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  • 1.
    Aalto, K
    et al.
    Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland.
    Korhonen, L
    Department of Neuroscience, Neurobiology, Uppsala University, Box 587, S-75123, Uppsala, Sweden.
    Lahdenne, P
    Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland.
    Pelkonen, P
    Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland.
    Lindholm, D
    Department of Neuroscience, Neurobiology, Uppsala University, Box 587, S-75123, Uppsala, Sweden.
    Nerve growth factor in serum of children with systemic lupus erythematosus is correlated with disease activity2002Inngår i: Cytokine, ISSN 1043-4666, E-ISSN 1096-0023, Vol. 20, nr 3, s. 136-139Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Nerve growth factor (NGF) is a neurotrophic factor, which is expressed both in the nervous system and in peripheral organs. NGF is also present in mast cells, and in B- and T-lymphocytes, and may play a role in the immune cell development and differentiation. Various cytokines have been shown to affect NGF expression, and NGF is elevated in inflammation and in some autoimmune diseases. Here we have studied NGF concentrations in serum of pediatric patients with systemic lupus erythematosus (SLE) using a two-site enzyme-linked immunosorbent assay (ELISA). We have further correlated the levels of NGF to the inflammatory state of the disease. The mean value of serum NGF in SLE patients was significantly increased compared with controls (3346 vs 627 pg/ml). There was a correlation between the activity of SLE and the levels of NGF. The results show that NGF is elevated in childhood SLE and that the levels are correlated with disease activity. The present results suggest that NGF may play a role in the pathogenesis of SLE and may have a prognostic value in evaluating the course of the disease and in outlining the medication. (C) 2002 Elsevier Science Ltd. All rights reserved.

  • 2.
    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
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Kardiologiska kliniken US.
    Treatment strategies in Alzheimers disease: a review with focus on selenium supplementation2016Inngår i: Biometals, ISSN 0966-0844, E-ISSN 1572-8773, Vol. 29, nr 5, s. 827-839Artikkel i tidsskrift (Fagfellevurdert)
    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.

    Fulltekst (pdf)
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  • 3.
    Acevedo, Juan Pablo
    et al.
    Univ Los Andes, Chile; Cells Cells, Chile.
    Angelopoulos, Ioannis
    Univ Los Andes, Chile; Cells Cells, Chile.
    van Noort, Danny
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Teknisk biologi. Linköpings universitet, Tekniska fakulteten. Univ Los Andes, Chile.
    Khoury, Maroun
    Univ Los Andes, Chile; Cells Cells, Chile; Consorcio Regenero, Chile.
    Microtechnology applied to stem cells research and development2018Inngår i: Regenerative Medicine, ISSN 1746-0751, E-ISSN 1746-076X, Vol. 13, nr 2, s. 233-248Artikkel, forskningsoversikt (Fagfellevurdert)
    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.

  • 4.
    Ackerley, Rochelle
    et al.
    Aix Marseille Univ, France.
    Croy, Ilona
    Tech Univ Dresden, Germany.
    Olausson, Håkan
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Neurofysiologiska kliniken US.
    Badre, Gaby
    Gothenburg Univ, Sweden.
    Investigating the Putative Impact of Odors Purported to Have Beneficial Effects on Sleep: Neural and Perceptual Processes2020Inngår i: Chemosensory Perception, ISSN 1936-5802, E-ISSN 1936-5810, Vol. 13, nr 2, s. 93-105Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Introduction Olfaction has an important role in physiological and affective processes, as well as the potential to have profound effects on activities such as sleep and learning. We investigated two commercially manufactured odors ("Deep Sleep" and "Oriental," from This Works) purported to promote sleep, compared with control odor, where we aimed to explore whether neural and behavioral differences existed after odor inhalation. Methods In a neuroimaging study, 30 healthy participants were exposed to the odors via an olfactometer during functional magnetic resonance imaging (fMRI). In a further behavioral study using 12 chronic insomniacs, we investigated whether the commercial odors showed effects on sleep during a double-blind, randomized home evaluation. Results In the neuroimaging, the odors were related to activation of olfactory-relevant areas, such as the orbitofrontal cortex, and we found positive connectivity between the piriform cortex and the hippocampus, amygdala, insula, and middle cingulate cortex. Deep Sleep specifically activated the superior temporal gyrus, whereas Oriental activated the caudate. Further, these commercial odors showed some beneficial impact on sleep. Conclusions The perceptual and neural impacts of the commercial odors showed that olfactory stimulation can potentially aid sleep and modify affective processes in a number of ways. Implications The present work opens up opportunities for further investigations into how different odors may lead to specific behavioral and physiological modifications, such as their impact on sleep and well-being, which may provide non-pharmacological alternative approaches.

    Fulltekst (pdf)
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  • 5.
    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.2014Inngår i: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 155, nr 9, s. 1802-1813Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 6.
    Agnvall, Beatrix
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    Bélteky, Johan
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    Jensen, Per
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    Brain size is reduced by selectionfor tameness in Red Junglefowl–correlated effects in vital organs2017Inngår i: Scientific Reports, E-ISSN 2045-2322, Vol. 7, artikkel-id 3306Artikkel i tidsskrift (Fagfellevurdert)
    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.

    Fulltekst (pdf)
    fulltext
  • 7.
    Aguila, Monica
    et al.
    UCL Inst Ophthalmol, England.
    Bellingham, James
    UCL Inst Ophthalmol, England.
    Athanasiou, Dimitra
    UCL Inst Ophthalmol, England.
    Bevilacqua, Dalila
    UCL Inst Ophthalmol, England.
    Duran, Yanai
    UCL Inst Ophthalmol, England.
    Maswood, Ryea
    UCL Inst Ophthalmol, England.
    Parfitt, David A.
    UCL Inst Ophthalmol, England.
    Iwawaki, Takao
    Kanazawa Med Univ, Japan.
    Spyrou, Ioannis
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för klinisk kemi. Linköpings universitet, Medicinska fakulteten.
    Smith, Alexander J.
    UCL Inst Ophthalmol, England.
    Ali, Robin R.
    UCL Inst Ophthalmol, England.
    Cheetham, Michael E.
    UCL Inst Ophthalmol, England.
    AAV-mediated ERdj5 overexpression protects against P23H rhodopsin toxicity2020Inngår i: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 29, nr 8, s. 1310-1318Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Rhodopsin misfolding caused by the P23H mutation is a major cause of autosomal dominant retinitis pigmentosa (adRP). To date, there are no effective treatments for adRP. The BiP co-chaperone and reductase ERdj5 (DNAJC10) is part of the endoplasmic reticulum (ER) quality control machinery, and previous studies have shown that overexpression of ERdj5 in vitro enhanced the degradation of P23H rhodopsin, whereas knockdown of ERdj5 increased P23H rhodopsin ER retention and aggregation. Here, we investigated the role of ERdj5 in photoreceptor homeostasis in vivo by using an Erdj5 knockout mouse crossed with the P23H knock-in mouse and by adeno-associated viral (AAV) vector-mediated gene augmentation of ERdj5 in P23H-3 rats. Electroretinogram (ERG) and optical coherence tomography of Erdj5(-/-) and P23H(+/-):Erdj5(-/-) mice showed no effect of ERdj5 ablation on retinal function or photoreceptor survival. Rhodopsin levels and localization were similar to those of control animals at a range of time points. By contrast, when AAV2/8-ERdj5-HA was subretinally injected into P23H-3 rats, analysis of the full-field ERG suggested that overexpression of ERdj5 reduced visual function loss 10 weeks post-injection (PI). This correlated with a significant preservation of photoreceptor cells at 4 and 10 weeks PI. Assessment of the outer nuclear layer (ONL) morphology showed preserved ONL thickness and reduced rhodopsin retention in the ONL in the injected superior retina. Overall, these data suggest that manipulation of the ER quality control and ER-associated degradation factors to promote mutant protein degradation could be beneficial for the treatment of adRP caused by mutant rhodopsin.

    Fulltekst (pdf)
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  • 8.
    Aguilar-Calvo, Patricia
    et al.
    Univ Calif San Diego, CA 92093 USA; Univ Calif San Diego, CA 92093 USA.
    Bett, Cyrus
    Univ Calif San Diego, CA 92093 USA; Univ Calif San Diego, CA 92093 USA.
    Sevillano, Alejandro M.
    Univ Calif San Diego, CA 92093 USA; Univ Calif San Diego, CA 92093 USA.
    Kurt, Timothy D.
    Univ Calif San Diego, CA 92093 USA; Univ Calif San Diego, CA 92093 USA.
    Lawrence, Jessica
    Univ Calif San Diego, CA 92093 USA; Univ Calif San Diego, CA 92093 USA.
    Soldau, Katrin
    Univ Calif San Diego, CA 92093 USA; Univ Calif San Diego, CA 92093 USA.
    Hammarström, Per
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Nilsson, Peter
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Sigurdson, Christina J.
    Univ Calif San Diego, CA 92093 USA; Univ Calif San Diego, CA 92093 USA; Univ Calif Davis, CA USA.
    Generation of novel neuroinvasive prions following intravenous challenge2018Inngår i: Brain Pathology, ISSN 1015-6305, E-ISSN 1750-3639, Vol. 28, nr 6, s. 999-1011Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Prions typically spread into the central nervous system (CNS), likely via peripheral nerves. Yet prion conformers differ in their capacity to penetrate the CNS; certain fibrillar prions replicate persistently in lymphoid tissues with no CNS entry, leading to chronic silent carriers. Subclinical carriers of variant Creutzfeldt-Jakob (vCJD) prions in the United Kingdom have been estimated at 1:2000, and vCJD prions have been transmitted through blood transfusion, however, the circulating prion conformers that neuroinvade remain unclear. Here we investigate how prion conformation impacts brain entry of transfused prions by challenging mice intravenously to subfibrillar and fibrillar strains. We show that most strains infiltrated the brain and caused terminal disease, however, the fibrillar prions showed reduced CNS entry in a strain-dependent manner. Strikingly, the highly fibrillar mCWD prion strain replicated in the spleen and emerged in the brain as a novel strain, indicating that a new neuroinvasive prion had been generated from a previously non-neuroinvasive strain. The new strain showed altered plaque morphology, brain regions targeted and biochemical properties and these properties were maintained upon intracerebral passage. Intracerebral passage of prion-infected spleen re-created the new strain. Splenic prions resembled the new strain biochemically and intracerebral passage of prion-infected spleen re-created the new strain, collectively suggesting splenic prion replication as a potential source. Taken together, these results indicate that intravenous exposure to prion-contaminated blood or blood products may generate novel neuroinvasive prion conformers and disease phenotypes, potentially arising from prion replication in non-neural tissues or from conformer selection.

