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  • 1.
    Aare, Sudhakar Reddy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Intensive Care Unit Muscle Wasting: Skeletal Muscle Phenotype and Underlying Molecular Mechanisms2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Acute quadriplegic myopathy (AQM), or critical illness myopathy, is a common debilitating acquired disorder in critically ill intensive care unit (ICU) patients characterized by generalized muscle wasting and weakness of limb and trunk muscles. A preferential loss of the thick filament protein myosin is considered pathognomonic of this disorder, but the myosin loss is observed relatively late during the disease progression. In attempt to explore the potential role of factors considered triggering AQM in sedated mechanically ventilated (MV) ICU patients, we have studied the early effects, prior to the myosin loss, of neuromuscular blockade (NMB), corticosteroids (CS) and sepsis separate or in combination in a porcine experimental ICU model. Specific interest has been focused on skeletal muscle gene/protein expression and regulation of muscle contraction at the muscle fiber level. This project aims at improving our understanding of the molecular mechanisms underlying muscle specific differences in response to the ICU intervention and the role played by the different triggering factors.

    The sparing of masticatory muscle fiber function was coupled to an up-regulation of heat shock protein genes and down-regulation of myostatin are suggested to be key factors in the relative sparing of masticatory muscles. Up-regulation of chemokine activity genes and down-regulation of heat shock protein genes play a significant role in the limb muscle dysfunction associated with sepsis. The effects of corticosteroids in the development of limb muscle weakness reveals up-regulation of kinase activity and transcriptional regulation genes and the down-regulation of heat shock protein, sarcomeric, cytoskeletal and oxidative stress responsive genes. In contrast to limb and craniofacial muscles, the respiratory diaphragm muscle responded differently to the different triggering factors. MV itself appears to play a major role for the diaphragm muscle dysfunction. By targeting these genes, future experiments can give an insight into the development of innovative treatments expected at protecting muscle mass and function in critically ill ICU patients.

    List of papers
    1. Mechanisms underlying the sparing of masticatory versus limb muscle function in an experimental critical illness model
    Open this publication in new window or tab >>Mechanisms underlying the sparing of masticatory versus limb muscle function in an experimental critical illness model
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    2011 (English)In: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 43, no 24, p. 1334-1350Article in journal (Refereed) Published
    Abstract [en]

    Acute quadriplegic myopathy (AQM) is a common debilitating acquired disorder in critically ill intensive care unit (ICU) patients which is characterized by tetraplegia/generalized weakness of limb and trunk muscles. Masticatory muscles, on the other hand, are typically spared or less affected, yet the mechanisms underlying this striking muscle-specific difference remain unknown. This study aims to evaluate physiological parameters and the gene expression profiles of masticatory and limb muscles exposed to factors suggested to trigger AQM, such as mechanical ventilation, immobilization, neuromuscular blocking agents (NMBA), corticosteroids (CS) and sepsis for five days by using a unique porcine model mimicking the ICU conditions. Single muscle fiber cross-sectional area and force-generating capacity, i.e., maximum force normalized to fiber cross-sectional area (specific force), revealed maintained masseter single muscle fiber cross-sectional area and specific-force after five days exposure to all triggering factors. This is in sharp contrast to observations in limb and trunk muscles, showing a dramatic decline in specific force in response to five days exposure to the triggering factors. Significant differences in gene expression were observed between craniofacial and limb muscles, indicating a highly complex and muscle specific response involving transcription and growth factors, heat shock proteins, matrix metalloproteinase inhibitor, oxidative stress responsive elements and sarcomeric proteins underlying the relative sparing of cranial versus spinal nerve innervated muscles during exposure to the ICU intervention.

    National Category
    Neurology
    Identifiers
    urn:nbn:se:uu:diva-164317 (URN)10.1152/physiolgenomics.00116.2011 (DOI)000298403600002 ()22010006 (PubMedID)
    Available from: 2011-12-19 Created: 2011-12-19 Last updated: 2017-12-08Bibliographically approved
    2. The role of sepsis in the development of limb muscle weakness in a porcine intensive care unit model
    Open this publication in new window or tab >>The role of sepsis in the development of limb muscle weakness in a porcine intensive care unit model
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    2012 (English)In: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 44, no 18, p. 865-877Article in journal (Refereed) Published
    Abstract [en]

    Severe muscle wasting and loss of muscle function in critically ill mechanically ventilated intensive care unit (ICU) patients have significant negative consequences on their recovery and rehabilitation that persist long after their hospital discharge; moreover the underlying mechanisms are unclear. Mechanical ventilation (MV) and immobilization-induced modifications play an important role in these consequences, including endotoxin induced sepsis. The present study aims to investigate how sepsis aggravates ventilator and immobilization-related limb muscle dysfunction. Hence, biceps femoris muscle gene expression was investigated in pigs exposed to ICU intervention, i.e., immobilization, sedation, and MV, alone or in combination with sepsis for five days. In previous studies, we have shown that ICU intervention alone or in combination with sepsis did not affect muscle fiber size on day 5, but a significant decrease was observed in single fiber maximal force normalized to cross-sectional area (specific force) when sepsis was added to the ICU intervention. According to microarray data, the addition of sepsis to the ICU intervention induced a deregulation of more than 500 genes, such as an increased expression of genes involved in chemokine activity, kinase activity and transcriptional regulation. Genes involved in the regulation of the oxidative stress response, cytoskeletal/sarcomeric and heat shock proteins were on the other hand down-regulated when sepsis was added to the ICU intervention. Thus, sepsis has a significant negative effect on muscle function in critically ill ICU patients and chemokine activity and heat shock protein genes are forwarded to play an instrumental role in this specific muscle wasting condition.

    Keywords
    Sepsis, porcine, muscle wasting, intensive care
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-180380 (URN)10.1152/physiolgenomics.00031.2012 (DOI)000309109100001 ()
    Available from: 2012-09-05 Created: 2012-09-05 Last updated: 2017-12-07Bibliographically approved
    3. Effects of corticosteroids in the development of limb muscle weakness in a porcine intensive care unit model
    Open this publication in new window or tab >>Effects of corticosteroids in the development of limb muscle weakness in a porcine intensive care unit model
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    2013 (English)In: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 45, no 8, p. 312-320Article in journal (Refereed) Published
    Abstract [en]

    Severe muscle wasting is a debilitating condition in critically ill intensive care unit (ICU) patients, characterized by general muscle weakness and dysfunction, resulting in a prolonged mobilization, delayed weaning from the ventilator and a decreased quality of life post-ICU. The mechanisms underlying limbmuscle weakness in ICU patients are complex and involve the impact of primary disease, but also factors common to critically ill ICU patients such as sepsis, mechanical ventilation (MV), immobilization and systemic administration of corticosteroids (CS).  These factors may have additive negative effects on skeletal muscle structure and function, but their respective role alone remain unknown. The primary aim of this study was to examine how CS administration potentiates ventilator and immobilization-related limb muscle dysfunction at the gene level. Comparing biceps femoris gene expression in pigs exposed to MV and CS for five days with only MV pigs for the same duration of time showed a distinct deregulation of 186 genes using microarray. Surprisingly, the decreased force-generation capacity at the single muscle fiber reported in response to the addition of CS administration in mechanically ventilated and immobilized pigs was not associated with an additional up-regulation of proteolytic pathways. On the other hand, an altered expression of genes regulating kinase activity, cell cycle, transcription, channel regulation, oxidative stress response , cytoskeletal, sarcomeric and heat shock protein as well as protein synthesis at the translational level appear to play an additive deleterious role for the  limb muscle weakness in immobilized ICU patients.

     

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-180375 (URN)10.1152/physiolgenomics.00123.2012 (DOI)000317662000002 ()23429211 (PubMedID)
    Available from: 2012-09-05 Created: 2012-09-05 Last updated: 2017-12-07Bibliographically approved
    4. Diaphragm muscle weakness in an experimental porcine intensive care unit model
    Open this publication in new window or tab >>Diaphragm muscle weakness in an experimental porcine intensive care unit model
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    2011 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 6, article id e20558Article in journal (Refereed) Published
    Abstract [en]

    In critically ill patients, mechanisms underlying diaphragm muscle remodeling and resultant dysfunction contributing to weaning failure remain unclear. Ventilator-induced modifications as well as sepsis and administration of pharmacological agents such as corticosteroids and neuromuscular blocking agents may be involved. Thus, the objective of the present study was to examine how sepsis, systemic corticosteroid treatment (CS) and neuromuscular blocking agent administration (NMBA) aggravate ventilator-related diaphragm cell and molecular dysfunction in the intensive care unit. Piglets were exposed to different combinations of mechanical ventilation and sedation, endotoxin-induced sepsis, CS and NMBA for five days and compared with sham-operated control animals. On day 5, diaphragm muscle fibre structure (myosin heavy chain isoform proportion, cross-sectional area and contractile protein content) did not differ from controls in any of the mechanically ventilated animals. However, a decrease in single fibre maximal force normalized to cross-sectional area (specific force) was observed in all experimental piglets. Therefore, exposure to mechanical ventilation and sedation for five days has a key negative impact on diaphragm contractile function despite a preservation of muscle structure. Post-translational modifications of contractile proteins are forwarded as one probable underlying mechanism. Unexpectedly, sepsis, CS or NMBA have no significant additive effects, suggesting that mechanical ventilation and sedation are the triggering factors leading to diaphragm weakness in the intensive care unit.

