/JPD-150759 (DOI)000378352200004 ()
    Note

    Funding agencies:This work was supported by the Swedish Alzheimer foundation, the Swedish Dementia foundation, Linkoping University Neurobiology Center, Karin & Sten CBD Solutions AB, AZ-KI TSC, ALF, US National Institutes of Health R01AG038791 and U54NS092089, the Tau Consortium, the Hellman Family Foundation.

    Vid tiden för disputationen förelåg publikationen endast som manuskript

    Available from: 2015-10-29 Created: 2015-10-29 Last updated: 2018-01-10Bibliographically approved
    4. The role of LAMP-2 in AβPP processing and Aβ degradation; implications for Alzheimer’s Disease
    Open this publication in new window or tab >>The role of LAMP-2 in AβPP processing and Aβ degradation; implications for Alzheimer’s Disease
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    2015 (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Dysfunction in the lysosomal network, i.e., the endosomal, lysosomal and autophagy systems, are implicated in the pathways in Alzheimer’s disease brain pathology. This dysfunction is mirrored in the cerebrospinal fluid where a specific subset of lysosomal network proteins are found at elevated levels, lysosomal associated membrane protein-2 (LAMP-2) being one of the identified lysosomal proteins. Here we report that hippocampus and frontal cortex in Alzheimer’s disease cases have increased mRNA and protein expression of LAMP-2, and thus these brain areas are likely involved in the increased LAMP-2 levels seen in cerebrospinal fluid from Alzheimer’s disease patients. The increased LAMP-2 levels correlated with increased levels of β-amyloid1-42 (Aβ1-42). Oligomeric Aβ1-42 caused an upregulation of intracellular LAMP-2 in neuroblastoma cells, but did not trigger the release of LAMP-2 to the extracellular milieu, indicating that other cell types or mechanisms are responsible for the LAMP-2 release seen in cerebrospinal fluid. Overexpression of LAMP-2 in neuroblastoma cells caused a trend of reduction of secreted Aβ1-42 and changed the processing pattern of the Aβ precursor protein. These results indicate that Aβ1-42 mediated increase of LAMP-2 expression can act as a regulator of Aβ generation and secretion. LAMP-2 overexpression did not change the cellular uptake of extracellularly added Aβ1-42, but caused a delayed clearance of Aβ1-42. Whether the prolonged intracellular localization of Aβ1-42 in LAMP-2 overexpressing cells can change the transmission or degradation of Aβ remains to be investigated.

    Keywords
    AβPP processing, Alzheimer’s disease, β-amyloid, autophagy, LAMP-2, lysosome
    National Category
    Cell and Molecular Biology Chemical Sciences
    Identifiers
    urn:nbn:se:liu:diva-122345 (URN)
    Available from: 2015-10-29 Created: 2015-10-29 Last updated: 2018-01-10Bibliographically approved
  • 33.
    Borch Petersen, Eline
    et al.
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, The Swedish Institute for Disability Research. Linköping University, Department of Clinical and Experimental Medicine, Division of Speech language pathology, Audiology and Otorhinolaryngology. Eriksholm Research Centre.
    Wöstmann, Malte
    Department of Psychology, University of Lübeck, Lübeck, Germany.
    Obleser, Jonas
    Department of Psychology, University of Lübeck, Lübeck, Germany.
    Lunner, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Speech language pathology, Audiology and Otorhinolaryngology. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, The Swedish Institute for Disability Research. Eriksholm Research Centre, Snekkersten, Denmark.
    Neural tracking of attended versus ignored speech is differentially affected by hearing loss2017In: Journal of Neurophysiology, ISSN 0022-3077, E-ISSN 1522-1598, Vol. 117, no 1, p. 18-27Article in journal (Refereed)
    Abstract [en]

    Hearing loss manifests as a reduced ability to understand speech, particularly in multitalker situations. In these situations, younger normal-hearing listeners' brains are known to track attended speech through phase-locking of neural activity to the slow-varying envelope of the speech. This study investigates how hearing loss, compensated by hearing aids, affects the neural tracking of the speech-onset envelope in elderly participants with varying degree of hearing loss (n = 27, 62–86 yr; hearing thresholds 11–73 dB hearing level). In an active listening task, a to-be-attended audiobook (signal) was presented either in quiet or against a competing to-be-ignored audiobook (noise) presented at three individualized signal-to-noise ratios (SNRs). The neural tracking of the to-be-attended and to-be-ignored speech was quantified through the cross-correlation of the electroencephalogram (EEG) and the temporal envelope of speech. We primarily investigated the effects of hearing loss and SNR on the neural envelope tracking. First, we found that elderly hearing-impaired listeners' neural responses reliably track the envelope of to-be-attended speech more than to-be-ignored speech. Second, hearing loss relates to the neural tracking of to-be-ignored speech, resulting in a weaker differential neural tracking of to-be-attended vs. to-be-ignored speech in listeners with worse hearing. Third, neural tracking of to-be-attended speech increased with decreasing background noise. Critically, the beneficial effect of reduced noise on neural speech tracking decreased with stronger hearing loss. In sum, our results show that a common sensorineural processing deficit, i.e., hearing loss, interacts with central attention mechanisms and reduces the differential tracking of attended and ignored speech.