  • 9.
    Aho, Nikolas
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Proczkowska-Björklund, Marie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Svedin, Carl Göran
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Närsjukvården i centrala Östergötland, Barn- och ungdomspsykiatriska kliniken.
    Victimization, polyvictimization , and health in Swedish adolescents2016Inngår i: Adolescent Health, Medicine and Therapeutics, ISSN 1179-318X, Vol. 7, s. 89-99Artikkel i tidsskrift (Fagfellevurdert)
    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.

    Fulltekst (pdf)
    fulltext
  • 10.
    Alickovic, Emina
    et al.
    Linköpings universitet, Institutionen för systemteknik, Reglerteknik. Linköpings universitet, Tekniska fakulteten. Oticon AS, Denmark.
    Ng, Hoi Ning, Elaine
    Linköpings universitet, Institutionen för beteendevetenskap och lärande, Handikappvetenskap. Linköpings universitet, Filosofiska fakulteten. Linköpings universitet, Institutet för handikappvetenskap (IHV). Oticon AS, Denmark.
    Fiedler, Lorenz
    Oticon AS, Denmark.
    Santurette, Sebastien
    Oticon AS, Denmark; Tech Univ Denmark, Denmark.
    Innes-Brown, Hamish
    Oticon AS, Denmark.
    Graversen, Carina
    Oticon AS, Denmark.
    Effects of Hearing Aid Noise Reduction on Early and Late Cortical Representations of Competing Talkers in Noise2021Inngår i: Frontiers in Neuroscience, ISSN 1662-4548, E-ISSN 1662-453X, Vol. 15, artikkel-id 636060Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objectives Previous research using non-invasive (magnetoencephalography, MEG) and invasive (electrocorticography, ECoG) neural recordings has demonstrated the progressive and hierarchical representation and processing of complex multi-talker auditory scenes in the auditory cortex. Early responses (<85 ms) in primary-like areas appear to represent the individual talkers with almost equal fidelity and are independent of attention in normal-hearing (NH) listeners. However, late responses (>85 ms) in higher-order non-primary areas selectively represent the attended talker with significantly higher fidelity than unattended talkers in NH and hearing-impaired (HI) listeners. Motivated by these findings, the objective of this study was to investigate the effect of a noise reduction scheme (NR) in a commercial hearing aid (HA) on the representation of complex multi-talker auditory scenes in distinct hierarchical stages of the auditory cortex by using high-density electroencephalography (EEG). Design We addressed this issue by investigating early (<85 ms) and late (>85 ms) EEG responses recorded in 34 HI subjects fitted with HAs. The HA noise reduction (NR) was either on or off while the participants listened to a complex auditory scene. Participants were instructed to attend to one of two simultaneous talkers in the foreground while multi-talker babble noise played in the background (+3 dB SNR). After each trial, a two-choice question about the content of the attended speech was presented. Results Using a stimulus reconstruction approach, our results suggest that the attention-related enhancement of neural representations of target and masker talkers located in the foreground, as well as suppression of the background noise in distinct hierarchical stages is significantly affected by the NR scheme. We found that the NR scheme contributed to the enhancement of the foreground and of the entire acoustic scene in the early responses, and that this enhancement was driven by better representation of the target speech. We found that the target talker in HI listeners was selectively represented in late responses. We found that use of the NR scheme resulted in enhanced representations of the target and masker speech in the foreground and a suppressed representation of the noise in the background in late responses. We found a significant effect of EEG time window on the strengths of the cortical representation of the target and masker. Conclusion Together, our analyses of the early and late responses obtained from HI listeners support the existing view of hierarchical processing in the auditory cortex. Our findings demonstrate the benefits of a NR scheme on the representation of complex multi-talker auditory scenes in different areas of the auditory cortex in HI listeners.

    Fulltekst (pdf)
    fulltext
  • 11.
    Analytis, Pantelis P.
    et al.
    Cornell Univ, USA.
    Barkoczi, Daniel
    Linköpings universitet, Institutionen för ekonomisk och industriell utveckling, Institutet för analytisk sociologi, IAS. Linköpings universitet, Filosofiska fakulteten.
    Herzog, Stefan M.
    Max Planck Inst Human Dev, Germany.
    Social learning strategies for matters of taste2018Inngår i: Nature Human Behaviour, E-ISSN 2397-3374, Vol. 2, nr 6, s. 415-424Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Most choices people make are about 'matters of taste', on which there is no universal, objective truth. Nevertheless, people can learn from the experiences of individuals with similar tastes who have already evaluated the available options-a potential harnessed by recommender systems. We mapped recommender system algorithms to models of human judgement and decision-making about 'matters of fact' and recast the latter as social learning strategies for matters of taste. Using computer simulations on a large-scale, empirical dataset, we studied how people could leverage the experiences of others to make better decisions. Our simulations showed that experienced individuals can benefit from relying mostly on the opinions of seemingly similar people; by contrast, inexperienced individuals cannot reliably estimate similarity and are better off picking the mainstream option despite differences in taste. Crucially, the level of experience beyond which people should switch to similarity-heavy strategies varies substantially across individuals and depends on how mainstream (or alternative) an individual's tastes are and the level of dispersion in taste similarity with the other people in the group.

  • 12.
    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
    Linköpings universitet, Institutionen för beteendevetenskap och lärande, Psykologi. Linköpings universitet, Filosofiska fakulteten. 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.2015Inngår i: JAMA psychiatry, ISSN 2168-6238, E-ISSN 2168-622X, Vol. 72, nr 7, s. 659-667Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 13.
    Andin, Josefine
    et al.
    Linköpings universitet, Institutionen för beteendevetenskap och lärande, Handikappvetenskap. Linköpings universitet, Filosofiska fakulteten.
    Dahlström, Örjan
    Linköpings universitet, Institutionen för beteendevetenskap och lärande, Handikappvetenskap. Linköpings universitet, Filosofiska fakulteten.
    Fransson, Peter
    Karolinska institutet, Department of Clinical Neuroscience.
    Rönnberg, Jerker
    Linköpings universitet, Institutionen för beteendevetenskap och lärande, Handikappvetenskap. Linköpings universitet, Filosofiska fakulteten.
    Rudner, Mary
    Linköpings universitet, Institutionen för beteendevetenskap och lärande, Handikappvetenskap. Linköpings universitet, Filosofiska fakulteten.
    Greater reliance on magnitude manipulation during mental arithmetic in deaf signers compared to hearing non-signers: fMRI evidence2015Konferansepaper (Fagfellevurdert)
    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.

  • 14.
    Andin, Josefine
    et al.
    Linköpings universitet, Institutionen för beteendevetenskap och lärande, Handikappvetenskap. Linköpings universitet, Filosofiska fakulteten. Linköpings universitet, Institutet för handikappvetenskap (IHV). Orebro Univ, Sweden.
    Elwér, Åsa
    Linköpings universitet, Institutionen för beteendevetenskap och lärande, Pedagogik och didaktik. Linköpings universitet, Utbildningsvetenskap.
    Maki-Torkko, Elina
    Orebro Univ, Sweden.
    Arithmetic in the adult deaf signing brain2020Inngår i: Journal of Neuroscience Research, ISSN 0360-4012, E-ISSN 1097-4547, Vol. 98, nr 4, s. 643-654Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We have previously shown that deaf signers recruit partially different brain regions during simple arithmetic compared to a group of hearing non-signers, despite similar performance. Specifically, hearing individuals show more widespread activation in brain areas that have been related to the verbal system of numerical processing, i.e., the left angular and inferior frontal gyrus, whereas deaf individuals engaged brain areas that have been related to the quantity system of numerical processing, i.e., the right horizontal intraparietal sulcus. This indicates that compared to hearing non-signers, deaf signers can successfully make use of processes located in partially different brain areas during simple arithmetic. In this study, which is a conceptual replication and extension of the above-presented study, the main aim is to understand similarities and differences in neural correlates supporting arithmetic in deaf compared to hearing individuals. The primary objective is to investigate the role of the right horizontal intraparietal gyrus, the left inferior frontal gyrus, the hippocampus, and the left angular gyrus during simple and difficult arithmetic and how these regions are connected to each other. A second objective is to explore what other brain regions support arithmetic in deaf signers. Up to 34 adult deaf signers and the same amount of hearing non-signers will be enrolled in an functional magnetic resonance imaging study that will include simple and difficult subtraction and multiplication. Brain imaging data will be analyzed using whole-brain analysis, region of interest analysis and connectivity analysis. This is the first study to investigate neural underpinnings of arithmetic of different difficulties in deaf individuals.

    Fulltekst (pdf)
    fulltext
  • 15.
    Andin, Josefine
    et al.
    Linköpings universitet, Institutionen för beteendevetenskap och lärande, Avdelningen för funktionsnedsättning och samhälle. Linköpings universitet, Filosofiska fakulteten.
    Elwér, Åsa
    Linköpings universitet, Institutionen för beteendevetenskap och lärande, Pedagogik och didaktik. Linköpings universitet, Utbildningsvetenskap.
    Mäki-Torkko, Elina
    Örebro University, Sweden.
    Arithmetic in the signing brain: Differences and similarities in arithmetic processing between deaf signers and hearing non-signers2023Inngår i: Journal of Neuroscience Research, ISSN 0360-4012, E-ISSN 1097-4547, Vol. 101, nr 1, s. 172-195Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Deaf signers and hearing non-signers have previously been shown to recruit partially different brain regions during simple arithmetic. In light of the triple code model, the differences were interpreted as relating to stronger recruitment of the verbal system of numerical processing, that is, left angular and inferior frontal gyrus, in hearing non-signers, and of the quantity system of numerical processing, that is, right horizontal intraparietal sulcus, for deaf signers. The main aim of the present study was to better understand similarities and differences in the neural correlates supporting arithmetic in deaf compared to hearing individuals. Twenty-nine adult deaf signers and 29 hearing non-signers were enrolled in an functional magnetic resonance imaging study of simple and difficult subtraction and multiplication. Brain imaging data were analyzed using whole-brain analysis, region of interest analysis, and functional connectivity analysis. Although the groups were matched on age, gender, and nonverbal intelligence, the deaf group performed generally poorer than the hearing group in arithmetic. Nevertheless, we found generally similar networks to be involved for both groups, the only exception being the involvement of the left inferior frontal gyrus. This region was activated significantly stronger for the hearing compared to the deaf group but showed stronger functional connectivity with the left superior temporal gyrus in the deaf, compared to the hearing, group. These results lend no support to increased recruitment of the quantity system in deaf signers. Perhaps the reason for performance differences is to be found in other brain regions not included in the original triple code model.