    National Category
    Physiology
    Research subject
    Clinical Neurophysiology
    Identifiers
    urn:nbn:se:uu:diva-155622 (URN)10.1371/journal.pone.0020558 (DOI)000291730000014 ()21698290 (PubMedID)
    Available from: 2011-06-27 Created: 2011-06-27 Last updated: 2018-01-12Bibliographically approved
  • 2.
    Abu Hamdeh, Sami
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Shevchenko, Ganna
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Mi, Jia
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Musunuri, Sravani
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Proteomic differences between focal and diffuse traumatic brain injury in human brain tissue2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 6807Article in journal (Refereed)
    Abstract [en]

    The early molecular response to severe traumatic brain injury (TBI) was evaluated using biopsies of structurally normal-appearing cortex, obtained at location for intracranial pressure (ICP) monitoring, from 16 severe TBI patients. Mass spectrometry (MS; label free and stable isotope dimethyl labeling) quantitation proteomics showed a strikingly different molecular pattern in TBI in comparison to cortical biopsies from 11 idiopathic normal pressure hydrocephalus patients. Diffuse TBI showed increased expression of peptides related to neurodegeneration (Tau and Fascin, p < 0.05), reduced expression related to antioxidant defense (Glutathione S-transferase Mu 3, Peroxiredoxin-6, Thioredoxin-dependent peroxide reductase; p < 0.05) and increased expression of potential biomarkers (e.g. Neurogranin, Fatty acid-binding protein, heart p < 0.05) compared to focal TBI. Proteomics of human brain biopsies displayed considerable molecular heterogeneity among the different TBI subtypes with consequences for the pathophysiology and development of targeted treatments for TBI.

  • 3.
    Abu Hamdeh, Sami
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Shevchenko, Ganna
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Mi, Jia
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Musunuri, Sravani
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Proteomic Differences Between Focal And Diffuse Traumatic Brain Injury In Human Brain Tissue2018In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 35, no 16, p. A238-A239Article in journal (Other academic)
  • 4.
    Abu Hamdeh, Sami
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Waara, Erik Rollman
    Möller, Christer
    Söderberg, Linda
    Basun, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. BioArctic Neuroscience AB, Stockholm, Sweden.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Hillered, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. BioArctic Neuroscience AB, Stockholm, Sweden.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Rapid amyloid-β oligomer and protofibril accumulation in traumatic brain injury2017In: Brain Pathology, ISSN 1015-6305, E-ISSN 1750-3639Article in journal (Refereed)
    Abstract [en]

    Deposition of amyloid-β (Aβ) is central to Alzheimer's disease (AD) pathogenesis and associated with progressive neurodegeneration in traumatic brain injury (TBI). We analyzed predisposing factors for Aβ deposition including monomeric Aβ40, Aβ42 and Aβ oligomers/protofibrils, Aβ species with pronounced neurotoxic properties, following human TBI. Highly selective ELISAs were used to analyze N-terminally intact and truncated Aβ40 and Aβ42, as well as Aβ oligomers/protofibrils, in human brain tissue, surgically resected from severe TBI patients (n = 12; mean age 49.5 ± 19 years) due to life-threatening brain swelling/hemorrhage within one week post-injury. The TBI tissues were compared to post-mortem AD brains (n = 5), to post-mortem tissue of neurologically intact (NI) subjects (n = 4) and to cortical biopsies obtained at surgery for idiopathic normal pressure hydrocephalus patients (iNPH; n = 4). The levels of Aβ40 and Aβ42 were not elevated by TBI. The levels of Aβ oligomers/protofibrils in TBI were similar to those in the significantly older AD patients and increased compared to NI and iNPH controls (P < 0.05). Moreover, TBI patients carrying the AD risk genotype Apolipoprotein E epsilon3/4 (APOE ε3/4; n = 4) had increased levels of Aβ oligomers/protofibrils (P < 0.05) and of both N-terminally intact and truncated Aβ42 (P < 0.05) compared to APOE ε3/4-negative TBI patients (n = 8). Neuropathological analysis showed insoluble Aβ aggregates (commonly referred to as Aβ plaques) in three TBI patients, all of whom were APOE ε3/4 carriers. We conclude that soluble intermediary Aβ aggregates form rapidly after TBI, especially among APOE ε3/4 carriers. Further research is needed to determine whether these aggregates aggravate the clinical short- and long-term outcome in TBI.

  • 5.
    Adori, Csaba
    et al.
    Karolinska Inst, Dept Neurosci, Retzius Lab, Retzius Vag 8, S-17177 Stockholm, Sweden.
    Barde, Swapnali
    Karolinska Inst, Dept Neurosci, Retzius Lab, Retzius Vag 8, S-17177 Stockholm, Sweden.
    Vas, Szilvia
    Semmelweis Univ, Dept Pharmacodynam, Nagyvarad Ter 4, H-1089 Budapest, Hungary; Hungarian Acad Sci, Neuropsychopharmacol & Neurochem Res Grp, Nagyvarad Ter 4, H-1089 Budapest, Hungary.
    Ebner, Karl
    Leopold Franzens Univ Innsbruck, CMBI, Inst Pharm, Dept Pharmacol & Toxicol, Innrain 80-82-3, A-6020 Innsbruck, Austria.
    Su, Jie
    Karolinska Inst, Dept Physiol & Pharmacol, Nanna Svartz Vag 2, S-17177 Stockholm, Sweden.
    Svensson, Camilla
    Karolinska Inst, Dept Physiol & Pharmacol, Nanna Svartz Vag 2, S-17177 Stockholm, Sweden.
    Mathé, Aleksander A
    Karolinska Inst, Sect Psychiat, Dept Clin Neurosci, Tomtebodavagen 18A, S-17177 Stockholm, Sweden.
    Singewald, Nicolas
    Leopold Franzens Univ Innsbruck, CMBI, Inst Pharm, Dept Pharmacol & Toxicol, Innrain 80-82-3, A-6020 Innsbruck, Austria.
    Reinscheid, Rainer R
    Univ Calif Irvine, Dept Pharmaceut Sci, Irvine, CA 92697 USA.
    Uhlén, Mathias
    Karolinska Inst, Dept Neurosci, Sci Life Lab, S-17165 Stockholm, Sweden; Royal Inst Technol, Albanova Univ Ctr, Sci Life Lab, S-17165 Stockholm, Sweden.
    Kultima, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Bagdy, György
    Semmelweis Univ, Dept Pharmacodynam, Nagyvarad Ter 4, H-1089 Budapest, Hungary; Hungarian Acad Sci, Neuropsychopharmacol & Neurochem Res Grp, Nagyvarad Ter 4, H-1089 Budapest, Hungary.
    Hökfelt, Tomas
    Karolinska Inst, Dept Neurosci, Retzius Lab, Retzius Vag 8, S-17177 Stockholm, Sweden.
    Exploring the role of neuropeptide S in the regulation of arousal: a functional anatomical study.2016In: Brain Structure and Function, ISSN 1863-2653, E-ISSN 1863-2661, Vol. 221, no 7, p. 3521-3546Article in journal (Refereed)
    Abstract [en]

    Neuropeptide S (NPS) is a regulatory peptide expressed by limited number of neurons in the brainstem. The simultaneous anxiolytic and arousal-promoting effect of NPS suggests an involvement in mood control and vigilance, making the NPS-NPS receptor system an interesting potential drug target. Here we examined, in detail, the distribution of NPS-immunoreactive (IR) fiber arborizations in brain regions of rat known to be involved in the regulation of sleep and arousal. Such nerve terminals were frequently apposed to GABAergic/galaninergic neurons in the ventro-lateral preoptic area (VLPO) and to tyrosine hydroxylase-IR neurons in all hypothalamic/thalamic dopamine cell groups. Then we applied the single platform-on-water (mainly REM) sleep deprivation method to study the functional role of NPS in the regulation of arousal. Of the three pontine NPS cell clusters, the NPS transcript levels were increased only in the peri-coerulear group in sleep-deprived animals, but not in stress controls. The density of NPS-IR fibers was significantly decreased in the median preoptic nucleus-VLPO region after the sleep deprivation, while radioimmunoassay and mass spectrometry measurements showed a parallel increase of NPS in the anterior hypothalamus. The expression of the NPS receptor was, however, not altered in the VLPO-region. The present results suggest a selective activation of one of the three NPS-expressing neuron clusters as well as release of NPS in distinct forebrain regions after sleep deprivation. Taken together, our results emphasize a role of the peri-coerulear cluster in the modulation of arousal, and the importance of preoptic area for the action of NPS on arousal and sleep.