  • 34.
    Borch-Petersen, Eline
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Technical Audiology. Linköping University, Faculty of Health Sciences.
    Lunner, Thomas
    Linköping University, The Swedish Institute for Disability Research. Linköping University, Department of Behavioural Sciences and Learning, Disability Research.
    Obleser, Jonas
    Frauenhaufer Institute.
    Stenfelt, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Technical Audiology. Linköping University, Faculty of Health Sciences.
    Measuring cognitive load during listening: Changes in the EEG with noise level2013Conference paper (Refereed)
  • 35.
    Brito, H. O.
    et al.
    University of Federal Parana, Brazil.
    Radulski, D. R.
    University of Federal Parana, Brazil.
    Björk Wilhelms, Daniel
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Emergency Medicine.
    Stojakovic, Andrea
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Brito, L. M. O.
    University of Federal Maranhao, Brazil.
    Engblom, David
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Franco, C. R. C.
    University of Federal Parana, Brazil.
    Zampronio, A. R.
    University of Federal Parana, Brazil.
    Female Sex Hormones Influence the Febrile Response Induced by Lipopolysaccharide, Cytokines and Prostaglandins but not by Interleukin-1 beta in Rats2016In: Journal of neuroendocrinology (Print), ISSN 0953-8194, E-ISSN 1365-2826, Vol. 28, no 10Article in journal (Refereed)
    Abstract [en]

    There are differences in the immune response, and particularly fever, between males and females. In the present study, we investigated how the febrile responses induced by lipopolysaccharide (LPS) and different endogenous pyrogens were affected by female gonadal hormones. The febrile response to i.p. injection of LPS (50g/kg) was 40% lower in female rats compared to male or ovariectomised (OVX) female rats. Accordingly, oestrogen replacement in OVX animals reduced LPS-induced fever. Treatment with the prostaglandin synthesis inhibitor indomethacin (2mg/kg, i.p. 30min before) reduced the febrile response induced by LPS in both OVX (88%) and sham-operated (71%) rats. In line with the enhanced fever in OVX rats, there was increased expression of cyclooxygenase-2 (COX-2) in the hypothalamus and elevated levels of prostaglandin E-2 (PGE(2)). In addition, OVX rats were hyper-responsive to PGE(2) injected i.c.v. By contrast to the enhanced fever in response to LPS and PGE(2), the febrile response induced by i.c.v. injection of interleukin (IL)-1 was unaffected by ovariectomy, whereas the responses induced by tumour necrosis factor (TNF)- and macrophage inflammatory protein (MIP)-1 were completely abrogated. These results suggest that the mediators involved in the febrile response in females are similar to males, although the reduction of female hormones may decrease the responsiveness of some mediators such as TNF- and MIP-1. Compensatory mechanisms may be activated in females after ovariectomy such as an augmented synthesis of COX-2 and PGE(2).

  • 36. Brownell, William E
    et al.
    Jacob, Stefan
    Hakizimana, Pierre
    Karolinska Institutet / Karolinska University Hospital, Stockholm, Sweden.
    Ulfendahl, Mats
    Fridberger, Anders
    Karolinska Institutet / Karolinska University Hospital, Stockholm, Sweden.
    Membrane cholesterol modulates cochlear electromechanics2011In: Pflügers Archiv: European Journal of Physiology, ISSN 0031-6768, E-ISSN 1432-2013, Vol. 461, no 6, p. 677-686Article in journal (Refereed)
    Abstract [en]

    Changing the concentration of cholesterol in the plasma membrane of isolated outer hair cells modulates electromotility and prestin-associated charge movement, suggesting that a similar manipulation would alter cochlear mechanics. We examined cochlear function before and after depletion of membrane cholesterol with methyl-β-cyclodextrin (MβCD) in an excised guinea pig temporal bone preparation. The mechanical response of the cochlear partition to acoustic and/or electrical stimulation was monitored using laser interferometry and time-resolved confocal microscopy. The electromechanical response in untreated preparations was asymmetric with greater displacements in response to positive currents. Exposure to MβCD increased the magnitude and asymmetry of the response, without changing the frequency tuning of sound-evoked mechanical responses or cochlear microphonic potentials. Sodium salicylate reversibly blocked the enhanced electromechanical response in cholesterol depleted preparations. The increase of sound-evoked vibrations during positive current injection was enhanced following MβCD in some preparations. Imaging was used to assess cellular integrity which remained unchanged after several hours of exposure to MβCD in several preparations. The enhanced electromechanical response reflects an increase in outer hair cell electromotility and may reveal features of cholesterol distribution and trafficking in outer hair cells.

  • 37.
    Bäckryd, Emmanuel
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center.
    The Cerebrospinal Fluid in Severe Pain Conditions: Clinical, Pharmacological and Proteomic Aspects2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The treatment of both cancer pain and non-cancer chronic pain is still suboptimal. The overall aim of this PhD thesis was to conduct translational pain research at the interface between clinical pain medicine and the field of human proteomics, using the practice of intrathecal analgesia at our institution as a starting point. Hence, the cerebrospinal fluid (CSF) is at the centre of the present dissertation, both as a target for infusing analgesics (Papers I and II – clinical and pharmacological aspects) and as an important biofluid for human biomarker studies (Papers III and IV – proteomic aspects). In Paper I, 28 cases of intrathecal analgesia in cancer patients were prospectively followed. Movement-evoked breakthrough pain remained a major clinical problem throughout the study month despite otherwise successful intrathecal analgesia (defined as good control of spontaneous resting pain paralleled by a marked decrease of concomitant systemic opioid doses). This study therefore illustrates the importance of considering not only spontaneous resting pain but also movement-evoked breakthrough pain.

    In Paper II, an expert-based algorithm for trialing the intrathecal analgesic ziconotide by bolus injections was evaluated in an open-label study of 23 patients with chronic neuropathic pain. We found few responders (13%) according to the strict criteria of the algorithm, but ziconotide bolus injection trialing seems feasible. The predictive power of ziconotide bolus trialing remains unclear, and the pharmacological profile of ziconotide (with very slow tissue penetration due to high hydrophilicity) calls the rationale for ziconotide bolus trialing into question.

    In Paper III, we found low levels of beta-endorphin in the CSF of chronic neuropathic pain patients (n=15) compared to healthy controls (n=19). We speculate that this might indicate dysfunctional top-down control of nociception. Substance P levels in the CSF did not differ by univariate statistics. In Paper IV, the CSF proteome of 11 patients with chronic neuropathic pain and 11 healthy controls was exploratively studied, combining gel-based proteomics with multivariate data analysis. After eliminating four proteins associated with age, 32 proteins were found to highly discriminate between groups. Among these, the seven proteins having the highest discriminatory power between patients and controls were: one isoform of angiotensinogen, two isoforms of alpha-1-antitrypsin, three isoforms of haptoglobin, and one isoform of pigment epithelium-derived factor.