    Fulltekst (pdf)
    fulltext
  • 16.
    Andin, Josefine
    et al.
    Linköpings universitet, Institutionen för beteendevetenskap och lärande, Handikappvetenskap. Linköpings universitet, Filosofiska fakulteten. Linköpings universitet, Institutet för handikappvetenskap (IHV).
    Fransson, Peter
    Karolinska Inst, Sweden.
    Dahlström, Örjan
    Linköpings universitet, Institutionen för beteendevetenskap och lärande, Psykologi. Linköpings universitet, Filosofiska fakulteten. Linköpings universitet, Institutet för handikappvetenskap (IHV).
    Rönnberg, Jerker
    Linköpings universitet, Institutionen för beteendevetenskap och lärande, Handikappvetenskap. Linköpings universitet, Filosofiska fakulteten. Linköpings universitet, Institutet för handikappvetenskap (IHV).
    Rudner, Mary
    Linköpings universitet, Institutionen för beteendevetenskap och lärande, Handikappvetenskap. Linköpings universitet, Filosofiska fakulteten. Linköpings universitet, Institutet för handikappvetenskap (IHV).
    The neural basis of arithmetic and phonology in deaf signing individuals2019Inngår i: Language, Cognition and Neuroscience, ISSN 2327-3798, E-ISSN 2327-3801, Vol. 34, nr 7, s. 813-825Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Deafness is generally associated with poor mental arithmetic, possibly due to neuronal differences in arithmetic processing across language modalities. Here, we investigated for the first time the neuronal networks supporting arithmetic processing in adult deaf signers. Deaf signing adults and hearing non-signing peers performed arithmetic and phonological tasks during fMRI scanning. At whole brain level, activation patterns were similar across groups. Region of interest analyses showed that although both groups activated phonological processing regions in the left inferior frontal gyrus to a similar extent during both phonological and multiplication tasks, deaf signers showed significantly more activation in the right horizontal portion of the inferior parietal sulcus. This region is associated with magnitude manipulation along the mental number line. This pattern of results suggests that deaf signers rely more on magnitude manipulation than hearing non-signers during multiplication, but that phonological involvement does not differ significantly between groups.Abbreviations: AAL: Automated Anatomy Labelling; fMRI: functional magnetic resonance imaging; HIPS: horizontal portion of the intraparietal sulcus; lAG: left angular gyrus; lIFG: left inferior frontal gyrus; rHIPS: right horizontal portion of the intraparietal sulcus

    Fulltekst (pdf)
    fulltext
  • 17.
    Andin, Josefine
    et al.
    Linköpings universitet, Institutionen för beteendevetenskap och lärande, Handikappvetenskap. Linköpings universitet, Filosofiska fakulteten.
    Holmer, Emil
    Linköpings universitet, Institutionen för beteendevetenskap och lärande, Handikappvetenskap. Linköpings universitet, Filosofiska fakulteten. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    Reorganization of large-scale brain networks in deaf signing adults: The role of auditory cortex in functional reorganization following deafness2022Inngår i: Neuropsychologia, ISSN 0028-3932, E-ISSN 1873-3514, Vol. 166, artikkel-id 108139Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    If the brain is deprived of input from one or more senses during development, functional and structural reorganization of the deprived regions takes place. However, little is known about how sensory deprivation affects large-scale brain networks. In the present study, we use data-driven independent component analysis (ICA) to characterize large-scale brain networks in 15 deaf early signers and 24 hearing non-signers based on resting-state functional MRI data. We found differences between the groups in independent components representing the left lateralized control network, the default network, the ventral somatomotor network, and the attention network. In addition, we showed stronger functional connectivity for deaf compared to hearing individuals from the middle and superior temporal cortices to the cingulate cortex, insular cortex, cuneus and precuneus, supramarginal gyrus, supplementary motor area, and cerebellum crus 1, and stronger connectivity for hearing non-signers to hippocampus, middle and superior frontal gyri, pre- and postcentral gyri, and cerebellum crus 8. These results show that deafness induces large-scale network reorganization, with the middle/superior temporal cortex as a central node of plasticity. Cross-modal reorganization may be associated with behavioral adaptations to the environment, including superior ability in some visual functions such as visual working memory and visual attention, in deaf signers.

    Fulltekst (pdf)
    fulltext
  • 18.
    Andin, Josefine
    et al.
    Linköpings universitet, Institutionen för beteendevetenskap och lärande, Handikappvetenskap. Linköpings universitet, Filosofiska fakulteten.
    Holmer, Emil
    Linköpings universitet, Institutionen för beteendevetenskap och lärande, Handikappvetenskap. Linköpings universitet, Filosofiska fakulteten.
    Krister, Schönström
    Department of Linguistics, Stockholm University, Stockholm, Sweden.
    Rudner, Mary
    Linköpings universitet, Institutionen för beteendevetenskap och lärande, Psykologi. Linköpings universitet, Filosofiska fakulteten. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV. Swedish Institute for Disability Research, Linnaeus Centre HEAD, Sweden.
    Working Memory for Signs with Poor Visual Resolution: fMRI Evidence of Reorganizationof Auditory Cortex in Deaf Signers2021Inngår i: Cerebral Cortex, ISSN 1047-3211, E-ISSN 1460-2199, Vol. 31, nr 7, s. 3165-3176Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Stimulus degradation adds to working memory load during speech processing.We investigated whether this applies to signprocessing and, if so, whether the mechanism implicates secondary auditory cortex.We conducted an fMRI experimentwhere 16 deaf early signers (DES) and 22 hearing non-signers performed a sign-based n-back task with three load levels andstimuli presented at high and low resolution.We found decreased behavioral performance with increasing load anddecreasing visual resolution, but the neurobiological mechanisms involved differed between the two manipulations and didso for both groups. Importantly, while the load manipulation was, as predicted, accompanied by activation in thefrontoparietal working memory network, the resolution manipulation resulted in temporal and occipital activation.Furthermore, we found evidence of cross-modal reorganization in the secondary auditory cortex: DES had strongeractivation and stronger connectivity between this and several other regions.We conclude that load and stimulus resolutionhave different neural underpinnings in the visual–verbal domain, which has consequences for current working memorymodels, and that for DES the secondary auditory cortex is involved in the binding of representations when task demandsare low.

    Fulltekst (pdf)
    fulltext
  • 19.
    Antelius, Eleonor
    et al.
    Linköpings universitet, Institutionen för samhälls- och välfärdsstudier, Avdelningen Åldrande och social förändring. Linköpings universitet, Filosofiska fakulteten.
    Kiwi, Mahin
    Linköpings universitet, Institutionen för samhälls- och välfärdsstudier, Avdelningen Åldrande och social förändring. Linköpings universitet, Filosofiska fakulteten.
    Strandroos, Lisa
    Linköpings universitet, Institutionen för samhälls- och välfärdsstudier, Avdelningen Åldrande och social förändring. Linköpings universitet, Filosofiska fakulteten.
    Ethnographic methods for understanding practices around dementia among culturally and linguistically diverse people2018Inngår i: Social research methods in dementia studies: inclusion and innovation / [ed] John Keady, Lars-Christer Hydén, Ann Johnson, Caroline Swarbrick, Abingdon, Oxon: Routledge, 2018, s. 121-139Kapittel i bok, del av antologi (Annet vitenskapelig)
  • 20.
    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
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    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
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Närsjukvården i centrala Östergötland, Psykiatriska kliniken.
    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 humans2018Inngår i: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 23, nr 6, s. 1466-1473Artikkel i tidsskrift (Fagfellevurdert)
    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.

    Fulltekst (pdf)
    fulltext
  • 21.
    Augier, Eric
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Dulman, Russell S.
    NIAAA, MD USA.
    Damadzic, Ruslan
    NIAAA, MD USA.
    Pilling, Andrew
    NIAAA, MD USA.
    Hamilton, Paul
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Heilig, Markus
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Närsjukvården i centrala Östergötland, Psykiatriska kliniken.
    The GABA(B) Positive Allosteric Modulator ADX71441 Attenuates Alcohol Self-Administration and Relapse to Alcohol Seeking in Rats2017Inngår i: Neuropsychopharmacology, ISSN 0893-133X, E-ISSN 1740-634X, Vol. 42, nr 9, s. 1789-1799Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 22.
    Awad, Amar
    et al.
    Umea Univ, Sweden.
    Levi, Richard
    Linköpings universitet, Institutionen för hälsa, medicin och vård, Avdelningen för prevention, rehabilitering och nära vård. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Rehabiliteringsmedicinska kliniken.
    Waller, Mikael
    Sunderby Hosp, Sweden.
    Westling, Goran
    Umea Univ, Sweden.
    Lindgren, Lenita
    Umea Univ, Sweden.
    Eriksson, Johan
    Umea Univ, Sweden.
    Preserved somatosensory conduction in complete spinal cord injury: Discomplete SCI2020Inngår i: Clinical Neurophysiology, ISSN 1388-2457, E-ISSN 1872-8952, Vol. 131, nr 5, s. 1059-1067Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: Spinal cord injury (SCI) disrupts the communication between brain and body parts innervated from below-injury spinal segments, but rarely results in complete anatomical transection of the spinal cord. The aim of this study was to investigate residual somatosensory conduction in clinically complete SCI, to corroborate the concept of sensory discomplete SCI. Methods: We used fMRI with a somatosensory protocol in which blinded and randomized tactile and nociceptive stimulation was applied on both legs (below-injury level) and one arm (above-injury level) in eleven participants with chronic complete SCI. The experimental design accounts for possible confounding mechanical (e.g. vibration) and cortico-cortical top-down mechanisms (e.g. attention/expectation). Results: Somatosensory stimulation on below-level insensate body regions activated the somatotopically corresponding part of the contralateral primary somatosensory cortex in six out of eleven participants. Conclusions: Our results represent afferent-driven cortical activation through preserved somatosensory connections to the brain in a subgroup of participants with clinically complete SCI, i.e. sensory discomplete SCI. Significance: Identifying patients with residual somatosensory connections might open the door for new rehabilitative and restorative strategies as well as inform research on SCI-related conditions such as neuropathic pain and spasticity. (C) 2020 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.