  • 6.
    Aggarwal, Tanya
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Hoeber, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Regenerative neurobiology.
    Ivert, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Regenerative neurobiology.
    Vasylovska, Svitlana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Regenerative neurobiology.
    Kozlova, Elena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Regenerative neurobiology.
    Boundary Cap Neural Crest Stem Cells Promote Survival of Mutant SOD1 Motor Neurons2017In: Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, ISSN 1878-7479, Vol. 14, no 3, p. 773-783Article in journal (Refereed)
    Abstract [en]

    ALS is a devastating disease resulting in degeneration of motor neurons (MNs) in the brain and spinal cord. The survival of MNs strongly depends on surrounding glial cells and neurotrophic support from muscles. We previously demonstrated that boundary cap neural crest stem cells (bNCSCs) can give rise to neurons and glial cells in vitro and in vivo and have multiple beneficial effects on co-cultured and co-implanted cells, including neural cells. In this paper, we investigate if bNCSCs may improve survival of MNs harboring a mutant form of human SOD1 (SOD1(G93A)) in vitro under normal conditions and oxidative stress and in vivo after implantation to the spinal cord. We found that survival of SOD1(G93A) MNs in vitro was increased in the presence of bNCSCs under normal conditions as well as under oxidative stress. In addition, when SOD1(G93A) MN precursors were implanted to the spinal cord of adult mice, their survival was increased when they were co-implanted with bNCSCs. These findings show that bNCSCs support survival of SOD1(G93A) MNs in normal conditions and under oxidative stress in vitro and improve their survival in vivo, suggesting that bNCSCs have a potential for the development of novel stem cell-based therapeutic approaches in ALS models.

  • 7.
    Ahmad, Abdulbaghi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Children of Kurdistan: Survivors of trauma and terror2000In: Child suffering in the world: Child maltreatment by parents, culture and governments in different countries and cultures / [ed] Marvasti JA, New York: 010 Publishers, 2000, p. 153-177Chapter in book (Refereed)
  • 8.
    Ahmad, Abdulbaghi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    von Knorring, Anne-Liis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Tiden läkar inte alla sår2002In: Stress: molekylerna, individen, organisationen samhället / [ed] Ekman R & Arnetz B, Liber, 2002, 1Chapter in book (Refereed)
  • 9. Ahmad, Abdulbaghi
    et al.
    von Knorring, Anne-Liis
    Tiden läkar inte alla sår2006In: Stress, molekyl, individ, organisation och samhälle / [ed] Ekman R & Arnetz B, Liber, 2006, 2, p. 128-138Chapter in book (Refereed)
  • 10.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Tau pathology in aging and AD: beyond neurofibrillary tangles (grains, astrocytes, etc.)2014In: Brain Pathology, ISSN 1015-6305, E-ISSN 1750-3639, Vol. 24, no S1, p. 20-21Article in journal (Other academic)
  • 11.
    Alafuzoff, Irina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Pikkarainen, Maria
    Univ Eastern Finland, Dept Clin Med, Kuopio, Finland.
    Neumann, Manuela
    Univ Tubingen, German Ctr Neurodegenerat Dis, Dept Neuropatol, Tubingen, Germany; DZNE, Tubingen, Germany.
    Arzberger, Thomas
    Univ Munich, Ctr Neuropathol & Prion Res, Munich, Germany.
    Al-Sarraj, Safa
    Kings Coll Hosp London, Inst Psychiat, Dept Clin Neuropathol, London, England; MRC, London Neurodegenerat Dis Brain Bank, London, England.
    Bodi, Istvan
    Kings Coll Hosp London, Inst Psychiat, Dept Clin Neuropathol, London, England; MRC, London Neurodegenerat Dis Brain Bank, London, England.
    Bogdanovic, Nenad
    Univ Oslo, Inst Clin Med, Dept Geriatr, Oslo, Norway.
    Bugiani, Orso
    IRCSS Fdn Ist Neurol Carlo Besta, Div Neuropathol & Neurol 5, Milan, Italy.
    Ferrer, Isidro
    Univ Barcelona, CEBERNED, Bellvitge Univ Hosp, Inst Neuropathol, Barcelona, Spain.
    Gelpi, Ellen
    Biobanc Hosp Clin IDIBAPS, Neurol Tissue Bank, Barcelona, Spain.
    Gentleman, Stephen
    Univ London Imperial Coll Sci Technol & Med, Dept Med, Neuropathol Unit, London, England.
    Giaccone, Giorgio
    IRCSS Fdn Ist Neurol Carlo Besta, Div Neuropathol & Neurol 5, Milan, Italy.
    Graeber, Manuel B.
    Univ Sydney, Fac Med, Sydney, NSW 2006, Australia; Univ Sydney, Fac Hlth Sci, Brain & Mind Res Inst, Sydney, NSW 2006, Australia.
    Hortobagyi, Tibor
    Univ Debrecen, Instutute Pathol, Dept Neuropathol, Debrecen, Hungary.
    Ince, Paul G.
    Univ Sheffield, Sheffield Inst Translat Neurosci, Sheffield, S Yorkshire, England.
    Ironside, James W.
    Univ Edinburgh, Western Gen Hosp, Natl CJD Res & Surveillance Unit, Edinburgh, Midlothian, Scotland.
    Kavantzas, Nikolaos
    Natl & Capodistrian Univ Athens, Dept Pathol, Athens, Greece.
    King, Andrew
    Kings Coll Hosp London, Inst Psychiat, Dept Clin Neuropathol, London, England; MRC, London Neurodegenerat Dis Brain Bank, London, England.
    Korkolopoulou, Penelope
    Natl & Capodistrian Univ Athens, Dept Pathol, Athens, Greece.
    Kovács, Gábor G.
    Med Univ Vienna, Inst Neurol, Vienna, Austria.
    Meyronet, David
    Univ Lyon, Hosp Civils Lyon, Ctr Pathol & Neuropathol Est, Lyon Neurosci Res Ctr, Lyon, France.
    Monoranu, Camelia
    Univ Wurzburg, Abt Neuropathol, Pathol Inst, D-97070 Wurzburg, Germany.
    Nilsson, Tatjana
    Karolinska Inst, Dept Geriatr, Stockholm, Sweden.
    Parchi, Piero
    Univ Bologna, Ist Sci Neurol, Dept Biomed & Neuromotor Sci, IRCCS, Bologna, Italy.
    Patsouris, Efstratios
    Natl & Capodistrian Univ Athens, Dept Pathol, Athens, Greece.
    Revesz, Tamas
    UCL Inst Neurol, Queen Sq Brain Bank, Dept Mol Neurosci, London, England.
    Roggendorf, Wolfgang
    Univ Wurzburg, Abt Neuropathol, Pathol Inst, D-97070 Wurzburg, Germany.
    Rozemuller, Annemieke
    Vrije Univ Amsterdam, Med Ctr, Amsterdam, Netherlands.
    Seilhean, Danielle
    Univ Paris 06, AP HP, Lab Neuropathol Raymond Escourolle, Paris, France; INSERM, Paris, France.
    Streichenberger, Nathalie
    Univ Lyon, Hosp Civils Lyon, Ctr Pathol & Neuropathol Est, Lyon Neurosci Res Ctr, Lyon, France.
    Thal, Dietmar R.
    Univ Ulm, Inst Pathol, Neuropathol Lab, D-89069 Ulm, Germany.
    Wharton, Stephen B.
    Univ Sheffield, Sheffield Inst Translat Neurosci, Sheffield, S Yorkshire, England.
    Kretzschmar, Hans
    Univ Munich, Ctr Neuropathol & Prion Res, Munich, Germany.
    Neuropathological assessments of the pathology in frontotemporal lobar degeneration with TDP43-positive inclusions: an inter-laboratory study by the BrainNet Europe consortium2015In: Journal of neural transmission, ISSN 0300-9564, E-ISSN 1435-1463, Vol. 122, no 7, p. 957-972Article in journal (Refereed)
    Abstract [en]

    The BrainNet Europe consortium assessed the reproducibility in the assignment of the type of frontotemporal lobar degeneration (FTLD) with TAR DNA-binding protein (TDP) 43 following current recommendations. The agreement rates were influenced by the immunohistochemical (IHC) method and by the classification strategy followed. p62-IHC staining yielded good uniform quality of stains, but the most reliable results were obtained implementing specific Abs directed against the hallmark protein TDP43. Both assessment of the type and the extent of lesions were influenced by the Abs and by the quality of stain. Assessment of the extent of the lesions yielded poor results repeatedly; thus, the extent of pathology should not be used in diagnostic consensus criteria. Whilst 31 neuropathologists typed 30 FTLD-TDP cases, inter-rater agreement ranged from 19 to 100 per cent, being highest when applying phosphorylated TDP43/IHC. The agreement was highest when designating Type C or Type A/B. In contrast, there was a poor agreement when attempting to separate Type A or Type B FTLD-TDP. In conclusion, we can expect that neuropathologist, independent of his/her familiarity with FTLD-TDP pathology, can identify a TDP43-positive FTLD case. The goal should be to state a Type (A, B, C, D) or a mixture of Types (A/B, A/C or B/C). Neuropathologists, other clinicians and researchers should be aware of the pitfalls whilst doing so. Agreement can be reached in an inter-laboratory setting regarding Type C cases with thick and long neurites, whereas the differentiation between Types A and B may be more troublesome.