    In conclusion, this PhD thesis demonstrates the fruitfulness of studying the CSF, both as a target for infusing analgesics and as a potential mirror of the neurobiological processes involved in pathological pain conditions. The thesis points to the need for more research into the mechanisms of different pain conditions, in order to hopefully achieve the vision of mechanism-based pain diagnoses.

    List of papers
    1. Movement-evoked breakthrough cancer pain despite intrathecal analgesia: a prospective series
    Open this publication in new window or tab >>Movement-evoked breakthrough cancer pain despite intrathecal analgesia: a prospective series
    2011 (English)In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 55, no 9, p. 1139-1146Article in journal (Refereed) Published
    Abstract [en]

    Background: Intrathecal analgesia (ITA) is a valuable treatment option for intractable cancer-related pain. However, the issue of movement-evoked breakthrough pain (BTP) has not been specifically investigated in the ITA setting. The aim of the study was to evaluate the effect of ITA on spontaneous resting pain intensity (SRPI), doses of non-ITA opioids, and specifically on movement-evoked pain intensity (MEPI). less thanbrgreater than less thanbrgreater thanMethods: We prospectively studied 28 consecutive patients who graded SRPI and MEPI on a 0-10 numerical rating scale (NRS) at the time of ITA procedure, after 1 week, and after 1 month. Mild pain was defined as NRS andlt;= 3 and severe pain as NRS andgt;= 7. Concomitant doses of opioids were registered. less thanbrgreater than less thanbrgreater thanResults: After 1 week, no patient had severe SRPI compared with 31% before ITA, and the proportion of patients with mild SRPI had increased from 27% to 76%. Meanwhile, the median daily dose of non-ITA opioids decreased from 575 to 120 mg of oral morphine equivalents. The effect on SRPI and on doses of non-ITA opioids remained essentially unchanged during the study month, but the proportion of patients having severe MEPI did not change significantly: 44% still had severe MEPI after 1 week and 40% after 1 month. less thanbrgreater than less thanbrgreater thanConclusion: Movement-evoked BTP was a major clinical problem throughout the study month despite otherwise successful ITA. Improving the quality of life of patients with intractable cancer-related pain should include developing strategies to better deal with movement-evoked BTP.

    Place, publisher, year, edition, pages
    Wiley-Blackwell, 2011
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-71376 (URN)10.1111/j.1399-6576.2011.02510.x (DOI)000295102500015 ()
    Available from: 2011-10-14 Created: 2011-10-14 Last updated: 2017-12-08
    2. Ziconotide Trialing by Intrathecal Bolus Injections: An Open-Label Non-Randomized Clinical Trial in Postoperative/Posttraumatic Neuropathic Pain Patients Refractory to Conventional Treatment
    Open this publication in new window or tab >>Ziconotide Trialing by Intrathecal Bolus Injections: An Open-Label Non-Randomized Clinical Trial in Postoperative/Posttraumatic Neuropathic Pain Patients Refractory to Conventional Treatment
    2015 (English)In: Neuromodulation (Malden, Mass.), ISSN 1094-7159, E-ISSN 1525-1403, Vol. 18, no 5, p. 404-413Article in journal (Refereed) Published
    Abstract [en]

    Objectives: The aim of this open-label, non-randomized, clinical trial was to evaluate the feasibility of trialing ziconotide by intrathecal bolus injections. Material and Methods: Twenty-three patients, who had peripheral neuropathic pain refractory to pharmacological treatment and were under consideration for Spinal Cord Stimulation, received up to three ziconotide bolus injections according to a comprehensive algorithm. After a first injection of 2.5g, the patients progressed in the algorithm depending on the presence or absence of pain reduction and significant adverse events. A patient was considered a "responder" if experiencing pain reduction and no significant adverse event on two consecutive occasions at the same dosage. Results: We found a low proportion of responders (13%). However 30% of patients experienced greater than= 30% pain reduction on a least one injection, yielding a number needed to treat of similar to 3 for clinically significant pain relief. Pain intensity changed significantly over time (0-6h) (p = 0.047) after a mean ziconotide dose of 2.75 mu g. Adverse events were as expected, and no serious adverse event occurred. We did not find any statistical association between response to Spinal Cord Stimulation and response to ziconotide. Conclusions: Ziconotide bolus injection trialing seems feasible, but the proportion of responders in the present study was low. Adverse events were as expected, and no serious adverse event occurred. The predictive power of ziconotide bolus trialing remains unclear, and the pharmacological profile of ziconotide (slow tissue penetration due to high hydrophilicity) calls the rationale for bolus trialing into question.

    Place, publisher, year, edition, pages
    Wiley, 2015
    Keywords
    Bolus; intrathecal; spinal; trialing; ziconotide
    National Category
    Clinical Medicine Basic Medicine
    Identifiers
    urn:nbn:se:liu:diva-120352 (URN)10.1111/ner.12293 (DOI)000357388400010 ()25879804 (PubMedID)
    Note

    Funding Agencies|County Council of Ostergotland; Swedish Research Council

    Available from: 2015-07-31 Created: 2015-07-31 Last updated: 2018-01-11
    3. Do low levels of Beta-endorphin in the cerebrospinal fluid indicate defective top-down inhibition in patients with chronic neuropathic pain? A cross-sectional, comparative study
    Open this publication in new window or tab >>Do low levels of Beta-endorphin in the cerebrospinal fluid indicate defective top-down inhibition in patients with chronic neuropathic pain? A cross-sectional, comparative study
    2014 (English)In: Pain medicine (Malden, Mass.), ISSN 1526-2375, E-ISSN 1526-4637, Vol. 15, no 1, p. 111-119Article in journal (Refereed) Published
    Abstract [en]

    Objective

    Pain medicine still lacks mechanism-specific biomarkers to guide diagnosis and treatment, and defective top-down modulation is an important factor in the pathophysiology of chronic pain conditions. Using modern analytical tools and advanced multivariate statistical analysis, the aim of this study was to revisit two classical potential biomarkers of pro- and anti-nociception in humans (substance P and beta-endorphin), focusing particularly on the cerebrospinal fluid (CSF).