  • 23.
    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 activity2017Inngår i: PLoS biology, ISSN 1544-9173, E-ISSN 1545-7885, Vol. 15, nr 3, artikkel-id e2000698Artikkel i tidsskrift (Fagfellevurdert)
    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.

    Fulltekst (pdf)
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  • 24. Bestill onlineKjøp publikasjonen >>
    Aziz, Abdul Maruf Asif
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Neuropeptide Receptors as Treatment Targets in Alcohol Use Disorders2017Doktoravhandling, med artikler (Annet vitenskapelig)
    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.

    Delarbeid
    1. The nociceptin/orphanin FQ receptor agonist SR-8993 as a candidate therapeutic for alcohol use disorders: validation in rat models
    Åpne denne publikasjonen i ny fane eller vindu >>The nociceptin/orphanin FQ receptor agonist SR-8993 as a candidate therapeutic for alcohol use disorders: validation in rat models
    Vise andre…
    2016 (engelsk)Inngår i: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 233, nr 19-20, s. 3553-3563Artikkel i tidsskrift (Fagfellevurdert) 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.

    sted, utgiver, år, opplag, sider
    Springer, 2016
    Emneord
    Nociception/orphanin FQ, Agonist, Wistar rat, Alcohol, Operant, Reinstatement, Elevated plus-maze
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-132347 (URN)10.1007/s00213-016-4385-8 (DOI)000383672500006 ()27515665 (PubMedID)
    Merknad

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

    Tilgjengelig fra: 2016-11-12 Laget: 2016-11-01 Sist oppdatert: 2017-08-21bibliografisk kontrollert
    2. Melanin-Concentrating Hormone and Its MCH-1 Receptor: Relationship Between Effects on Alcohol and Caloric Intake
    Åpne denne publikasjonen i ny fane eller vindu >>Melanin-Concentrating Hormone and Its MCH-1 Receptor: Relationship Between Effects on Alcohol and Caloric Intake
    Vise andre…
    2016 (engelsk)Inngår i: Alcoholism: Clinical and Experimental Research, ISSN 0145-6008, E-ISSN 1530-0277, Vol. 40, nr 10, s. 2199-2207Artikkel i tidsskrift (Fagfellevurdert) 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.

    sted, utgiver, år, opplag, sider
    Wiley-Blackwell, 2016
    Emneord
    Alcohol Escalation, Reward, Motivation, Calorie Intake, Melanin-Concentrating Hormone Receptor-1
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-132522 (URN)10.1111/acer.13181 (DOI)000385542900017 ()27579857 (PubMedID)
    Tilgjengelig fra: 2016-11-14 Laget: 2016-11-13 Sist oppdatert: 2018-03-19bibliografisk kontrollert
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    Neuropeptide Receptors as Treatment Targets in Alcohol Use Disorders
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  • 25.
    Bang, Peter
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Igelström, Kajsa
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Modality-specific associations of sensory deficits with autistic traitsManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Background

    Atypical sensory processing measured by self- or parent-report co-segregates with quantitative autistic traits (QAT) and has potential endophenotypic properties relevant to the mechanisms of autism. However, it is not known whether this association reflects a generalized sensory dysfunction or combinations of modality-specific mechanisms. Collinearity between QAT and modality-specific sensory scales limits the use of multiple regression to determine relative importance. Therefore, we combined a Bayesian variable selection method with dominance analysis to obtain a more nuanced understanding of potential modality-specific associations.

    Methods

    We recruited two independent cohorts of adults online to complete the Broad Autism Phenotype Questionnaire and the Glasgow Sensory Questionnaire (N = 592 in total). Subscale scores were derived for social, communicative, and rigid QAT and for the visual, auditory, tactile, olfactory, gustatory, proprioceptive, and vestibular sensory modalities. For each QAT, we performed a stochastic search variable selection (SSVS) procedure on the sensory modality subscales to test which sensory modalities predicted QAT while controlling for uncertainty in the other variables. Dominance analysis was then applied to the models identified by the SSVS to evaluate the relative importance of sensory modalities in predicting QAT.

    Results

    Only auditory scores reliably predicted all three QAT. The proprioceptive scale, which included motor and interoceptive deficits, specifically predicted communicative QAT. The tactile scale, which included touch sensitivity and atypical pain/temperature processing, specifically predicted social QAT.

    Limitations

    The findings must be interpreted in light of limitations of the Glasgow Sensory Questionnaire. For example, associations between QAT and visual, olfactory, gustatory, or vestibular modalities might appear if measured in a different way. The study relied on self-report by anonymous participants, which precluded clinical evaluation of sensory difficulties. It is also important to note that the modalities found to lack associations with QAT are nevertheless known to be clinically significant in autism.

    Conclusions

    Auditory processing deficits, such as noise sensitivity, strongly predicted all QAT, whereas other sensory modalities did not. Thus, auditory processing could be further studied as a potential sensory endophenotype for autism. The results also indicate potential roles for tactile dysfunction in atypical social interaction and proprioceptive/motor dysfunction in pragmatic language. 

  • 26.
    Barbier, Estelle
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Barchiesi, Riccardo
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Domi, Ana
    Univ Gothenburg, Sweden.
    Chanthongdee, Kanat
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten. Mahidol Univ, Thailand.
    Domi, Esi
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Augier, Gaëlle
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Augier, Eric
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Xu, Li
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten. Sichuan Prov Peoples Hosp, Peoples R China.
    Adermark, Louise
    Univ Gothenburg, Sweden.
    Heilig, Markus
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Psykiatricentrum, Psykiatriska kliniken i Linköping.
    Downregulation of Synaptotagmin 1 in the Prelimbic Cortex Drives Alcohol-Associated Behaviors in Rats2021Inngår i: Biological Psychiatry, ISSN 0006-3223, E-ISSN 1873-2402, Vol. 89, nr 4, s. 398-406Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Alcohol addiction is characterized by persistent neuroadaptations in brain structures involved in motivation, emotion, and decision making, including the medial prefrontal cortex, the nucleus accumbens, and the amygdala. We previously reported that induction of alcohol dependence was associated with long-term changes in the expression of genes involved in neurotransmitter release. Specifically, Syt1, which plays a key role in neurotransmitter release and neuronal functions, was downregulated. Here, we therefore examined the role of Syt1 in alcohol-associated behaviors in rats. METHODS: We evaluated the effect of Syt1 downregulation using an adeno-associated virus (AAV) containing a short hairpin RNA against Syt1. Cre-dependent Syt1 was also used in combination with an rAAV2 retro-Cre virus to assess circuit-specific effects of Syt1 knockdown (KD). RESULTS: Alcohol-induced downregulation of Syt1 is specific to the prelimbic cortex (PL), and KD of Syt1 in the PL resulted in escalated alcohol consumption, increased motivation to consume alcohol, and increased alcohol drinking despite negative consequences ("compulsivity"). Syt1 KD in the PL altered the excitation/inhibition balance in the basolateral amygdala, while the nucleus accumbens core was unaffected. Accordingly, a projection-specific Syt1 KD in the PL-basolateral amygdala projection was sufficient to increase compulsive alcohol drinking, while a KD of Syt1 restricted to PL-nucleus accumbens core projecting neurons had no effect on tested alcohol-related behaviors. CONCLUSIONS: Together, these data suggest that dysregulation of Syt1 is an important mechanism in long-term neuroadaptations observed after a history of alcohol dependence, and that Syt1 regulates alcohol-related behaviors in part by affecting a PL-basolateral amygdala brain circuit.

    Fulltekst (pdf)
    fulltext
  • 27.
    Barbier, Estelle
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Heilig, Markus
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Närsjukvården i centrala Östergötland, Psykiatriska kliniken.
    mTORC and ProSAPiP1: How Alcohol Changes Synapses of Reward Circuitry2017Inngår i: Neuron, ISSN 0896-6273, E-ISSN 1097-4199, Vol. 96, nr 1Artikkel i tidsskrift (Annet vitenskapelig)
    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.

  • 28.
    Barbier, Estelle
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    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
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    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
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Wahlestedt, C.
    University of Miami, FL 33136 USA; University of Miami, FL 33136 USA.
    Heilig, Markus
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Närsjukvården i centrala Östergötland, Psykiatriska kliniken. NIAAA, MD USA.
    Dependence-induced increase of alcohol self-administration and compulsive drinking mediated by the histone methyltransferase PRDM22017Inngår i: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 22, nr 12, s. 1746-1758Artikkel i tidsskrift (Fagfellevurdert)
    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.