  • 12.
    Alaie, Iman
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Frick, Andreas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Marteinsdottir, Ina
    Hartvig, Per
    Tillfors, Maria
    Eriksson, Elias
    Fredrikson, Mats
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Furmark, Tomas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Serotonin Synthesis Rate and the Tryptophan Hydroxylase-2 G-703T Polymorphism in Social Anxiety Disorder2014In: Biological Psychiatry, ISSN 0006-3223, E-ISSN 1873-2402, Vol. 75, no 9, p. 357S-357SArticle in journal (Other academic)
  • 13.
    Aldskogius, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Regenerative neurobiology.
    Animal models of spinal cord repair2012Collection (editor) (Other academic)
  • 14. Aldskogius, Håkan
    et al.
    Kozlova, Elena
    Dorsal root injury for the study of spinal cord injury repair2012In: Animal models of spinal cord repair, New York Heidelberg Dordrecht London: Humana Press, 2012, p. 109-129Chapter in book (Other academic)
    Abstract [en]

    Dorsal root injury provides opportunities for highly reproducible lesions and for detailed anatomical, physiological and behavioral outcome assessment with high precision and validity. Dorsal root injury models are used to several aspects of relevance to spinal cord injury repair: i) mechanisms of regeneration failure in the central nervous system and how to overcome it, ii) axon degeneration, as well as myelin degradation and elimination in the central nervous system - their roles and possible manipulations in spinal cord repair, iii) consequences in the spinal cord of mimicking human plexus injuries by dorsal root avulsion, including its effect on neuron survival, inflammatory processes and vascular dysfunction, and iv) therapeutic strategies which may be translated to the treatment of clinical plexus avulsion injuries. This chapter describes various dorsal root injury models, their relationship to basic and translational aspects of spinal cord injury repair, as well as basic experimental procedures associated with these models in rat and mouse.

  • 15. Alheim, K
    et al.
    Andersson, C
    Tingsborg, S
    Ziolkowska, M
    Schultzberg, M
    Bartfai, T
    Interleukin 1 expression is inducible by nerve growth factor in PC12 pheochromocytoma cells.1991In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 88, no 20, p. 9302-6Article in journal (Refereed)
    Abstract [en]

    Expression of the cytokine interleukin 1 alpha (IL-1 alpha) was demonstrated in the rat PC12 pheochromocytoma cell line by (i) immunohistochemistry using rabbit polyclonal antisera raised against the recombinant murine IL-1 alpha, (ii) an ELISA, and (iii) a specific cell conversion bioassay based on the use of LBRM33-1A5 cells. IL-1 alpha mRNA was demonstrated in the PC12 cells, by PCR amplification. Constitutive expression of IL-1 alpha in PC12 cells was demonstrated in all experiments, although the cellular levels of IL-1 alpha-like immunoreactivity varied. The expression of IL-1 alpha, as studied at the mRNA level, was inducible by mouse nerve growth factor (7S NGF), and the gene product level was inducible in a dose- and time-dependent fashion by 7S NGF. The maximum induction corresponds to a 600% increase in IL-1 alpha-like immunoreactivity above the expression level found in noninduced cells and occurred after a 3-day incubation of the cells with NGF at 0.75 micrograms/ml of culture medium. The significance of the ability of NGF to induce IL-1 expression lies in the fact that IL-1 itself also acts as a growth factor that promotes glial proliferation and, even more importantly, IL-1 itself induces the expression of NGF at peripheral nerve injury [Lindholm, D., Heumann, R., Meyer, M. & Thoenen, H. (1987) Nature (London) 330, 658-659].

  • 16.
    Alm, Per A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Logopedi.
    Stamning och skenande tal (løbsk tale): Om orsaker, mekanismer och behandling, med utgångspunkt från hjärnan2008In: Proceedings fra 1ste nordiske konference om stammen løbsk tale, Nyborg, Danmark, 2008Conference paper (Other academic)
  • 17.
    Alm, Per A
    Department of Clinical Neurosciences, Division of Psychiatry, Lund University, Lund, Sweden.
    Stuttering, emotions, and heart rate during anticipatory anxiety:: a critical review2004In: Journal of fluency disorders, ISSN 0094-730X, E-ISSN 1873-801X, Vol. 29, no 2, p. 123-133Article in journal (Refereed)
    Abstract [en]

    Persons who stutter often report their stuttering is influenced by emotional reactions, yet the nature of such relation is still unclear. Psychophysiological studies of stuttering have failed to find any major association between stuttering and the activity of the sympathetic nervous system. A review of published studies of heart rate in relation to stressful speech situations indicate that adults who stutter tend to show a paradoxical reduction of heart rate compared with nonstuttering persons. Reduction of heart rate has also been observed in humans and mammals during anticipation of an unpleasant stimulus, and is proposed to be an indication of anticipatory anxiety resulting in a “freezing response” with parasympathetic inhibition of the heart rate. It is suggested that speech-related anticipatory anxiety in persons who stutter is likely to be a secondary, conditioned reaction based on previous experiences of stuttering.

  • 18.
    Alm, Per A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Logopedi.
    Stuttering in relation to anxiety, temperament, and personality: Review and analysis with focus on causality2014In: Journal of fluency disorders, ISSN 0094-730X, E-ISSN 1873-801X, Vol. 40, p. 5-21Article, review/survey (Refereed)
    Abstract [en]

    Anxiety and emotional reactions have a central role in many theories of stuttering, for example that persons who stutter would tend to have an emotionally sensitive temperament. The possible relation between stuttering and certain traits of temperament or personality were reviewed and analyzed, with focus on temporal relations (i.e., what comes first). It was consistently found that preschool children who stutter (as a group) do not show any tendencies toward elevated temperamental traits of shyness or social anxiety compared with children who do not stutter. Significant group differences were, however, repeatedly reported for traits associated with inattention and hyperactivity/impulsivity, which is likely to reflect a subgroup of children who stutter. Available data is not consistent with the proposal that the risk for persistent stuttering is increased by an emotionally reactive temperament in children who stutter. Speech-related social anxiety develops in many cases of stuttering, before adulthood. Reduction of social anxiety in adults who stutter does not in itself appear to result in significant improvement of speech fluency. Studies have not revealed any relation between the severity of the motor symptoms of stuttering and temperamental traits. It is proposed that situational variability of stuttering, related to social complexity, is an effect of interference from social cognition and not directly from the emotions of social anxiety. In summary, the studies in this review provide strong evidence that persons who stutter are not characterized by constitutional traits of anxiety or similar constructs. Educational Objectives: This paper provides a review and analysis of studies of anxiety, temperament, and personality, organized with the objective to clarify cause and effect relations. Readers will be able to (a) understand the importance of effect size and distribution of data for interpretation of group differences; (b) understand the role of temporal relations for interpretation of cause and effect; (c) discuss the results of studies of anxiety, temperament and personality in relation to stuttering; and (d) discuss situational variations of stuttering and the possible role of social cognition. (C) 2014 Elsevier Inc. All rights reserved.

  • 19.
    Almandoz Gil, Leire
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Characterization of Physiological and Pathological Alpha-Synuclein: Implications for Parkinson’s Disease and Related Disorders2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Aggregated alpha-synuclein is the main component of Lewy bodies and Lewy neurites, intraneuronal inclusions found in the brains of Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) patients (synucleinopathies). Alpha-synuclein is a presynaptic protein, which is most commonly an unfolded monomer in its physiological state. However, under pathological conditions it can start to misfold and enter an aggregation pathway that will lead to the formation of oligomers of increasing size and finally insoluble fibrils. The oligomers have been hypothesized to be the most neurotoxic species, but studies of their properties have been hindered by their heterogeneity and kinetic instability. The overall aim of this thesis was to characterize and compare physiological and pathological forms of alpha-synuclein from different sources: recombinant monomers, oligomers formed in vitro through exposure to oxidative stress related reactive aldehydes, aggregates from a synucleinopathy mouse model and from synucleinopathy patients.

    In paper I we studied the effect of low molar excess of two lipid peroxidation products, 4-oxo-2-nonenal (ONE) and 4-hydroxy-2-nonenal (HNE), on the oligomerization of alpha-synuclein. Through biophysical methods we observed that, although both aldehydes bound to alpha-synuclein directly, ONE produced SDS-stable oligomers more rapidly than HNE. Moreover, ONE induced oligomerization at both acidic and neutral pH, while HNE only formed oligomers at neutral pH.