    Design

    Cross-sectional, comparative, observational study.

    Subjects

    Patients with chronic, post-traumatic and/or post-surgical, neuropathic pain refractory to conventional treatment (N = 15) and healthy controls (N = 19) were included.

    Methods

    Samples were taken from CSF and blood, and levels of substance P and beta-endorphin were investigated using a Luminex technology kit.

    Results

    We found low levels of beta-endorphin in the CSF of neuropathic pain patients (66 ± 11 pcg/mL) compared with healthy controls (115 ± 14 pcg/mL) (P = 0.017). Substance P levels in the CSF did not differ (20 ± 2 pcg/mL, 26 ± 2, P = 0.08). However, our multivariate data analysis showed that belonging to the patient group was associated with low levels of both substances in the CSF. A higher correlation between the levels of beta-endorphin and substance P in CSF was found in healthy controls than in patients (rs = 0.725, P < 0.001 vs rs = 0.574, P = 0.032).

    Conclusions

    Patients with chronic neuropathic pain due to trauma or surgery had low levels of beta-endorphin in the CSF. We speculate that this could indicate a defective top-down modulation of pain in chronic neuropathic pain. Our results also illustrate the importance of taking a system-wide, multivariate approach when searching for biomarkers.

    Place, publisher, year, edition, pages
    Wiley-Blackwell, 2014
    Keywords
    Beta-Endorphin; Biomarker; Cerebrospinal Fluid; Neuropathic; Pain; Substance P
    National Category
    Clinical Medicine
    Identifiers
    urn:nbn:se:liu:diva-104231 (URN)10.1111/pme.12248 (DOI)000329756400011 ()
    Available from: 2014-02-12 Created: 2014-02-12 Last updated: 2017-12-06Bibliographically approved
    4. Multivariate proteomic analysis of the cerebrospinal fluid of patients with peripheral neuropathic pain and healthy controls: a hypothesis-generating pilot study
    Open this publication in new window or tab >>Multivariate proteomic analysis of the cerebrospinal fluid of patients with peripheral neuropathic pain and healthy controls: a hypothesis-generating pilot study
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    2015 (English)In: Journal of Pain Research, ISSN 1178-7090, E-ISSN 1178-7090, Vol. 8, p. 321-333Article in journal (Refereed) Published
    Abstract [en]

    Pain medicine lacks objective biomarkers to guide diagnosis and treatment. Combining two-dimensional gel proteomics with multivariate data analysis by projection, we exploratively analyzed the cerebrospinal fluid of eleven patients with severe peripheral neuropathic pain due to trauma and/or surgery refractory to conventional treatment and eleven healthy controls. Using orthogonal partial least squares discriminant analysis, we identified a panel of 36 proteins highly discriminating between the two groups. Due to a possible confounding effect of age, a new model with age as outcome variable was computed for patients (n=11), and four out of 36 protein spots were excluded due to a probable influence of age. Of the 32 remaining proteins, the following seven had the highest discriminatory power between the two groups: an isoform of angiotensinogen (upregulated in patients), two isoforms of alpha-1-antitrypsin (downregulated in patients), three isoforms of haptoglobin (upregulated in patients), and one isoform of pigment epithelium-derived factor (downregulated in patients). It has recently been hypothesized that the renin–angiotensin system may play a role in the pathophysiology of neuropathic pain, and a clinical trial of an angiotensin II receptor antagonist was recently published. It is noteworthy that when searching for neuropathic pain biomarkers with a purely explorative methodology, it was indeed a renin–angiotensin system protein that had the highest discriminatory power between patients and controls in the present study. The results from this hypothesis-generating pilot study have to be confirmed in larger, hypothesis-driven studies with age-matched controls, but the present study illustrates the fruitfulness of combining proteomics with multivariate data analysis in hypothesis-generating pain biomarker studies in humans.

    Place, publisher, year, edition, pages
    Dovepress, 2015
    Keywords
    Cerebrospinal fluid, multivariate data analysis, neuropathic pain, proteomics
    National Category
    Nursing Surgery
    Identifiers
    urn:nbn:se:liu:diva-121493 (URN)10.2147/JPR.S82970 (DOI)000364718500002 ()26170714 (PubMedID)
    Note

    Funding agencies: Swedish Research Council; Swedish Council for Working Life and Social Research [2010-0913]; County Council of Ostergotland (Sinnescentrum); Halsofonden foundation

    Available from: 2015-09-22 Created: 2015-09-22 Last updated: 2017-12-05Bibliographically approved
  • 38.
    Böhme, Rebecca
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Charite, Germany.
    Lorenz, Robert C.
    Charite, Germany; Max Planck Institute Human Dev, Germany.
    Gleich, Tobias
    Charite, Germany; NeuroCure Excellence Cluster, Germany.
    Romund, Lydia
    Charite, Germany.
    Pelz, Patricia
    Charite, Germany.
    Golde, Sabrina
    Charite, Germany.
    Flemming, Eva
    Charite, Germany.
    Wold, Andrew
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Deserno, Lorenz
    Charite, Germany; Max Planck Institute Human Cognit and Brain Science, Germany; Otto von Guericke University, Germany.
    Behr, Joachim
    Charite, Germany; Charite, Germany; Medical School Brandenburg, Germany.
    Raufelder, Diana
    Freie University, Germany.
    Heinz, Andreas
    Charite, Germany.
    Beck, Anne
    Charite, Germany.
    Reversal learning strategy in adolescence is associated with prefrontal cortex activation2017In: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 45, no 1, p. 129-137Article in journal (Refereed)
    Abstract [en]

    Adolescence is a critical maturation period for human cognitive control and executive function. In this study, a large sample of adolescents (n=85) performed a reversal learning task during functional magnetic resonance imaging. We analyzed behavioral data using a reinforcement learning model to provide individually fitted parameters and imaging data with regard to reward prediction errors (PE). Following a model-based approach, we formed two groups depending on whether individuals tended to update expectations predominantly for the chosen stimulus or also for the unchosen one. These groups significantly differed in their problem behavior score obtained using the child behavior checklist (CBCL) and in a measure of their developmental stage. Imaging results showed that dorsolateral striatal areas covaried with PE. Participants who relied less on learning based on task structure showed less prefrontal activation compared with participants who relied more on task structure. An exploratory analysis revealed that PE-related activity was associated with pubertal development in prefrontal areas, insula and anterior cingulate. These findings support the hypothesis that the prefrontal cortex is implicated in mediating flexible goal-directed behavioral control.