    Fulltekst (pdf)
    fulltext
  • 29.
    Barchiesi, Riccardo
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Chanthongdee, Kanat
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten. Mahidol Univ, Thailand.
    Petrella, Michele
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Xu, Li
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Söderholm, Simon
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för molekylär medicin och virologi. Linköpings universitet, Medicinska fakulteten.
    Domi, Esi
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Augier, Gaëlle
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Coppola, Andrea
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Wiskerke, Joost
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Szczot, Ilona
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Domi, Ana
    Univ Gothenburg, Sweden.
    Adermark, Louise
    Univ Gothenburg, Sweden.
    Augier, Eric
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Cantù, Claudio
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för molekylär medicin och virologi. Linköpings universitet, Medicinska fakulteten.
    Heilig, Markus
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Psykiatricentrum, Psykiatriska kliniken i Linköping.
    Barbier, Estelle
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    An epigenetic mechanism for over-consolidation of fear memories2022Inngår i: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 27, nr 12, s. 4893-4904Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Excessive fear is a hallmark of anxiety disorders, a major cause of disease burden worldwide. Substantial evidence supports a role of prefrontal cortex-amygdala circuits in the regulation of fear and anxiety, but the molecular mechanisms that regulate their activity remain poorly understood. Here, we show that downregulation of the histone methyltransferase PRDM2 in the dorsomedial prefrontal cortex enhances fear expression by modulating fear memory consolidation. We further show that Prdm2 knock-down (KD) in neurons that project from the dorsomedial prefrontal cortex to the basolateral amygdala (dmPFC-BLA) promotes increased fear expression. Prdm2 KD in the dmPFC-BLA circuit also resulted in increased expression of genes involved in synaptogenesis, suggesting that Prdm2 KD modulates consolidation of conditioned fear by modifying synaptic strength at dmPFC-BLA projection targets. Consistent with an enhanced synaptic efficacy, we found that dmPFC Prdm2 KD increased glutamatergic release probability in the BLA and increased the activity of BLA neurons in response to fear-associated cues. Together, our findings provide a new molecular mechanism for excessive fear responses, wherein PRDM2 modulates the dmPFC -BLA circuit through specific transcriptomic changes.

    Fulltekst (pdf)
    fulltext
  • 30.
    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
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten.
    Theodorsson, Elvar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    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 peptide2016Inngår i: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, ISSN 0027-8424, Vol. 113, nr 52, s. E8472-E8481Artikkel i tidsskrift (Fagfellevurdert)
    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.

    Fulltekst (pdf)
    fulltext
  • 31.
    Barros Da Cunha, Felipe
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    Stingo Hirmas, Diego Vittorio
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    Cardoso, Rita France
    Linköpings universitet, Institutionen för fysik, kemi och biologi. Linköpings universitet, Tekniska fakulteten.
    Wright, Dominic
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    Henriksen, Rie
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    Neuronal and non-neuronal scaling across brain regions within an intercross of domestic and wild chickens2022Inngår i: Frontiers in Neuroanatomy, E-ISSN 1662-5129, Vol. 16, artikkel-id 1048261Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The allometric scaling of the brain size and neuron number across species has been extensively studied in recent years. With the exception of primates, parrots, and songbirds, larger brains have more neurons but relatively lower neuronal densities than smaller brains. Conversely, when considering within-population variability, it has been shown that mice with larger brains do not necessarily have more neurons but rather more neurons in the brain reflect higher neuronal density. To what extent this intraspecific allometric scaling pattern of the brain applies to individuals from other species remains to be explored. Here, we investigate the allometric relationships among the sizes of the body, brain, telencephalon, cerebellum, and optic tectum, and the numbers of neurons and non-neuronal cells of the telencephalon, cerebellum, and optic tectum across 66 individuals originated from an intercross between wild and domestic chickens. Our intercross of chickens generates a population with high variation in brain size, making it an excellent model to determine the allometric scaling of the brain within population. Our results show that larger chickens have larger brains with moderately more neurons and non-neuronal cells. Yet, absolute number of neurons and non-neuronal cells correlated strongly and positively with the density of neurons and non-neuronal cells, respectively. As previously shown in mice, this scaling pattern is in stark contrast with what has been found across different species. Our findings suggest that neuronal scaling rules across species are not a simple extension of the neuronal scaling rules that apply within a species, with important implications for the evolutionary developmental origins of brain diversity.

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    fulltext
  • 32.
    Barry, Melissa
    et al.
    Department of Anatomy and the Brain Health Research Centre, University of Otago, Dunedin, New Zealand.
    Boddington, Laura
    Department of Anatomy and the Brain Health Research Centre, University of Otago, Dunedin, New Zealand.
    Igelström, Kajsa
    Department of Anatomy and the Brain Health Research Centre, University of Otago, Dunedin, New Zealand.
    Gray, Jason
    Department of Anatomy and the Brain Health Research Centre, University of Otago, Dunedin, New Zealand.
    Shemmell, Jon
    School of Physical Education and the Brain Health Research Centre, University of Otago, Dunedin, New Zealand.
    Tseng, K-Y
    Department of Cellular & Molecular Pharmacology, The Chicago Medical School, Rosalind Franklin University of Medicine & Science, North Chicago, IL, USA.
    Oorschot, Dorothy
    Department of Anatomy and the Brain Health Research Centre, University of Otago, Dunedin, New Zealand.
    Reynolds, John
    Department of Anatomy and the Brain Health Research Centre, University of Otago, Dunedin, New Zealand.
    Utility of intracerebral theta burst electrical stimulation to attenuate interhemispheric inhibition and to promote motor recovery after cortical injury in an animal model2014Inngår i: Experimental Neurology, ISSN 0014-4886, E-ISSN 1090-2430, Vol. 261, s. 258-266Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Following a cerebral cortex injury such as stroke, excessive inhibition around the core of the injury is thought to reduce the potential for new motor learning. In part, this may be caused by an imbalance of interhemispheric inhibition (IHI); therefore, treatments that relieve the inhibitory drive from the healthy hemisphere to the peri-lesional area may enhance motor recovery. Theta burst stimulation delivered by transcranial magnetic stimulation has been tested as a means of normalizing IHI, but clinical results have been variable. Here we use a new rat model of synaptic IHI to demonstrate that electrical intracranial theta burst stimulation causes long-lasting changes in motor cortex excitability. Further, we show that contralateral intermittent theta burst stimulation (iTBS) blocks IHI via a mechanism involving cannabinoid receptors. Finally, we show that contralesional iTBS applied during recovery from cortical injury in rats improves the recovery of motor function. These findings suggest that theta burst stimulation delivered through implanted electrodes may be a promising avenue to explore for augmenting rehabilitation from brain injury.

  • 33.
    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 measurements2010Inngår i: Conference proceedings from the 12th International Workshop for Young Mathematicians "Probability and Statistics", Krakow, Poland, 20th till 26th September 2009, 2010, s. 21-42Konferansepaper (Annet vitenskapelig)
    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.

  • 34. Bestill onlineKjøp publikasjonen >>
    Bauer, Susanne
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Cell type-specific translatome analysis of mouse models of three genetic neurodegenerative diseases2023Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The burden neurodegenerative diseases place on patients, their loved ones, and the healthcare system is significant, and despite extensive research efforts, there is currently no cure. Since degenerative changes in the brain can begin years before symptoms appear, early intervention is critical. Additionally, neurodegenerative diseases target certain brain regions and neuron types early on. A more comprehensive understanding of the affected cells during the presymptomatic phase is therefore crucial for an effective and targeted intervention. 

    Herein, we isolated, sequenced, and analyzed translatome samples from six neuronal cell types in knock-in mouse models of three monogenic neurodegenerative diseases at a presymptomatic stage: genetic Creutzfeldt-Jakob disease (gCJD), fatal familial insomnia (FFI), and Huntington’s disease (HD). To obtain the translatome samples, we used RiboTag to immunoprecipitate HA-tagged ribosomes with their translating mRNAs from targeted cell types. We analyzed six cell types across two brain regions: cerebral and cerebellar glutamatergic and GABAergic neurons, and cerebral parvalbumin (PV) and somatostatin (SST)-expressing neurons. 

    In the first paper, we focused our analysis on the prion diseases, gCJD (E200K) and FFI (D178N). Here observed a similar response of SST+ neurons, a cell type not previously reported as affected, in both disease models. This was characterized by upregulation of ribosomeassociated genes, and downregulation of cytoskeleton and synapse-associated genes in FFI. Weighted gene co-expression network analysis of SST+ neurons pointed towards the downregulation of mTOR inhibition as a potential mechanism underlying the observed gene expression changes. 

    In the second paper, we analyzed a 129S4-HdhQ200 knock-in mouse model of HD. Histological and behavioral assessment revealed pathological changes in the striatum and cerebellum at 9 months and a later, mild behavioral phenotype. Translatome analysis indicated a surprisingly strong response in reportedly resistant glutamatergic neurons of the cerebellum, marked by upregulation of cell cycle regulators Ccnd1 and chromobox protein genes. 

    In the third paper, we aimed to compare disease-specific responses of PV+ neurons across the three disease models. This analysis revealed a milder response in HD compared to prion disease at comparable disease stages. Functional analysis further indicated PV+ neurons may respond differently in the investigated diseases, showing upregulation of immune response-associated pathways in gCJD, neurodegenerative-disease pathways in FFI, and autophagy in HD. 

    Lastly, the generation of mouse models such as were used in papers I-III requires stable and predictable transgene expression without interfering with the expression of endogenous genes. In the fourth paper, we conducted a pilot study to compare three potential loci, Rpl6, Rpl7, and Eef1a1, as potential safe harbors for transgene integration. Preliminary results indicated that the Rpl6 locus may be best suited for our purposes. 

    Furthermore, this work generated a novel dataset consisting of translatome profiles of six cell types in three neurodegenerative disease models. This provides gene expression data at a previously unavailable level of cellular resolution, especially in prion disease. We believe that this data will serve as a valuable resource for future research and help expand our understanding of the early molecular mechanisms in neurodegenerative disease beyond the scope of this thesis. 