    In paper II we mapped the surface exposed epitopes of in vitro and in vivo generated alpha-synuclein species by using immunoglobulin Y antibodies raised against short linear peptides covering most of the alpha-synuclein sequence. Monomers were found to react with most antibodies, while the latter part of the N-terminus and mid-region of HNE oligomers and fibrils was found to be occluded in oligomers and fibrils. Through immunohistochemistry we compared alpha-synuclein aggregates in brain tissue from patients with synucleinopathies as well as from a mouse model expressing A30P human alpha-synuclein. Although the exposed epitopes were found to be similar overall, subtle differences were detected in the C-terminus.

    An additional aim of this thesis was to characterize synaptic aggregates of alpha-synuclein. In paper III we obtained synaptosomal preparations of the A30P mouse model and found that a subset of the alpha-synuclein present in the synaptosomes was proteinase K resistant and therefore aggregated. Further biochemical analyses showed that the aggregated alpha-synuclein mainly was of human, i.e. transgenic, origin and that Ser 129 was not phosphorylated, which otherwise is a common post translational modification of alpha-synuclein in Lewy bodies.

    It has been suggested that alpha-synuclein plays a role in neurotransmitter release by binding to the SNARE protein VAMP-2 and thereby chaperoning the SNARE complex assembly. In paper IV we used proximity ligation assay to visualize the co-localization of alpha-synuclein and the SNARE proteins in primary neurons from non-transgenic and A30P transgenic mice.

    In conclusion, in this thesis we have characterized a variety of alpha-synuclein species and shed light on the diversity of alpha-synuclein aggregates. Additionally, we have characterized synaptic species of alpha-synuclein and analyzed the co-localization between alpha-synuclein and SNARE proteins in neurons.

    List of papers
    1. Low molar excess of 4-oxo-2-nonenal and 4-hydroxy-2-nonenal promote oligomerization of alpha-synuclein through different pathways
    Open this publication in new window or tab >>Low molar excess of 4-oxo-2-nonenal and 4-hydroxy-2-nonenal promote oligomerization of alpha-synuclein through different pathways
    Show others...
    2017 (English)In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 110, p. 421-431Article in journal (Refereed) Published
    Abstract [en]

    Aggregated alpha-synuclein is the main component of Lewy bodies, intraneuronal inclusions found in brains with Parkinson's disease and dementia with Lewy bodies. A body of evidence implicates oxidative stress in the pathogenesis of these diseases. For example, a large excess (30:1, aldehyde:protein) of the lipid peroxidation end products 4-oxo-2-nonenal (ONE) or 4-hydroxy-2-nonenal (HNE) can induce alpha-synuclein oligomer formation. The objective of the study was to investigate the effect of these reactive aldehydes on alpha-synuclein at a lower molar excess (3:1) at both physiological (7.4) and acidic (5.4) pH. As observed by size-exclusion chromatography, ONE rapidly induced the formation of alpha-synuclein oligomers at both pH values, but the effect was less pronounced under the acidic condition. In contrast, only a small proportion of alpha-synuclein oligomers were formed with low excess HNE-treatment at physiological pH and no oligomers at all under the acidic condition. With prolonged incubation times (up to 96 h), more alpha-synuclein was oligomerized at physiological pH for both ONE and HNE. As determined by Western blot, ONE-oligomers were more SDS-stable and to a higher-degree cross-linked as compared to the HNE-induced oligomers. However, as shown by their greater sensitivity to proteinase K treatment, ONE-oligomers, exhibited a less compact structure than HNE-oligomers. As indicated by mass spectrometry, ONE modified most Lys residues, whereas HNE primarily modified the His50 residue and fewer Lys residues, albeit to a higher degree than ONE. Taken together, our data show that the aldehydes ONE and HNE can modify alpha-synuclein and induce oligomerization, even at low molar excess, but to a higher degree at physiological pH and seemingly through different pathways.

    Keywords
    Alpha-synuclein, Oligomers, 4-oxo-2-nonenal, 4-hydroxy-2-nonenal, Oxidative stress
    National Category
    Medical and Health Sciences Engineering and Technology Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-326663 (URN)10.1016/j.freeradbiomed.2017.07.004 (DOI)000406049200038 ()28690195 (PubMedID)
    Funder
    Swedish Research Council, 2011-4519, 2012-2172, 2010-6745Marianne and Marcus Wallenberg FoundationThe Swedish Brain FoundationSwedish Society of MedicineÅke Wiberg Foundation
    Note

    Correction in: Free Radical Biology and Medicine, vol. 117, pages 258-258.

    DOI: 10.1016/j.freeradbiomed.2018.02.007

    Available from: 2017-07-19 Created: 2017-07-19 Last updated: 2018-07-27Bibliographically approved
    2. Mapping of Surface-Exposed Epitopes of In Vitro and In Vivo Aggregated Species of Alpha-Synuclein
    Open this publication in new window or tab >>Mapping of Surface-Exposed Epitopes of In Vitro and In Vivo Aggregated Species of Alpha-Synuclein
    Show others...
    2017 (English)In: Cellular and molecular neurobiology, ISSN 0272-4340, E-ISSN 1573-6830, Vol. 37, no 7, p. 1217-1226Article in journal (Refereed) Published
    Abstract [en]

    Aggregated alpha-synuclein is the main component of Lewy bodies, intraneuronal deposits observed in Parkinson's disease and dementia with Lewy bodies. The objective of the study was to identify surface-exposed epitopes of alpha-synuclein in vitro and in vivo formed aggregates. Polyclonal immunoglobulin Y antibodies were raised against short linear peptides of the alpha-synuclein molecule. An epitope in the N-terminal region (1-10) and all C-terminal epitopes (90-140) were found to be exposed in an indirect enzyme-linked immunosorbent assay (ELISA) using recombinant monomeric, oligomeric, and fibrillar alpha-synuclein. In a phospholipid ELISA, the N-terminus and mid-region of alpha-synuclein (i.e., 1-90) were associated with phosphatidylserine and thus occluded from antibody binding. The antibodies that reacted most strongly with epitopes in the in vitro aggregates (i.e., 1-10 and epitopes between positions 90-140) also labeled alpha-synuclein inclusions in brains from transgenic (Thy-1)-h[A30P] alpha-synuclein mice and Lewy bodies and Lewy neurites in brains of patients with alpha-synucleinopathies. However, differences in reactivity were observed with the C-terminal antibodies when brain tissue from human and transgenic mice was compared. Taken together, the study shows that although similar epitopes are exposed in both in vitro and in vivo formed alpha-synuclein inclusions, structural heterogeneity can be observed between different molecular species.

    Keywords
    Parkinson's disease, Dementia with Lewy bodies, Alpha-synuclein, Epitope mapping
    National Category
    Geriatrics
    Identifiers
    urn:nbn:se:uu:diva-334384 (URN)10.1007/s10571-016-0454-0 (DOI)000409352200007 ()
    Available from: 2017-12-15 Created: 2017-12-15 Last updated: 2018-02-23Bibliographically approved
    3. Characterization of synaptic aggregates of alpha-synuclein in (Thy-1)-h[A30P] alpha-synuclein mice
    Open this publication in new window or tab >>Characterization of synaptic aggregates of alpha-synuclein in (Thy-1)-h[A30P] alpha-synuclein mice
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Neurosciences
    Identifiers
    urn:nbn:se:uu:diva-342341 (URN)
    Available from: 2018-02-20 Created: 2018-02-20 Last updated: 2018-02-23
    4. In situ proximity ligation assay reveals co-localization of alpha-synuclein and SNARE proteins in murine primary neurons
    Open this publication in new window or tab >>In situ proximity ligation assay reveals co-localization of alpha-synuclein and SNARE proteins in murine primary neurons
    Show others...
    2018 (English)In: Frontiers in Neurology, ISSN 1664-2295, E-ISSN 1664-2295, Vol. 9, article id 180Article in journal (Refereed) Published
    Abstract [en]

    The aggregation of alpha-synuclein (alpha Syn) is the pathological hallmark of Parkinson's disease, dementia with Lewy bodies and related neurological disorders. However, the physiological function of the protein and how this function relates to its pathological effects remain poorly understood. One of the proposed roles of aSyn is to promote the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex assembly by binding to VAMP-2. The objective of this study was to visualize the co-localization between aSyn and the SNARE proteins (VAMP-2, SNAP-25, and syntaxin-1) for the first time using in situ proximity ligation assay (PLA). Cortical primary neurons were cultured from either non-transgenic or transgenic mice expressing human aSyn with the A30P mutation under the Thy-1 promoter. With an antibody recognizing both mouse and human aSyn, a PLA signal indicating close proximity between aSyn and the three SNARE proteins was observed both in the soma and throughout the processes. No differences in the extent of PLA signals were seen between non-transgenic and transgenic neurons. With an antibody specific against human aSyn, the PLA signal was mostly located to the soma and was only present in a few cells. Taken together, in situ PLA is a method that can be used to investigate the co-localization of aSyn and the SNARE proteins in primary neuronal cultures