  • 39.
    Cardin, Velia
    Linköping University, Department of Behavioural Sciences and Learning. Linköping University, Faculty of Arts and Sciences. Linköping University, The Swedish Institute for Disability Research. UCL, Dept Expt Psychol, Deafness Cognit & Language Res Ctr, London, England.
    Effects of Aging and Adult-Onset Hearing Loss on Cortical Auditory Regions2016In: Frontiers in Neuroscience, ISSN 1662-4548, E-ISSN 1662-453X, Vol. 10, no 199Article in journal (Refereed)
    Abstract [en]

    Hearing loss is a common feature in human aging. It has been argued that dysfunctions in central processing are important contributing factors to hearing loss during older age. Aging also has well documented consequences for neural structure and function, but it is not clear how these effects interact with those that arise as a consequence of hearing loss. This paper reviews the effects of aging and adult-onset hearing loss in the structure and function of cortical auditory regions. The evidence reviewed suggests that aging and hearing loss result in atrophy of cortical auditory regions and stronger engagement of networks involved in the detection of salient events, adaptive control and re-allocation of attention. These cortical mechanisms are engaged during listening in effortful conditions in normal hearing individuals. Therefore, as a consequence of aging and hearing loss, all listening becomes effortful and cognitive load is constantly high, reducing the amount of available cognitive resources. This constant effortful listening and reduced cognitive spare capacity could be what accelerates cognitive decline in older adults with hearing loss.

  • 40.
    Cardin, Velia
    et al.
    Linköping University, Department of Behavioural Sciences and Learning. University College London, Division of Psychology and Language Sciences.
    Smittenaar, Rebecca C.
    University College London, Experimental Psychology.
    Orfanidou, Eleni
    University of Crete, Greece.
    Rönnberg, Jerker
    Linköping University, Department of Behavioural Sciences and Learning, Disability Research. Linköping University, Faculty of Arts and Sciences.
    Capek, Cheryl M.
    University of Manchester, School of Psychological Sciences.
    Rudner, Mary
    Linköping University, Department of Behavioural Sciences and Learning, Disability Research. Linköping University, Faculty of Arts and Sciences.
    Woll, Bencie
    University College London, Division of Psychology and Language Sciences.
    Differential activity in Heschl's gyrus between deaf and hearing individuals is due to auditory deprivation rather than language modality2016In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 124, p. 96-106Article in journal (Refereed)
    Abstract [en]

    Sensory cortices undergo crossmodal reorganisation as a consequence of sensory deprivation. Congenital deafness in humans represents a particular case with respect to other types of sensory deprivation, because cortical reorganisation is not only a consequence of auditory deprivation, but also of language-driven mechanisms. Visual crossmodal plasticity has been found in secondary auditory cortices of deaf individuals, but it is still unclear if reorganisation also takes place in primary auditory areas, and how this relates to language modality and auditory deprivation.

    Here, we dissociated the effects of language modality and auditory deprivation on crossmodal plasticity in Heschl's gyrus as a whole, and in cytoarchitectonic region Te1.0 (likely to contain the core auditory cortex). Using fMRI, we measured the BOLD response to viewing sign language in congenitally or early deaf individuals with and without sign language knowledge, and in hearing controls.

    Results show that differences between hearing and deaf individuals are due to a reduction in activation caused by visual stimulation in the hearing group, which is more significant in Te1.0 than in Heschl's gyrus as a whole. Furthermore, differences between deaf and hearing groups are due to auditory deprivation, and there is no evidence that the modality of language used by deaf individuals contributes to crossmodal plasticity in Heschl's gyrus.

  • 41.
    Case, Laura K.
    et al.
    NIH, MD 20892 USA.
    Laubacher, Claire M.
    NIH, MD 20892 USA.
    Olausson, Håkan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Wang, Binquan
    NIH, MD 20892 USA.
    Spagnolo, Primavera A.
    NIAAA, MD 20892 USA.
    Catherine Bushnell, M.
    NIH, MD 20892 USA.
    Encoding of Touch Intensity But Not Pleasantness in Human Primary Somatosensory Cortex2016In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 36, no 21, p. 5850-5860Article in journal (Refereed)
    Abstract [en]

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

  • 42.
    Chakrabarti, Sankha Shubhra
    et al.
    Banaras Hindu University, Division of Geriatrics, Department of Medicine, Banaras, India.
    Bir, Aritri
    ICARE Institute of Medical Sciences and Research — Biochemistry, Haldia, India.
    Poddar, Jit
    Institute of post Graduate Medical Education and Research, — Biochemistry, Kolkata, India.
    Sinha, Maitrayee Sardar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Ganguly, Anirban
    Institute of Post Graduate Medical Education and Research — Biochemistry, Kolkata, India.
    Chakrabarti, Sasanka
    ICARE Institute Medical Science and Research, India.
    Ceramide and Sphingosine-1-Phosphate in Cell Death Pathways: Relevance to the Pathogenesis of Alzheimers Disease2016In: Current Alzheimer Research, ISSN 1567-2050, E-ISSN 1875-5828, Vol. 13, no 11, p. 1232-1248Article, review/survey (Refereed)
    Abstract [en]

    The metabolic turnover of sphingolipids produces several signaling molecules that profoundly affect the proliferation, differentiation and death of cells. In particular, an enormous body of information is available that defines the varied role of ceramide and sphingosine-1-phosphate in cell death and survival. This review specifically examines the role of ceramide and sphingosine-1-phosphate in triggering neuronal death in Alzheimers disease by analyzing the data from post-mortem studies and experimental research. There is compelling evidence that ceramide plays a key role in the neurodegeneration and amyloidogenesis occurring in the brain in Alzheimers disease. Further, it appears that ceramide and amyloid beta protein orchestrate an attack on mitochondria to set in the pathways of cell death. However, the complexity of metabolic and signaling pathways of sphingolipid derivatives precludes an immediate identification of effective drug targets for the therapy of Alzheimers disease.