    Delarbeid
    1. Translatome profiling in fatal familial insomnia implicates TOR signaling in somatostatin neurons
    Åpne denne publikasjonen i ny fane eller vindu >>Translatome profiling in fatal familial insomnia implicates TOR signaling in somatostatin neurons
    Vise andre…
    2022 (engelsk)Inngår i: Life Science Alliance, E-ISSN 2575-1077, Vol. 5, nr 11, artikkel-id e202201530Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Selective neuronal vulnerability is common in neurodegenerative diseases but poorly understood. In genetic prion diseases, in-cluding fatal familial insomnia (FFI) and Creutzfeldt-Jakob dis-ease (CJD), different mutations in the Prnp gene manifest as clinically and neuropathologically distinct diseases. Here we report with electroencephalography studies that theta waves are mildly increased in 21 mo old knock-in mice modeling FFI and CJD and that sleep is mildy affected in FFI mice. To define affected cell types, we analyzed cell type-specific translatomes from six neuron types of 9 mo old FFI and CJD mice. Somatostatin (SST) neurons responded the strongest in both diseases, with unex-pectedly high overlap in genes and pathways. Functional analyses revealed up-regulation of neurodegenerative disease pathways and ribosome and mitochondria biogenesis, and down-regulation of synaptic function and small GTPase-mediated signaling in FFI, implicating down-regulation of mTOR signaling as the root of these changes. In contrast, responses in glutamatergic cerebellar neurons were disease-specific. The high similarity in SST neurons of FFI and CJD mice suggests that a common therapy may be beneficial for multiple genetic prion diseases.

    sted, utgiver, år, opplag, sider
    Life Science Allience, 2022
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-189755 (URN)10.26508/lsa.202201530 (DOI)000870440200001 ()36192034 (PubMedID)
    Merknad

    Funding Agencies|Swedish Research Council [2018-05973]; Swedish Bioinformatics Advisory Program - National Bioinformatics Infrastructure Sweden (NBIS); Knut and Alice Wallenberg foundation; German Center for Neurodegenerative Diseases (DZNE)

    Tilgjengelig fra: 2022-11-07 Laget: 2022-11-07 Sist oppdatert: 2023-04-28
    2. Cerebellar granule neurons induce Cyclin D1 before the onset of motor symptoms in Huntingtons disease mice
    Åpne denne publikasjonen i ny fane eller vindu >>Cerebellar granule neurons induce Cyclin D1 before the onset of motor symptoms in Huntingtons disease mice
    Vise andre…
    2023 (engelsk)Inngår i: Acta neuropathologica communications, E-ISSN 2051-5960, Vol. 11, nr 1, artikkel-id 17Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Although Huntingtons disease (HD) is classically defined by the selective vulnerability of striatal projection neurons, there is increasing evidence that cerebellar degeneration modulates clinical symptoms. However, little is known about cell type-specific responses of cerebellar neurons in HD. To dissect early disease mechanisms in the cerebellum and cerebrum, we analyzed translatomes of neuronal cell types from both regions in a new HD mouse model. For this, HdhQ200 knock-in mice were backcrossed with the calm 129S4 strain, to constrain experimental noise caused by variable hyperactivity of mice in a C57BL/6 background. Behavioral and neuropathological characterization showed that these S4-HdhQ200 mice had very mild behavioral abnormalities starting around 12 months of age that remained mild up to 18 months. By 9 months, we observed abundant Huntingtin-positive neuronal intranuclear inclusions (NIIs) in the striatum and cerebellum. The translatome analysis of GABAergic cells of the cerebrum further confirmed changes typical of HD-induced striatal pathology. Surprisingly, we observed the strongest response with 626 differentially expressed genes in glutamatergic neurons of the cerebellum, a population consisting primarily of granule cells, commonly considered disease resistant. Our findings suggest vesicular fusion and exocytosis, as well as differentiation-related pathways are affected in these neurons. Furthermore, increased expression of cyclin D1 (Ccnd1) in the granular layer and upregulated expression of polycomb group complex protein genes and cell cycle regulators Cbx2, Cbx4 and Cbx8 point to a putative role of aberrant cell cycle regulation in cerebellar granule cells in early disease.

    sted, utgiver, år, opplag, sider
    BMC, 2023
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-191739 (URN)10.1186/s40478-022-01500-x (DOI)000918127100001 ()36670467 (PubMedID)
    Merknad

    Funding Agencies|Linkoeping University; German Center for Neurodegenerative Diseases; Wallenberg Center for Molecular Medicine at Linkoeping University; Knut and Alice Wallenberg Foundation [KAW 2019-0047]; Swedish Research Council [2018-05973]

    Tilgjengelig fra: 2023-02-13 Laget: 2023-02-13 Sist oppdatert: 2023-04-28
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  • 35.
    Bauer, Susanne
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Chen, Chwen-Yu
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Jonson, Maria
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Kaczmarczyk, Lech
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för neurobiologi. Linköpings universitet, Medicinska fakulteten. German Ctr Neurodegenerat Dis, Germany.
    Magadi, Srivathsa
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Jackson, Walker
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för neurobiologi. Linköpings universitet, Medicinska fakulteten. German Ctr Neurodegenerat Dis, Germany.
    Cerebellar granule neurons induce Cyclin D1 before the onset of motor symptoms in Huntingtons disease mice2023Inngår i: Acta neuropathologica communications, E-ISSN 2051-5960, Vol. 11, nr 1, artikkel-id 17Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Although Huntingtons disease (HD) is classically defined by the selective vulnerability of striatal projection neurons, there is increasing evidence that cerebellar degeneration modulates clinical symptoms. However, little is known about cell type-specific responses of cerebellar neurons in HD. To dissect early disease mechanisms in the cerebellum and cerebrum, we analyzed translatomes of neuronal cell types from both regions in a new HD mouse model. For this, HdhQ200 knock-in mice were backcrossed with the calm 129S4 strain, to constrain experimental noise caused by variable hyperactivity of mice in a C57BL/6 background. Behavioral and neuropathological characterization showed that these S4-HdhQ200 mice had very mild behavioral abnormalities starting around 12 months of age that remained mild up to 18 months. By 9 months, we observed abundant Huntingtin-positive neuronal intranuclear inclusions (NIIs) in the striatum and cerebellum. The translatome analysis of GABAergic cells of the cerebrum further confirmed changes typical of HD-induced striatal pathology. Surprisingly, we observed the strongest response with 626 differentially expressed genes in glutamatergic neurons of the cerebellum, a population consisting primarily of granule cells, commonly considered disease resistant. Our findings suggest vesicular fusion and exocytosis, as well as differentiation-related pathways are affected in these neurons. Furthermore, increased expression of cyclin D1 (Ccnd1) in the granular layer and upregulated expression of polycomb group complex protein genes and cell cycle regulators Cbx2, Cbx4 and Cbx8 point to a putative role of aberrant cell cycle regulation in cerebellar granule cells in early disease.

    Fulltekst (pdf)
    fulltext
  • 36.
    Bauer, Susanne
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Dittrich, Lars
    German Ctr Neurodegenerat Dis, Germany.
    Kaczmarczyk, Lech
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för neurobiologi. Linköpings universitet, Medicinska fakulteten. German Ctr Neurodegenerat Dis, Germany.
    Schleif, Melvin
    German Ctr Neurodegenerat Dis, Germany.
    Benfeitas, Rui
    Stockholm Univ, Sweden.
    Jackson, Walker
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för neurobiologi. Linköpings universitet, Medicinska fakulteten. German Ctr Neurodegenerat Dis, Germany.
    Translatome profiling in fatal familial insomnia implicates TOR signaling in somatostatin neurons2022Inngår i: Life Science Alliance, E-ISSN 2575-1077, Vol. 5, nr 11, artikkel-id e202201530Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Selective neuronal vulnerability is common in neurodegenerative diseases but poorly understood. In genetic prion diseases, in-cluding fatal familial insomnia (FFI) and Creutzfeldt-Jakob dis-ease (CJD), different mutations in the Prnp gene manifest as clinically and neuropathologically distinct diseases. Here we report with electroencephalography studies that theta waves are mildly increased in 21 mo old knock-in mice modeling FFI and CJD and that sleep is mildy affected in FFI mice. To define affected cell types, we analyzed cell type-specific translatomes from six neuron types of 9 mo old FFI and CJD mice. Somatostatin (SST) neurons responded the strongest in both diseases, with unex-pectedly high overlap in genes and pathways. Functional analyses revealed up-regulation of neurodegenerative disease pathways and ribosome and mitochondria biogenesis, and down-regulation of synaptic function and small GTPase-mediated signaling in FFI, implicating down-regulation of mTOR signaling as the root of these changes. In contrast, responses in glutamatergic cerebellar neurons were disease-specific. The high similarity in SST neurons of FFI and CJD mice suggests that a common therapy may be beneficial for multiple genetic prion diseases.

    Fulltekst (pdf)
    fulltext
  • 37.
    Bednarska, Olga
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Magtarmmedicinska kliniken.
    Peripheral and Central Mechanisms in Irritable Bowel Syndrome: in search of links2019Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Irritable bowel syndrome (IBS) is a chronic visceral pain disorder with female predominance, characterized by recurrent abdominal pain and disturbed bowel habits in the absence of an identifiable organic cause. This prevalent and debilitating disease, which accounts for a substantial economic and individual burden, lacks exact diagnostic tools and effective treatment, since its pathophysiology remains uncertain. The bidirectional and multilayered brain-gut axis is a well-established disease model, however, the interactions between central and peripheral mechanisms along the brain-gut axis remain incompletely understood. One of the welldescribed triggering factors, yet accounting for only a fraction of IBS prevalence, is bacterial gastroenteritis that affects mucosal barrier function. Altered gut microbiota composition as well as disturbed intestinal mucosal barrier function and its neuroimmune regulation have been reported in IBS, however, the impact of live bacteria, neither commensal nor pathogenic, on intestinal barrier has not been studied yet. Furthermore, abnormal central processing of visceral sensations and psychological factors such as maladaptive coping have previously been suggested as centrally-mediated pathophysiological mechanisms of importance in IBS. Brain imaging studies have demonstrated an imbalance in descending pain modulatory networks and alterations in brain regions associated with interoceptive awareness and pain processing and modulation, particularly in anterior insula (aINS), although biochemical changes putatively underlying these central alterations remain poorly understood. Most importantly, however, possible associations between these documented changes on central and peripheral levels, which may as complex interactions contribute to disease onset and chronification of symptoms, are widely unknown.

    This thesis aimed to investigate the peripheral and central mechanisms in women with IBS compared to female healthy controls (HC) and to explore possible mutual associations between these mechanisms.

    In Paper I, we studied paracellular permeability and passage of live bacteria, both commensal and pathogenic through colonic biopsies mounted in Ussing chambers. We explored the regulation of the mucosal barrier function by mast cells and the neuropeptide vasoactive intestinal polypeptide (VIP) as well as a correlation between mucosal permeability and gastrointestinal and psychological symptoms. We observed increased paracellular permeability and the passage of commensal and pathogenic live bacteria in patients with IBS compared with HC, which was diminished by blocking the VIP receptors as well as after stabilizing mast cells in both groups. Moreover, higher paracellular permeability was associated with less somatic and psychological symptoms in patients.