    Place, publisher, year, edition, pages
    Frontiers Media S.A., 2018
    National Category
    Neurosciences
    Identifiers
    urn:nbn:se:uu:diva-342580 (URN)10.3389/fneur.2018.00180 (DOI)000428063500001 ()29623065 (PubMedID)
    Funder
    Marianne and Marcus Wallenberg FoundationThe Swedish Brain FoundationSwedish Society of MedicineMagnus Bergvall Foundation
    Available from: 2018-02-22 Created: 2018-02-22 Last updated: 2018-06-28Bibliographically approved
  • 20.
    Almandoz-Gil, Leire
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Persson, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lindström, Veronica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Bergström, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    In situ proximity ligation assay reveals co-localization of alpha-synuclein and SNARE proteins in murine primary neurons2018In: Frontiers in Neurology, ISSN 1664-2295, E-ISSN 1664-2295, Vol. 9, article id 180Article in journal (Refereed)
    Abstract [en]

    The aggregation of alpha-synuclein (alpha Syn) is the pathological hallmark of Parkinson's disease, dementia with Lewy bodies and related neurological disorders. However, the physiological function of the protein and how this function relates to its pathological effects remain poorly understood. One of the proposed roles of aSyn is to promote the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex assembly by binding to VAMP-2. The objective of this study was to visualize the co-localization between aSyn and the SNARE proteins (VAMP-2, SNAP-25, and syntaxin-1) for the first time using in situ proximity ligation assay (PLA). Cortical primary neurons were cultured from either non-transgenic or transgenic mice expressing human aSyn with the A30P mutation under the Thy-1 promoter. With an antibody recognizing both mouse and human aSyn, a PLA signal indicating close proximity between aSyn and the three SNARE proteins was observed both in the soma and throughout the processes. No differences in the extent of PLA signals were seen between non-transgenic and transgenic neurons. With an antibody specific against human aSyn, the PLA signal was mostly located to the soma and was only present in a few cells. Taken together, in situ PLA is a method that can be used to investigate the co-localization of aSyn and the SNARE proteins in primary neuronal cultures

  • 21.
    Almandoz-Gil, Leire
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Persson, Emma
    Rofo, Fadi
    Ekmark-Lewén, Sara
    Ingelsson, Martin
    Bergström, Joakim
    Characterization of synaptic aggregates of alpha-synuclein in (Thy-1)-h[A30P] alpha-synuclein miceManuscript (preprint) (Other academic)
  • 22. Almeida, Alexandra D
    et al.
    Boije, Henrik
    Chow, Renee W
    He, Jie
    Tham, Jonathan
    Suzuki, Sachihiro C
    Harris, William A
    Spectrum of Fates: a new approach to the study of the developing zebrafish retina.2014In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 141, no 9, p. 1971-80Article in journal (Refereed)
    Abstract [en]

    The ability to image cells live and in situ as they proliferate and differentiate has proved to be an invaluable asset to biologists investigating developmental processes. Here, we describe a Spectrum of Fates approach that allows the identification of all the major neuronal subtypes in the zebrafish retina simultaneously. Spectrum of Fates is based on the combinatorial expression of differently coloured fluorescent proteins driven by the promoters of transcription factors that are expressed in overlapping subsets of retinal neurons. Here, we show how a Spectrum of Fates approach can be used to assess various aspects of neural development, such as developmental waves of differentiation, neuropil development, lineage tracing and hierarchies of fates in the developing zebrafish retina.

  • 23.
    Alsiö, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Univ Cambridge, Dept Psychol, Cambridge CB2 3EB, England.;Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge CB2 3EB, England..
    Nilsson, S. R. O.
    Univ Cambridge, Dept Psychol, Cambridge CB2 3EB, England.;Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge CB2 3EB, England..
    Gastambide, F.
    Eli Lilly & Co Ltd, Lilly Ctr Cognit Neurosci, Erl Wood Manor, Windlesham GU20 6PH, Surrey, England..
    Wang, R. A. H.
    Univ Cambridge, Dept Psychol, Cambridge CB2 3EB, England.;Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge CB2 3EB, England..
    Dam, S. A.
    Univ Cambridge, Dept Psychol, Cambridge CB2 3EB, England.;Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge CB2 3EB, England..
    Mar, A. C.
    Univ Cambridge, Dept Psychol, Cambridge CB2 3EB, England.;Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge CB2 3EB, England..
    Tricklebank, M.
    Eli Lilly & Co Ltd, Lilly Ctr Cognit Neurosci, Erl Wood Manor, Windlesham GU20 6PH, Surrey, England..
    Robbins, T. W.
    Univ Cambridge, Dept Psychol, Cambridge CB2 3EB, England.;Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge CB2 3EB, England..
    The role of 5-HT2C receptors in touchscreen visual reversal learning in the rat: a cross-site study2015In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 232, no 21-22, p. 4017-4031Article in journal (Refereed)
    Abstract [en]

    Reversal learning requires associative learning and executive functioning to suppress non-adaptive responding. Reversal-learning deficits are observed in e.g. schizophrenia and obsessive-compulsive disorder and implicate neural circuitry including the orbitofrontal cortex (OFC). Serotonergic function has been strongly linked to visual reversal learning in humans and experimental animals but less is known about which receptor subtypes are involved. The objectives of the study were to test the effects of systemic and intra-OFC 5-HT2C-receptor antagonism on visual reversal learning in rats and assess the psychological mechanisms underlying these effects within novel touchscreen paradigms. In experiments 1-2, we used a novel 3-stimulus task to investigate the effects of 5-HT2C-receptor antagonism through SB 242084 (0.1, 0.5 and 1.0 mg/kg i.p.) cross-site. Experiment 3 assessed the effects of SB 242084 in 2-choice reversal learning. In experiment 4, we validated a novel touchscreen serial visual reversal task suitable for neuropharmacological microinfusions by baclofen-/muscimol-induced OFC inactivation. In experiment 5, we tested the effect of intra-OFC SB 242084 (1.0 or 3.0 mu g/side) on performance in this task. In experiments 1-3, SB 242084 reduced early errors but increased late errors to criterion. In experiment 5, intra-OFC SB 242084 reduced early errors without increasing late errors in a reversal paradigm validated as OFC dependent (experiment 4). Intra-OFC 5-HT2C-receptor antagonism decreases perseveration in novel touchscreen reversal-learning paradigms for the rat. Systemic 5-HT2C-receptor antagonism additionally impairs late learning-a robust effect observed cross-site and potentially linked to impulsivity. These conclusions are discussed in terms of neural mechanisms underlying reversal learning and their relevance to psychiatric disorders.

  • 24.
    Alsiö, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Nordenankar, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Arvidsson, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Birgner, Carolina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Mahmoudi, Souha
    Halbout, Briac
    Smith, Casey
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Fortin, Guillaume M.
    Olson, Lars
    Descarries, Laurent
    Trudeau, Louis-Eric
    Kullander, Klas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Levesque, Daniel
    Wallén-Mackenzie, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Enhanced Sucrose and Cocaine Self-Administration and Cue-Induced Drug Seeking after Loss of VGLUT2 in Midbrain Dopamine Neurons in Mice2011In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 31, no 35, p. 12593-12603Article in journal (Refereed)
    Abstract [en]

    The mesostriatal dopamine (DA) system contributes to several aspects of responses to rewarding substances and is implicated in conditions such as drug addiction and eating disorders. A subset of DA neurons has been shown to express the type 2 Vesicular glutamate transporter (Vglut2) and may therefore corelease glutamate. In the present study, we analyzed mice with a conditional deletion of Vglut2 in DA neurons (Vglut2(f/f;DAT-Cre)) to address the functional significance of the glutamate-DA cophenotype for responses to cocaine and food reinforcement. Biochemical parameters of striatal DA function were also examined by using DA receptor autoradiography, immediate-early gene quantitative in situ hybridization after cocaine challenge, and DA-selective in vivo chronoamperometry. Mice in which Vglut2 expression had been abrogated in DA neurons displayed enhanced operant self-administration of both high-sucrose food and intravenous cocaine. Furthermore, cocaine seeking maintained by drug-paired cues was increased by 76%, showing that reward-dependent plasticity is perturbed in these mice. In addition, several lines of evidence suggest that adaptive changes occurred in both the ventral and dorsal striatum in the absence of VGLUT2: DA receptor binding was increased, and basal mRNA levels of the DA-induced early genes Nur77 and c-fos were elevated as after cocaine induction. Furthermore, in vivo challenge of the DA system by potassium-evoked depolarization revealed less DA release in both striatal areas. This study demonstrates that absence of VGLUT2 in DA neurons leads to perturbations of reward consumption as well as reward-associated memory, features of particular relevance for addictive-like behavior.