  • 43. Chen, Fangyi
    et al.
    Zha, Dingjun
    Fridberger, Anders
    Karolinska Institutet, Stockholm, Sweden.
    Zheng, Jiefu
    Choudhury, Niloy
    Jacques, Steven L
    Wang, Ruikang K
    Shi, Xiaorui
    Nuttall, Alfred L
    A differentially amplified motion in the ear for near-threshold sound detection2011In: Nature Neuroscience, ISSN 1097-6256, E-ISSN 1546-1726, Vol. 14, no 6, p. 770-774Article in journal (Refereed)
    Abstract [en]

    The ear is a remarkably sensitive pressure fluctuation detector. In guinea pigs, behavioral measurements indicate a minimum detectable sound pressure of ∼20 μPa at 16 kHz. Such faint sounds produce 0.1-nm basilar membrane displacements, a distance smaller than conformational transitions in ion channels. It seems that noise within the auditory system would swamp such tiny motions, making weak sounds imperceptible. Here we propose a new mechanism contributing to a resolution of this problem and validate it through direct measurement. We hypothesized that vibration at the apical side of hair cells is enhanced compared with that at the commonly measured basilar membrane side. Using in vivo optical coherence tomography, we demonstrated that apical-side vibrations peaked at a higher frequency, had different timing and were enhanced compared with those at the basilar membrane. These effects depend nonlinearly on the stimulus sound pressure level. The timing difference and enhancement of vibrations are important for explaining how the noise problem is circumvented.

  • 44.
    Chu, Tak-Ho
    et al.
    University of Calgary, Canada.
    Cummins, Karen
    University of Calgary, Canada.
    Sparling, Joseph S.
    University of Calgary, Canada.
    Tsutsui, Shigeki
    University of Calgary, Canada.
    Brideau, Craig
    University of Calgary, Canada.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Joseph, Jeffrey T.
    Alberta Health Serv, Canada.
    Stys, Peter K.
    University of Calgary, Canada.
    Axonal and myelinic pathology in 5xFAD Alzheimers mouse spinal cord2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 11, article id e0188218Article in journal (Refereed)
    Abstract [en]

    As an extension of the brain, the spinal cord has unique properties which could allow us to gain a better understanding of CNS pathology. The brain and cord share the same cellular components, yet the latter is simpler in cytoarchitecture and connectivity. In Alzheimers research, virtually all focus is on brain pathology, however it has been shown that transgenic Alzheimers mouse models accumulate beta amyloid plaques in spinal cord, suggesting that the cord possesses the same molecular machinery and conditions for plaque formation. Here we report a spatial-temporal map of plaque load in 5xFAD mouse spinal cord. We found that plaques started to appear at 11 weeks, then exhibited a time dependent increase and differential distribution along the cord. More plaques were found in cervical than other spinal levels at all time points examined. Despite heavy plaque load at 6 months, the number of cervical motor neurons in 5xFAD mice is comparable to wild type littermates. On detailed microscopic examination, fine beta amyloid-containing and beta sheet-rich thread-like structures were found in the peri-axonal space of many axons. Importantly, these novel structures appear before any plaque deposits are visible in young mice spinal cord and they co-localize with axonal swellings at later stages, suggesting that these thread-like structures might represent the initial stages of plaque formation, and could play a role in axonal damage. Additionally, we were able to demonstrate increasing myelinopathy in aged 5xFAD mouse spinal cord using the lipid probe Nile Red with high resolution. Collectively, we found significant amyloid pathology in grey and white matter of the 5xFAD mouse spinal cord which indicates that this structure maybe a useful platform to study mechanisms of Alzheimers pathology and disease progression.

  • 45.
    Ciccocioppo, Roberto
    et al.
    University of Camerino, Italy.
    Gehlert, Donald R.
    Lilly Research Laboratories, Indianapolis, IN, USA.
    Ryabinin, Andrey
    Oregon Health & Science University, Portland, OR, USA.
    Kaur, Simranjit
    Oregon Health & Science University, Portland, OR, USA.
    Cippitelli, Andrea
    University of Camerino, Italy.
    Thorsell, Annika
    National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
    Lê, Anh D.
    University of Toronto, Ontario, Canada.
    Hipskind, Philip A.
    Lilly Research Laboratories, Indianapolis, IN, USA.
    Hamdouchi, Chafiq
    Lilly Research Laboratories, Indianapolis, IN, USA.
    Lu, Jianliang
    Lilly Research Laboratories, Indianapolis, IN, USA.
    Hembre, Erik J.
    Lilly Research Laboratories, Indianapolis, IN, USA.
    Cramer, Jeffrey
    Lilly Research Laboratories, Indianapolis, IN, USA.
    Song, Min
    Lilly Research Laboratories, Indianapolis, IN, USA.
    McKinzie, David
    Lilly Research Laboratories, Indianapolis, IN, USA.
    Morin, Michelle
    Lilly Research Laboratories, Indianapolis, IN, USA.
    Economidou, Daina
    University of Camerino, Italy.
    Stopponi, Serena
    University of Camerino, Italy.
    Cannella, Nazzareno
    University of Camerino, Italy.
    Braconi, Simone
    University of Camerino, Italy.
    Kallupi, Marsida
    University of Camerino, Italy.
    de Guglielmo, Giordano
    University of Camerino, Italy.
    Massi, Maurizio
    University of Camerino, Italy.
    George, David T.
    National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
    Gilman, Jody
    National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
    Hersh, Jacqueline
    National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
    Tauscher, Johannes T.
    Lilly Research Laboratories, Indianapolis, IN, USA.
    Hunt, Stephen P.
    University College London, UK.
    Hommer, Daniel
    National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
    Heilig, Markus
    National Institute on Alcohol Abuse and Alcolholism, NIH; Bethesda, MD, USA.
    Stress-related neuropeptides and alcoholism: CRH, NPY, and beyond2009In: Alcohol, ISSN 0741-8329, E-ISSN 1873-6823, Vol. 43, no 7, p. 491-498Article in journal (Refereed)
    Abstract [en]