    In Paper II, we aimed to determine the association between colonic mucosa paracellular permeability and structural and resting state functional brain connectivity. We demonstrated different patterns of associations between mucosa permeability and functional and structural brain connectivity in IBS patients compared to HC. Specifically, lower paracellular permeability in IBS, similar to the levels detected in HC, was associated with more severe IBS symptoms and increased functional and structural connectivity between intrinsic brain resting state network and descending pain modulation brain regions. Our findings further suggested that this association between mucosa permeability and functional brain connectivity was mainly mediated by coping strategies.

    In Paper III, we investigated putative alterations in excitatory and inhibitory neurotransmission of aINS, as the brain’s key node of the salience network crucially involved in cognitive control, in IBS patients relative to HC and addressed possible connections with both symptoms and psychological factors. We found decreased concentrations of the excitatory neurotransmitter Glx in bilateral aINS in IBS patients compared to HC, while inhibitory neurotransmitter GABA+ levels were comparable. Further, we demonstrated hemisphere-specific associations between abdominal pain, coping and aINS excitatory neurotransmitter concentration.

    In conclusion, this thesis broadens the knowledge on peripheral and central mechanisms in IBS and presents novel findings that bring together the ends of brain-gut axis. Our results depict association between mucosal permeability, IBS symptoms and functional and structural connectivity engaging brain regions involved in emotion and pain modulation as well as underlying neurotransmitter alterations.

    Delarbeid
    1. Vasoactive Intestinal Polypeptide and Mast Cells Regulate Increased Passage of Colonic Bacteria in Patients With Irritable Bowel Syndrome
    Åpne denne publikasjonen i ny fane eller vindu >>Vasoactive Intestinal Polypeptide and Mast Cells Regulate Increased Passage of Colonic Bacteria in Patients With Irritable Bowel Syndrome
    Vise andre…
    2017 (engelsk)Inngår i: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 153, nr 4, s. 948-+Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    BACKGROUND amp; AIMS: Irritable bowel syndrome (IBS) is associated with intestinal dysbiosis and symptoms of IBS develop following gastroenteritis. We aimed to study the passage of live bacteria through the colonic epithelium, and determine the role of mast cells (MCs) and vasoactive intestinal polypeptide (VIP) in barrier regulation in IBS and healthy individuals. METHODS: Colon biopsies from 32 women with IBS and 15 age-matched healthy women (controls) were mounted in Ussing chambers; we measured numbers of fluorescently labeled Escherichia coli HS and Salmonella typhimurium that passed through from the mucosal side to the serosal side of the tissue. Some biopsies were exposed to agents that block the VIP receptors (VPAC1 and VPAC2) or MCs. Levels of VIP and tryptase were measured in plasma and biopsy lysates. Number of MCs and MCs that express VIP or VIP receptors were quantified by immunofluorescence. Biopsies from an additional 5 patients with IBS and 4 controls were mounted in chambers and Salmonella were added; we studied passage routes through the epithelium by transmission electron microscopy and expression of tight junctions by confocal microscopy. RESULTS: In colon biopsies from patients with IBS, larger numbers of E coli HS and S typhimurium passed through the epithelium than in biopsies from controls (P amp;lt;.0005). In transmission electron microscopy analyses, bacteria were found to cross the epithelium via only the transcellular route. Bacterial passage was reduced in biopsies from patients with IBS and controls after addition of antibodies against VPACs or ketotifen, which inhibits MCs. Plasma samples from patients with IBS had higher levels of VIP than plasma samples from controls. Biopsies from patients with IBS had higher levels of tryptase, larger numbers of MCs, and a higher percentage of MCs that express VPAC1 than biopsies from controls. In biopsies from patients with IBS, addition of Salmonella significantly reduced levels of occludin; subsequent addition of ketotifen significantly reversed this effect. CONCLUSIONS: We found that colonic epithelium tissues from patients with IBS have increased translocation of commensal and pathogenic live bacteria compared with controls. The mechanisms of increased translocation include MCs and VIP.

    sted, utgiver, år, opplag, sider
    W B SAUNDERS CO-ELSEVIER INC, 2017
    Emneord
    Intestinal Permeability; Bacteria; Ketotifen; Inflammation
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-142158 (URN)10.1053/j.gastro.2017.06.051 (DOI)000411835200024 ()28711627 (PubMedID)
    Merknad

    Funding Agencies|Stiftelsen Halsofonden, County Council of Ostergotland; Diarrheal Disease Research Centre, Linkoping University; AFA research foundation; Bengt-Ihre fonden, County Council of Ostergotland; Fondo de Investigacion Sanitaria, Instituto de Salud Carlos III, Subdireccion General de Investigacion Sanitaria, Ministerio de Economia y Competitividad [FI12/00254]; NIH [R01 DK048351]; [CP10/00502]; [PI13/00935]; [MV16/00028]; [CIBEREHD CB06/04/0021]

    Tilgjengelig fra: 2017-10-24 Laget: 2017-10-24 Sist oppdatert: 2024-01-10
    2. Interactions between gut permeability and brain structure and function in health and irritable bowel syndrome
    Åpne denne publikasjonen i ny fane eller vindu >>Interactions between gut permeability and brain structure and function in health and irritable bowel syndrome
    Vise andre…
    2019 (engelsk)Inngår i: NeuroImage: Clinical, E-ISSN 2213-1582, Vol. 21, artikkel-id 101602Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Changes in brain-gut interactions have been implicated in the pathophysiology of chronic visceral pain in irritable bowel syndrome (IBS). Different mechanisms of sensitization of visceral afferent pathways may contribute to the chronic visceral pain reports and associated brain changes that characterize IBS. They include increased gut permeability and gut associated immune system activation, and an imbalance in descending pain inhibitory and facilitatory mechanisms. In order to study the involvement of these mechanisms, correlations between gut epithelial permeability and live bacterial passage, and structural and functional brain connectivity were measured in women with moderate-to-severe IBS and healthy women. The relationships between gut permeability and functional and anatomical connectivity were significantly altered in IBS compared with the healthy women. IBS participants with lower epithelial permeability reported increased IBS symptoms, which was associated with increased functional and structural connectivity in endogenous pain facilitation regions. The findings suggest that relationships between gut permeability and the brain are significantly altered in IBS and suggest the existence of IBS subtypes based on these interactions.

    sted, utgiver, år, opplag, sider
    Elsevier, 2019
    Emneord
    Irritable bowel syndrome; Gut epithelial permeability; Resting state fMRI; Brain-gut interactions; Default mode network; Coping skills
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-155612 (URN)10.1016/j.nicl.2018.11.012 (DOI)000460337700015 ()30472166 (PubMedID)2-s2.0-85056893948 (Scopus ID)
    Merknad

    Funding Agencies|AFA FOrskning [AFA140417]; County Council of Ostergotland [SLS-693541, SLS-503411]; Region Ostergotland [LIO-700871, LIO-606201, LIO-536281, LIO-514271]; Deutsche Forschungsgemeinschaft [DFG IC 81/1-1]; Bengt-Ihre Fonden

    Tilgjengelig fra: 2019-03-20 Laget: 2019-03-20 Sist oppdatert: 2024-01-17bibliografisk kontrollert
    3. Reduced excitatory neurotransmitter levels in anterior insulae are associated with abdominal pain in irritable bowel syndrome
    Åpne denne publikasjonen i ny fane eller vindu >>Reduced excitatory neurotransmitter levels in anterior insulae are associated with abdominal pain in irritable bowel syndrome
    Vise andre…
    2019 (engelsk)Inngår i: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 160, nr 9, s. 2004-2012Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Irritable bowel syndrome (IBS) is a visceral pain condition with psychological comorbidity. Brain imaging studies in IBS demonstratealtered function in anterior insula (aINS), a key hub for integration of interoceptive, affective, and cognitive processes. However,alterations in aINS excitatory and inhibitory neurotransmission as putative biochemical underpinnings of these functional changesremain elusive. Using quantitative magnetic resonance spectroscopy, we compared women with IBS and healthy women (healthycontrols [HC]) with respect to aINS glutamate 1 glutamine (Glx) and g-aminobutyric acid (GABA1) concentrations and addressedpossible associations with symptoms. Thirty-nine women with IBS and 21 HC underwent quantitative magnetic resonancespectroscopy of bilateral aINS to assess Glx and GABA1 concentrations. Questionnaire data from all participants and prospectivesymptom-diary data from patients were obtained for regression analyses of neurotransmitter concentrations with IBS-related andpsychological parameters. Concentrations of Glx were lower in IBS compared with HC (left aINS P , 0.05, right aINS P , 0.001),whereas no group differences were detected for GABA1concentrations. Lower right-lateralized Glx concentrations in patients weresubstantially predicted by longer pain duration, while less frequent use of adaptive pain‐coping predicted lower Glx in left aINS. Ourfindings provide first evidence for reduced excitatory but unaltered inhibitory neurotransmitter levels in aINS in IBS. The results alsoindicate a functional lateralization of aINS with a stronger involvement of the right hemisphere in perception of abdominal pain and ofthe left aINS in cognitive pain regulation. Our findings suggest that glutaminergic deficiency may play a role in pain processing in IBS.

    sted, utgiver, år, opplag, sider
    Lippincott Williams & Wilkins, 2019
    Emneord
    Irritable bowel syndrome, Functional magnetic resonance imaging, Quantitative magnetic resonance spectroscopy, Insula, Visceral pain, Coping
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-160012 (URN)10.1097/j.pain.0000000000001589 (DOI)000512903900011 ()31045748 (PubMedID)
    Merknad

    Funding agencies: NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [P41-RR14075, R01 RR16594-01A1, R01 NS052585-01, K08 MH01573, K01 MH01798]; County Council of Ostergotland; AFA research foundation [DNR. 140407]; Bengt-Ihre f

    Tilgjengelig fra: 2019-09-02 Laget: 2019-09-02 Sist oppdatert: 2024-01-10bibliografisk kontrollert
    Fulltekst (pdf)
    Peripheral and Central Mechanisms in Irritable Bowel Syndrome: in search of links
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    presentationsbild
  • 38.
    Behjat, Hamid
    et al.
    Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, USA; Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, USA; Department of Biomedical Engineering, Lund University, Lund, Sweden.
    Aganj, Iman
    Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, USA; Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, Cambridge, USA.
    Abramian, David
    Linköpings universitet, Institutionen för medicinsk teknik, Avdelningen för medicinsk teknik. Linköpings universitet, Tekniska fakulteten. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    Eklund, Anders
    Linköpings universitet, Institutionen för medicinsk teknik, Avdelningen för medicinsk teknik. Linköpings universitet, Tekniska fakulteten. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV. Linköpings universitet, Institutionen för datavetenskap, Statistik och maskininlärning.
    Westin, Carl-Fredrik
    Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, USA.
    Characterization of Spatial Dynamics of Fmri Data in White Matter Using Diffusion-Informed White Matter Harmonics2021Inngår i: 2021 IEEE 18th International Symposium On Biomedical Imaging (ISBI), Institute of Electrical and Electronics Engineers (IEEE), 2021Konferansepaper (Fagfellevurdert)
    Abstract [en]

    In this work, we leverage the Laplacian eigenbasis of voxelwise white matter (WM) graphs derived from diffusionweighted MRI data, dubbed WM harmonics, to characterize the spatial structure of WM fMRI data. Our motivation for such a characterization is based on studies that show WM fMRI data exhibit a spatial correlational anisotropy that coincides with underlying fiber patterns. By quantifying the energy content of WM fMRI data associated with subsets of WM harmonics across multiple spectral bands, we show that the data exhibits notable subtle spatial modulations under functional load that are not manifested during rest. WM harmonics provide a novel means to study the spatial dynamics of WM fMRI data, in such way that the analysis is informed by the underlying anatomical structure.