  • 25.
    Alsiö, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Pickering, Christopher
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Lindblom, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Anxiolytic response after palatable diet consumption but not food restriction in rats2009In: Appetite, ISSN 0195-6663, E-ISSN 1095-8304, Vol. 52, no 3, p. 816-816Article in journal (Other academic)
  • 26.
    Alsiö, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Hulting, Anna-Lena
    Meyerson, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Lindblom, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Anxiety-like behaviour predicts the preference for a high-carbohydrate diet in outbred rats2007In: Behavioural Pharmacology, ISSN 0955-8810, E-ISSN 1473-5849, Vol. 18, p. S41-S41Article in journal (Other academic)
  • 27.
    Amandusson, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Axelson, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Comparison between adaptive and fixed stimulus paired-pulsetranscranial magnetic stimulation (ppTMS) in normal subjects2017In: Clinical Neurophysiology Practice, ISSN 2467-981X, p. 91-97Article in journal (Refereed)
    Abstract [en]

    Objectives

    Paired-pulse TMS (ppTMS) examines cortical excitability but may require lengthy test procedures and fine tuning of stimulus parameters due to the inherent variability of the elicited motor evoked potentials (MEPs) and their tendency to exhibit a ‘ceiling/floor effects’ in inhibition trials. Aiming to overcome some of these limitations, we implemented an ‘adaptive’ ppTMS protocol and compared the obtained excitability indices with those from ‘conventional’ fixed-stimulus ppTMS.

    Methods

    Short- and long interval intracortical inhibition (SICI and LICI) as well as intracortical facilitation (ICF) were examined in 20 healthy subjects by adaptive ppTMS and fixed-stimulus ppTMS. The test stimulus intensity was either adapted to produce 500 μV MEPs (by a maximum likelihood strategy in combination with parameter estimation by sequential testing) or fixed to 120% of resting motor threshold (rMT). The conditioning stimulus was 80% rMT for SICI and ICF and 120% MT for LICI in both tests.

    Results

    There were significant (p < 0.05) intraindividual correlations between the two methods for all excitability measures. There was a clustering of SICI and LICI indices near maximal inhibition (‘ceiling effect’) in fixed-stimulus ppTMS which was not observed for adaptive SICI and LICI.

    Conclusions

    Adaptive ppTMS excitability data correlates to those acquired from fixed-stimulus ppTMS.

    Significance

    Adaptive ppTMS is easy to implement and may serve as a more sensitive method to detect changes in cortical inhibition than fixed stimulus ppTMS. Whether equally confident data are produced by less stimuli with our adaptive approach (as already confirmed for motor threshold estimation) remains to be explored.

  • 28. Andersson, Julia
    et al.
    Helenius, Clara
    Effekter av neurokirurgi i vaket tillstånd på postoperativ tal- och språkförmåga2015Independent thesis Advanced level (degree of Master (One Year)), 20 credits / 30 HE creditsStudent thesis
    Abstract [sv]

    ABSTRACT

    Gliomas are the most common type of brain tumours and are often diffusely localised in areas that give permanent functional symptoms, so called eloquent areas. These areas partly control speech and language. Low-grade glioma (LGG) is the most suitable type of tumour for awake surgery. By performing surgery while the patient is awake, intra-operative testing of language and speech is possible and a more secure tumour resection can be performed. Patients that are to undergo such surgery execute a pre-operative speech and language testing, done by a speech and language pathologist, which is later used as a reference for the intra- and post-operative assessment. In this study the pre- and post-operative results for 20 patients with gliomas, who underwent awake surgery on 23 occasions at the Akademiska hospital in Uppsala from June 2013 until August 2015 were analysed. The aim of this study was to evaluate how the tumour resection affected speech and language. Furthermore, possible correlations between language deficits and tumour localisation were investigated. The results showed considerable variations in whether the patients improved and/or deteriorated. Overall, more patients deteriorated than improved. More pronounced deficits were shown for naming and verbal fluency pre- and post-operatively. A correlation analysis showed that patients with a tumour located in insula had greater difficulties with naming than patients with other tumour locations. This study provides an evaluation of the language outcomes of patients who underwent awake surgery in Uppsala. Additionally, the study resulted in an overview of the development of speech and language pathologists’ assessments since the start of awake surgery in 2013, and specific recommendations for improvement.

     

    Keywords: Low-grade gliomas, awake surgery, pre- and post-operative speech and language testing, speech and language pathology, naming, verbal fluency, insula

    SAMMANFATTNING

    Gliom är den vanligaste typen av hjärntumör och är ofta diffust lokaliserad i områden som ger bestående funktionsnedsättning vid skada, så kallade elokventa områden. Dessa områden kontrollerar bland annat tal och språk. Av dessa är det de lågmaligna/låggradiga gliomen (LGG) som oftast är aktuella för resektion i vaket tillstånd. Genom att utföra operationen när patienten är vaken tillåts intraoperativ testning av tal och språk vilket leder till säkrare resektion. Alla patienter som ska genomgå denna typ av operation utför preoperativ tal- och språkbedömning hos logoped, som senare används som referenspunkt för den intra- och postoperativa bedömningen. I denna studie analyserades pre- och postoperativa resultat för 20 patienter med gliom som opererats vid 23 olika tillfällen på Akademiska sjukhuset i Uppsala sedan verksamheten startade juni 2013. Två frågeställningar skulle besvaras: Hur har tumörresektionen påverkat tal- och språkförmågan hos patienter som genomgått kirurgi i vaket tillstånd? Finns det något samband mellan språkliga symptom och tumörlokalisation? Resultatet visade stora variationer i huruvida patienterna förbättrades och/eller försämrades i sin tal- och språkfunktion efter operation. Generellt noterades dock fler försämringar än förbättringar. Benämning och verbalt ordflöde var de två parametrar där störst svårigheter påvisades både pre- och postoperativt. Korrelationsanalys visade att patienter med tumörer i insula hade större svårigheter med benämning än patienter med övriga tumörlokalisationer. Förutom att beskriva det språkliga utfallet för de patienter som genomgått kirurgi i vaket tillstånd så har denna studie resulterat i en översikt av hur logopedbedömningarna sett ut pre- och postoperativt sedan vakenkirurgin infördes i Uppsala, och även förslag på hur de kan förbättras i framtiden.

     

    Nyckelord: Lågmaligna gliom, vakenkirurgi, pre- och postoperativ tal- och språkbedömning, logopedi, benämning, verbalt ordflöde, insula 

  • 29.
    Andrae, Johanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Hansson, Inga
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Afink, G B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Nistér, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Platelet-derived growth factor receptor-alpha in ventricular zone cells and in developing neurons.2001In: Molecular and Cellular Probes, ISSN 1044-7431, E-ISSN 1095-9327, Vol. 17, no 6Article in journal (Refereed)
    Abstract [en]

    Cells in the early neuroepithelium differentiate and give rise to all cells in the central nervous system (CNS). The ways from a multipotent CNS stem cell to specialized neurons and glia are not fully understood. Using immunohistochemistry we found that neuroepithelial cells express the platelet-derived growth factor receptor-alpha (PDGFR-alpha) in the neural plate at embryonic day 8.5 and onwards in the neural tube. The protein was polarized to ventricular endfeet. Furthermore, PDGFR-alpha expression was localized to cells undergoing early neuronal development. We also found PDGFR-alpha expression in developing granule cells in the postnatal cerebellum, in Purkinje cells in the adult cerebellum and on processes of developing dorsal root ganglion cells. Previous reports mainly describe PDGFR-alpha expression in oligodendrocyte precursors and glial cells. We believe, in line with a few previous reports, that the PDGFR-alpha in addition marks a pool of undifferentiated cells, which are able to differentiate into neurons.

  • 30. Andreou, Dimitrios
    et al.
    Söderman, Erik
    Axelsson, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Sedvall, Göran C
    Terenius, Lars
    Agartz, Ingrid
    Jönsson, Erik G
    Polymorphisms in genes implicated in dopamine, serotonin and noradrenalin metabolism suggest association with cerebrospinal fluid monoamine metabolite concentrations in psychosis2014In: Behavioral and Brain Functions, ISSN 1744-9081, E-ISSN 1744-9081, Vol. 10, p. 26-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) are the major monoamine metabolites in the central nervous system (CNS). Their cerebrospinal fluid (CSF) concentrations, reflecting the monoamine turnover rates in CNS, are partially under genetic influence and have been associated with schizophrenia. We have hypothesized that CSF monoamine metabolite concentrations represent intermediate steps between single nucleotide polymorphisms (SNPs) in genes implicated in monoaminergic pathways and psychosis.

    METHODS: We have searched for association between 119 SNPs in genes implicated in monoaminergic pathways [tryptophan hydroxylase 1 (TPH1), TPH2, tyrosine hydroxylase (TH), DOPA decarboxylase (DDC), dopamine beta-hydroxylase (DBH), catechol-O-methyltransferase (COMT), monoamine oxidase A (MAOA) and MAOB] and monoamine metabolite concentrations in CSF in 74 patients with psychotic disorder.

    RESULTS: There were 42 nominally significant associations between SNPs and CSF monoamine metabolite concentrations, which exceeded the expected number (20) of nominal associations given the total number of tests performed. The strongest association (p = 0.0004) was found between MAOB rs5905512, a SNP previously reported to be associated with schizophrenia in men, and MHPG concentrations in men with psychotic disorder. Further analyses in 111 healthy individuals revealed that 41 of the 42 nominal associations were restricted to patients with psychosis and were absent in healthy controls.