    This article summarizes the proceedings of a symposium held at the conference on "Alcoholism and Stress: A Framework for Future Treatment Strategies" in Volterra, Italy, May 6-9, 2008. Chaired by Markus Heilig and Roberto Ciccocioppo, this symposium offered a forum for the presentation of recent data linking neuropetidergic neurotransmission to the regulation of different alcohol-related behaviors in animals and in humans. Dr. Donald Gehlert described the development of a new corticotrophin-releasing factor receptor 1 antagonist and showed its efficacy in reducing alcohol consumption and stress-induced relapse in different animal models of alcohol abuse. Dr. Andrey Ryabinin reviewed recent findings in his laboratory, indicating a role of the urocortin 1 receptor system in the regulation of alcohol intake. Dr. Annika Thorsell showed data supporting the significance of the neuropeptide Y receptor system in the modulation of behaviors associated with a history of ethanol intoxication. Dr. Roberto Ciccocioppo focused his presentation on the nociceptin/orphanin FQ (N/OFQ) receptors as treatment targets for alcoholism. Finally, Dr. Markus Heilig showed recent preclinical and clinical evidence suggesting that neurokinin 1 antagonism may represent a promising new treatment for alcoholism. Collectively, these investigators highlighted the significance of neuropeptidergic neurotransmission in the regulation of neurobiological mechanisms of alcohol addiction. Data also revealed the importance of these systems as treatment targets for the development of new medication for alcoholism.

  • 46.
    Ciganovic, Nikola
    et al.
    Imperial Coll London, England.
    Warren, Rebecca L.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Keceli, Batu
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Jacob, Stefan
    Karolinska Inst, Sweden.
    Fridberger, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Reichenbach, Tobias
    Imperial Coll London, England; Univ Calif Santa Barbara, CA 93106 USA.
    Static length changes of cochlear outer hair cells can tune low-frequency hearing2018In: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 14, no 1, article id e1005936Article in journal (Refereed)
    Abstract [en]

    The cochlea not only transduces sound-induced vibration into neural spikes, it also amplifies weak sound to boost its detection. Actuators of this active process are sensory outer hair cells in the organ of Corti, whereas the inner hair cells transduce the resulting motion into electric signals that propagate via the auditory nerve to the brain. However, how the outer hair cells modulate the stimulus to the inner hair cells remains unclear. Here, we combine theoretical modeling and experimental measurements near the cochlear apex to study the way in which length changes of the outer hair cells deform the organ of Corti. We develop a geometry-based kinematic model of the apical organ of Corti that reproduces salient, yet counter-intuitive features of the organs motion. Our analysis further uncovers a mechanism by which a static length change of the outer hair cells can sensitively tune the signal transmitted to the sensory inner hair cells. When the outer hair cells are in an elongated state, stimulation of inner hair cells is largely inhibited, whereas outer hair cell contraction leads to a substantial enhancement of sound-evoked motion near the hair bundles. This novel mechanism for regulating the sensitivity of the hearing organ applies to the low frequencies that are most important for the perception of speech and music. We suggest that the proposed mechanism might underlie frequency discrimination at low auditory frequencies, as well as our ability to selectively attend auditory signals in noisy surroundings.

  • 47.
    Cippitelli, Andrea
    et al.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Damadzic, Ruslan
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Frankola, Kate
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Goldstein, Andrea
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Thorsell, Annika
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Singley, Erick
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Eskay, Robert L
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Heilig, Markus
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Alcohol-induced neurodegeneration, suppression of transforming growth factor-beta, and cognitive impairment in rats: prevention by group II metabotropic glutamate receptor activation2010In: Biological Psychiatry, ISSN 0006-3223, E-ISSN 1873-2402, Vol. 67, no 9, p. 823-830Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Glutamatergic neurotransmission has been implicated in mechanisms of alcohol-induced neurodegeneration and cognitive impairment, but the underlying mechanism remains unknown. Here, we examined whether the group II metabotropic glutamate receptor agonist LY379268 prevents neuronal death and learning deficits in a rat model of binge-like exposure to alcohol.

    METHODS: Following 4-day binge alcohol exposure concurrent with LY379268 or vehicle treatment, Fluoro-Jade B and transforming growth factor-beta (TGF-beta) staining were carried out, and reversal learning in the Morris water maze was assessed.

    RESULTS: Fluoro-Jade B staining indicating neurodegeneration was most extensive in the ventral hippocampus and the entorhinal cortex (EC). LY379268 was potently neuroprotective in the EC but not in the dentate gyrus of the hippocampus. In parallel, binge alcohol exposure suppressed TGF-beta expression in both the EC and dentate gyrus, whereas LY379268 increased TGF-beta in the EC only. Finally, neuroprotective effects of LY379268 were accompanied by prevention of deficits in spatial reversal learning.

    CONCLUSIONS: Our data support a neuroprotective role for group II metabotropic glutamate receptor agonists and TGF-beta in alcohol-induced neurodegeneration.