    Fulltekst (pdf)
    fulltext
  • 39.
    Belluardo, N
    et al.
    Department of Human Physiology, Faculty of Medicine, University of Palermo, I−941 25 Palermo, Italy.
    Korhonen, L
    Department of Neuroscience, Neurobiology, Uppsala University, BMC, Box 587, S−751 23,Uppsala, Sweden.
    Mudo, G
    Department of Human Physiology, Faculty of Medicine, University of Palermo, I−941 25 Palermo, Italy.
    Lindholm, D
    Department of Neuroscience, Neurobiology, Uppsala University, BMC, Box 587, S−751 23,Uppsala, Sweden.
    Neuronal expression and regulation of rat inhibitor of apoptosis protein-2 by kainic acid in the rat brain2002Inngår i: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 15, nr 1, s. 87-100Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Inhibitors of apoptosis proteins (IAPs) define a protein family with the ability to counteract cell death by the inhibition of different caspases activated during apoptosis. These proteins are present in different cells, however, the function and roles of IAPs in brain tissue are not fully understood. We report here that RIAP-2, the rat homologue of human cIAP-1/HIAP-2, is expressed in different areas of rat brain as shown by in situ hybridization and immunohistochemistry. Brain regions with relatively high expression of RIAP-2 mRNA included cortex, cerebellum and different subregions of rat hippocampus. Double labelling using a specific anti-RIAP antibody and markers for neurons and glial cells, showed that RIAP-2 is predominantly expressed by nerve cells. Kainic acid treatment, which induces seizures, transiently up-regulated RIAP-2 mRNA levels in cerebral cortex, in the CA1 and dentate gyrus regions of hippocampus, which returned to normal levels at 24 h. However in the CA3 region, RIAP-2 mRNA was decreased at 6 h following an early up-regulation. This region contains neurons particularly vulnerable to kainic acid induced cell degeneration. The decrease in RIAP-2 following kainic acid was also observed using immunohistochemistry. RIAP-2 protein did not colocalize with TUNEL labelling present in cells undergoing cell death. The results show that in the adult rat brain RIAP-2 is expressed mainly by neurons, and that the levels are regulated by kainic acid, which activates glutamate receptors. The decrease in RIAP-2 in specific neuronal populations may contribute to cell degeneration in vulnerable brain regions observed after kainic acid treatment.

  • 40.
    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.2013Inngår i: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 230, s. 139-150Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 41.
    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.2012Inngår i: Cerebral Cortex, ISSN 1047-3211, E-ISSN 1460-2199, Vol. 22, nr 7, s. 1690-1697Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 42.
    Bergsten, Elin
    et al.
    Helsingborg Hosp, Sweden; Lund Univ, Sweden.
    Rydberg, Mattias
    Lund Univ, Sweden; Skane Univ Hosp, Sweden.
    Dahlin, Lars
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten. Lund Univ, Sweden; Skane Univ Hosp, Sweden.
    Zimmerman, Malin
    Helsingborg Hosp, Sweden; Lund Univ, Sweden.
    Carpal Tunnel Syndrome and Ulnar Nerve Entrapment at the Elbow Are Not Associated With Plasma Levels of Caspase-3, Caspase-8 or HSP272022Inngår i: Frontiers in Neuroscience, ISSN 1662-4548, E-ISSN 1662-453X, Vol. 16, artikkel-id 809537Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BackgroundNerve compression disorders, such as carpal tunnel syndrome (CTS) and ulnar entrapment at the elbow (UNE), may be associated with apoptosis and neuroprotective mechanisms in the peripheral nerve that may be detected by biomarkers in the blood. The relationships between CTS and UNE and two biomarkers of apoptosis, i.e., caspase-3 and caspase-8, and the neuroprotective factor Heat Shock Protein 27 (HSP27) in plasma were examined in a population-based cohort. MethodThe biomarkers caspase-3, caspase-8 and HSP27 were measured in plasma at inclusion of 4,284 study participants aged 46-68 years in the population-based Malmo Diet and Cancer study (MDCS). End-point retrieval was made from national registers concerning CTS and UNE. Independent t-test was used to examine the association between caspase-3, caspase-8 and HSP27 plasma levels and incidence of CTS and UNE. Cox proportional hazards regression was used to investigate if plasma levels of caspase-3, caspase-8 and HSP27 affected time to diagnosis of CTS or UNE. ResultsDuring the mean follow-up time of 22 years, 189/4,284 (4%) participants were diagnosed with CTS and 42/4,284 (1%) were diagnosed with UNE. No associations were found between incident CTS or UNE and the biomarkers caspase-3, caspase-8 and HSP27 in plasma. ConclusionThe apoptotic biomarkers caspase-3 and caspase-8 and the neuroprotective factor HSP27 in plasma, factors conceivably related to a nerve injury, are not associated with the nerve compression disorders CTS and UNE in a general population.

    Fulltekst (pdf)
    fulltext
  • 43.
    Bergström, Linn
    Linköpings universitet, Institutionen för datavetenskap. 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 poäng / 30 hpOppgave
    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.

    Fulltekst (pdf)
    2016_IsVisualStimuliNeighboringAttendedStimuliSuppressedinHighPerceptualLoad_LinnBergstrom
  • 44.
    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
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Centrum för social och affektiv neurovetenskap (CSAN). Region Östergötland, Närsjukvården i centrala Östergötland, Psykiatriska kliniken.
    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 epidemiology2016Inngår i: Translational Psychiatry, E-ISSN 2158-3188, Vol. 6, nr e861Artikkel i tidsskrift (Fagfellevurdert)
    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.

    Fulltekst (pdf)
    fulltext
  • 45.
    Bessa Ferreira, Vitor Hugo
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten. Univ Tours, France.
    Lansade, Lea
    Univ Tours, France.
    Calandreau, Ludovic
    Univ Tours, France.
    Barros Da Cunha, Felipe
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    Jensen, Per
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    Are domesticated animals dumber than their wild relatives? A comprehensive review on the domestication effects on animal cognitive performance2023Inngår i: Neuroscience and Biobehavioral Reviews, ISSN 0149-7634, E-ISSN 1873-7528, Vol. 154, artikkel-id 105407Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Animal domestication leads to diverse behavioral, physiological, and neurocognitive changes in domesticated species compared to their wild relatives. However, the widely held belief that domesticated species are inherently less "intelligent" (i.e., have lower cognitive performance) than their wild counterparts requires further investigation. To investigate potential cognitive disparities, we undertook a thorough review of 88 studies comparing the cognitive performance of domesticated and wild animals. Approximately 30% of these studies showed superior cognitive abilities in wild animals, while another 30% highlighted superior cognitive abilities in domesticated animals. The remaining 40% of studies found similar cognitive performance between the two groups. Therefore, the question regarding the presumed intelligence of wild animals and the diminished cognitive ability of domesticated animals remains unresolved. We discuss important factors/limitations for interpreting past and future research, including environmental influences, diverse objectives of domestication (such as breed development), developmental windows, and methodological issues impacting cognitive comparisons. Rather than perceiving these limitations as constraints, future researchers should embrace them as opportunities to expand our understanding of the complex relationship between domestication and animal cognition.

  • 46.
    Bivik, Caroline
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Utvecklingsbiologi. Linköpings universitet, Hälsouniversitetet.
    Ulvklo, Carina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Utvecklingsbiologi. Linköpings universitet, Hälsouniversitetet.
    Lundin, Erika
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Nilsson, Patrik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Angel, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Utvecklingsbiologi. Linköpings universitet, Hälsouniversitetet.
    Thor, Stefan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Utvecklingsbiologi. Linköpings universitet, Hälsouniversitetet.
    A genetic screen for genes controlling Apterous neuron identity and FMRFamide expression2010Inngår i: Journal of neurogenetics, ISSN 0167-7063, E-ISSN 1563-5260, Vol. 24, nr Suppl. 1, s. 70-71Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    n/a

  • 47.
    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 receptors2010Inngår i: Addiction Biology, ISSN 1355-6215, E-ISSN 1369-1600, Vol. 15, nr 3, s. 299-303Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 48.
    Björk, Karl
    et al.
    Karolinska Institute, Stockholm, Sweden .
    Tronci, Valeria
    Psychobiology Section, NIDA, National Institutes of Health, Baltimore, MD, USA .
    Thorsell, Annika
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    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 alcohol2013Inngår i: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 230, nr 3, s. 439-449Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 49.
    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 touch2014Inngår i: Frontiers in Behavioral Neuroscience, ISSN 1662-5153, E-ISSN 1662-5153, Vol. 8, nr 24Artikkel i tidsskrift (Fagfellevurdert)
    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.

    Fulltekst (pdf)
    fulltext
  • 50.
    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.2010Inngår i: Experimental Brain Research, ISSN 0014-4819, E-ISSN 1432-1106, Vol. 207, nr 3, s. 149-155Artikkel i tidsskrift (Fagfellevurdert)
    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.

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