  • 48.
    Cippitelli, Andrea
    et al.
    National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
    Damadzic, Ruslan
    National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
    Hamelink, Carol
    National Institute of Mental Health, NIH, Bethesda, MD, USA.
    Brunnquell, Michael
    National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
    Thorsell, Annika
    National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
    Heilig, Markus
    National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
    Eskay, Robert L.
    National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
    Binge-like ethanol consumption increases corticosterone levels and neurodegneration whereas occupancy of type II glucocorticoid receptors with mifepristone is neuroprotective2014In: Addiction Biology, ISSN 1355-6215, E-ISSN 1369-1600, Vol. 19, no 1, p. 27-36Article in journal (Refereed)
    Abstract [en]

    Excessive ethanol (EtOH) use leads to impaired memory and cognition. Using a rat model of binge-like intoxication, we tested whether elevated corticosterone (Cort) levels contribute to the neurotoxic consequences of EtOH exposure. Rats were adrenalectomized (Adx) and implanted with cholesterol pellets, or cholesterol pellets containing Cort in order to achieve basal, medium, or high blood concentrations of Cort. Intragastric EtOH or an isocaloric control solution was given three times daily for 4 days to achieve blood alcohol levels ranging between 200 and 350 mg/dl. Mean 24-hour plasma levels of Cort were ∼110 and ∼40 ng/ml in intact EtOH-treated and intact control animals, respectively. Basal Cort replacement concentrations in EtOH-treated Adx animals did not exacerbate alcohol-induced neurodegeneration in the hippocampal dentate gyrus (DG) or the entorhinal cortex (EC) as observed by amino-cupric silver staining. In contrast, Cort replacement pellets resulting in plasma Cort levels twofold higher (medium) than normal, or greater than twofold higher (high) in Adx-Cort-EtOH animals increased neurodegeneration. In separate experiments, pharmacological blockade of the Type II glucocorticoid (GC) receptor was initiated with mifepristone (RU38486; 0, 5, 15 mg/kg/day, i.p.). At the higher dose, mifepristone decreased the number of degenerating hippocampal DG cells in binge-EtOH-treated intact animals, whereas, only a trend for reduction was observed in 15 mg/kg/day mifepristone-treated animals in the EC, as determined by fluoro-jade B staining. These results suggest that elevated circulating Cort in part mediates EtOH-induced neurotoxicity in the brain through activation of Type II GC receptors.

  • 49.
    Cippitelli, Andrea
    et al.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Damadzic, Ruslan
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Hansson, Anita C.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Singley, Erick
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Sommer, Wolfgang H.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Eskay, Robert
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Thorsell, Annika
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Heilig, Markus
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Neuropeptide Y (NPY) suppresses yohimbine-induced reinstatement of alcohol seeking2010In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 208, no 3, p. 417-426Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Reinstatement of responding to a previously alcohol-associated lever following extinction is an established model of relapse-like behavior and can be triggered by stress exposure. Here, we examined whether neuropeptide Y (NPY), an endogenous anti-stress mediator, blocks reinstatement of alcohol-seeking induced by the pharmacological stressor yohimbine.

    MATERIALS AND METHODS: NPY [5.0 or 10.0 mug/rat, intracerebroventricularly (ICV)] dose-dependently blocked the reinstatement of alcohol seeking induced by yohimbine (1.25 mg/kg, i.p.) but failed to significantly suppress the maintenance of alcohol self-administration. We then used c-fos expression mapping to examine neuronal activation following treatment with yohimbine or NPY alone or yohimbine following NPY pre-treatment.

    RESULTS AND DISCUSSION: The analysis was focused on a network of structures previously implicated in yohimbine-induced reinstatement, comprised of central (CeA) and basolateral (BLA) amygdala and the shell of the nucleus accumbens (Nc AccS). Within this network, both yohimbine and NPY potently induced neuronal activation, and their effects were additive, presumably indicating activation of excitatory and inhibitory neuronal populations, respectively.

    CONCLUSION: These results suggest that NPY selectively suppresses relapse to alcohol seeking induced by stressful events and support the NPY system as an attractive target for the treatment of alcohol addiction.

  • 50.
    Cippitelli, Andrea
    et al.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Damadzic, Ruslan
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Singley, Erick
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Thorsell, Annika
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Ciccocioppo, Roberto
    University of Camerino, Italy.
    Eskay, Robert L.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Heilig, Markus
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Pharmacological blockade of corticotropin-releasing hormone receptor 1 (CRH1R) reduces voluntary consumption of high alcohol concentrations in non-dependent Wistar rats2012In: Pharmacology, Biochemistry and Behavior, ISSN 0091-3057, E-ISSN 1873-5177, Vol. 100, no 3, p. 522-529Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: A dysregulation of the corticotropin-releasing hormone (CRH) system has been implicated in the development of excessive alcohol consumption and dependence. The aim of the present study was to evaluate whether the CRH system is also recruited when non-dependent Wistar rats escalate to high alcohol intake in the intermittent (alternate days) model of drinking.

    METHODS: We compared intermittent and continuous access to 20% (v/v) alcohol in a two-bottle free choice drinking paradigm. Following a total of twenty 24-hour exposures for every experimental group, we assessed signs of alcohol withdrawal, including anxiety-like behavior and sensitivity to stress. The selective CRH1 receptor (CRH1R) antagonist antalarmin (0, 10, 20 mg/kg, i.p.) was tested on alcohol consumption.

    RESULTS: Intermittent access to 20% alcohol led non-selected Wistar rats to escalate their voluntary intake to a high and stable level, whereas continuously exposed animals maintained a lower consumption. These groups did not differ in physical withdrawal signs. In addition, no differences were found when anxiogenic-like behavior was studied, neither under basal conditions or following restraint stress. Nevertheless, sensitivity to the treatment with the CRH1R antalarmin was observed since a reduction of 20% alcohol intake was found in both groups of animals regardless of the regimen of alcohol exposure. In addition, antalarmin was effective when injected to animals exposed to intermittent 10% (v/v) alcohol whereas it failed to suppress 10% continuous alcohol intake.

    CONCLUSIONS: Pharmacological blockade of CRH1R reduced alcohol drinking when sustained high levels of intake were achieved suggesting that the CRH system plays a key role when high doses of ethanol are consumed by non-dependent subjects. This supports the notion that CRH system not only maintains the dependent state but also engages the transition to dependence.

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