    CONCLUSIONS: The present study suggests that altered monoamine turnover rates in CNS reflect intermediate steps in the associations between SNPs and psychosis.

  • 31.
    Anens, Elisabeth
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiotheraphy.
    Emtner, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiotheraphy. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Zetterberg, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiotheraphy.
    Hellström, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiotheraphy.
    Physical activity in subjects with multiple sclerosis with focus on gender differences: a survey2014In: BMC Neurology, ISSN 1471-2377, E-ISSN 1471-2377, Vol. 14, p. 47-Article in journal (Refereed)
    Abstract [en]

    Background: There is increasing research that examines gender-issues in multiple sclerosis (MS), but little focus has been placed on gender-issues regarding physical activity. The aim of the present study was to describe levels of physical activity, self-efficacy for physical activity, fall-related self-efficacy, social support for physical activity, fatigue levels and the impact of MS on daily life, in addition to investigating gender differences. Methods: The sample for this cross-sectional cohort study consisted of 287 (84 men; 29.3%) adults with MS recruited from the Swedish Multiple Sclerosis Registry. A questionnaire was sent to the subjects consisting of the self-administrated measurements: Physical Activity Disability Survey - Revised, Exercise Self-Efficacy Scale, Falls-Efficacy Scale (Swedish version), Social Influences on Physical Activity, Fatigue Severity Scale and Multiple Sclerosis Impact Scale. Response rate was 58.2%. Results: Men were less physically active, had lower self-efficacy for physical activity and lower fall-related self-efficacy than women. This was explained by men being more physically affected by the disease. Men also received less social support for physical activity from family members. The level of fatigue and psychological consequences of the disease were similar between the genders in the total sample, but subgroups of women with moderate MS and relapsing remitting MS experienced more fatigue than men. Conclusions: Men were less physically active, probably a result of being more physically affected by the disease. Men being more physically affected explained most of the gender differences found in this study. However, the number of men in the subgroup analyses was small and more research is needed. A gender perspective should be considered in strategies for promoting physical activity in subjects with MS, e. g. men may need more support to be physically active.

  • 32.
    Anthony, Lowell B.
    et al.
    Univ Kentucky, Markey Canc Ctr, Div Med Oncol, Lexington, KY 40536 USA..
    Pavel, Marianne E.
    Charite, Campus Virchow Klinikum, D-13353 Berlin, Germany..
    Hainsworth, John D.
    Sarah Cannon Res Inst, Nashville, TN USA..
    Kvols, Larry K.
    H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA..
    Segal, Scott
    Novartis Pharmaceut, E Hanover, NJ USA..
    Hoersch, Dieter
    Zentralklin Bad Berka GmbH, Klin Innere Med Gastroenterol & Endokrinol, Zentrum Neuroendokrine Tumore, Bad Berka, Germany..
    Van Cutsem, Eric
    Univ Hosp Gasthuisberg, Leuven, Belgium..
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Yao, James C.
    Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA..
    Impact of Previous Somatostatin Analogue Use on the Activity of Everolimus in Patients with Advanced Neuroendocrine Tumors: Analysis from the Phase III RADIANT-2 Trial2015In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 102, no 1-2, p. 18-25Article in journal (Refereed)
    Abstract [en]

    Background/Aims: The phase III placebo-controlled RADI-ANT-2 trial investigated the efficacy of everolimus plus octreotide long-acting repeatable (LAR) in patients with advanced neuroendocrine tumors (NET) associated with carcinoid syndrome. Here we report a secondary analysis based on the previous somatostatin analogue (SSA) exposure status of patients enrolled in RADIANT-2. Methods: Patients were randomly assigned to receive oral everolimus 10 mg/day plus octreotide LAR 30 mg intramuscularly (i.m.) or to receive matching placebo plus octreotide LAR 30 mg i.m. every 28 days. SSA treatment before study enrollment was permitted. Patient characteristics and progression-free survival (PFS) were analyzed by treatment arm and previous SSA exposure status. Results: Of the 429 patients enrolled in RADI-ANT-2, 339 were previously exposed to SSA (95% received octreotide); 173 of 339 patients were in the everolimus plus octreotide LAR arm. All patients had a protocol-specified history of secretory symptoms, but analysis by type showed that more patients who previously received SSA therapy had a history of flushing symptoms (77%), diarrhea (86%), or both (63%) compared with SSA-naive patients (62, 62, and 24%, respectively). Patients who received everolimus plus octreotide LAR had longer median PFS regardless of previous SSA exposure (with: PFS 14.3 months, 95% confidence interval, CI, 12.0-20.1; without: 25.2 months, 95% CI, 12.0-not reached) compared with patients who received placebo plus octreotide LAR (with: 11.1 months, 95% CI, 8.4-14.6; without: 13.6 months, 95% CI, 8.2-22.7). Conclusion: Everolimus in combination with octreotide improves PFS in patients with advanced NET associated with carcinoid syndrome, regardless of previous SSA exposure.

  • 33. Aquilonius, Sten-Magnus
    et al.
    Bergström, Kjell
    Eckernäs, S.A
    Hartvig, Per
    Leenders, K.L.
    Lundkvist, Hans
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry.
    Rimland, Annika
    Ulin, Johan
    Långström, Bengt
    In vivo visualization of striatal dopamine reuptake sites using [11C]nomifensine and       positron emission tomography.,1987In: Acta Neurol. Scand., Vol. 76, p. 283-287Article in journal (Refereed)
  • 34. Archer, Trevor
    et al.
    Garcia, Danilo
    Fredriksson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Restoration of MPTP-induced deficits by exercise and Milmed (R) co-treatment2014In: PeerJ, ISSN 2167-8359, E-ISSN 2167-8359, Vol. 2, p. e531-Article in journal (Refereed)
    Abstract [en]

    1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces permanent neurochemical and functional deficits. Following the administration of either two or four injections of the dopamine neurotoxin, MPTP, at a dose of 40 mg/kg, C57/BL6 mice were given access to running-wheels (30-min sessions, four times/week, Monday-Thursday) and treatment with the treated yeast, Milmed (R) (four times/week, Monday-Thursday), or simply running-wheel exercise by itself, over ten weeks. It was observed that the combination of physical exercise and Milmed (R) treatment, the MPTP + Exercise + Yeast (MC) group [MPTP + Exercise + Milmed (R) (MC)], restored spontaneous motor activity markedly by test day 10, restored completely subthreshold L-Dopa-induced activity, and dopamine concentration to 76% of control values, in the condition wherein two administrations of MPTP (2 x 40 mg/kg) were given prior to initiation of exercise and/or Milmed (R) treatment. Physical exercise by itself, MPTP + Exercise (MC) group, attenuated these deficits only partially. Administration of MPTP four times (i.e., 40 mg/kg, s.c., once weekly over four weeks for a total of 160 mg/kg, MPTP + Exercise + Yeast (MC) group [MPTP + Exercise + Milmed (R) (SC)] and MPTP + Exercise (SC), induced a lesioning effect that was far too severe for either exercise alone or the exercise + Milmed (R) combination to ameliorate. Nevertheless, these findings indicate a powerful effect of physical exercise reinforced by Milmed (R) treatment in restoring MPTP-induced deficits of motor function and dopamine neurochemistry in mice.

  • 35.
    Arvidsson, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Motion and Emotion: Functional In Vivo Analyses of the Mouse Basal Ganglia2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    A major challenge in the field of neuroscience is to link behavior with specific neuronal circuitries and cellular events. One way of facing this challenge is to identify unique cellular markers and thus have the ability to, through various mouse genetics tools, mimic, manipulate and control various aspects of neuronal activity to decipher their correlation to behavior. The Vesicular Glutamate Transporter 2 (VGLUT2) packages glutamate into presynaptic vesicles for axonal terminal release. In this thesis, VGLUT2 was used to specifically target cell populations within the basal ganglia of mice with the purpose of investigating its connectivity, function and involvement in behavior. The motor and limbic loops of the basal ganglia are important for processing of voluntary movement and emotions. During such physiological events, dopamine plays a central role in modulating the activity of these systems.

    The brain reward system is mainly formed by dopamine projections from the ventral tegmental area (VTA) to the ventral striatum. Certain dopamine neurons within the VTA exhibit the ability to co-release dopamine and glutamate. In paper I, glutamate and dopamine co-release was targeted and our results demonstrate that the absence of VGLUT2 in dopamine neurons leads to perturbations of reward consumption and reward-associated memory, probably due to reduced DA release observed in the striatum as detected by in vivo chronoamperometry.

    In papers II and IV, VGLUT2 in a specific subpopulation within the subthalamic nucleus (STN) was identified and targeted. Based on the described role of the STN in movement control, we hypothesized that the mice would be hyperlocomotive. As shown in paper II, this was indeed the case. In paper IV, a putative reward-related phenotype was approached and we could show reduced operant-self administration of sugar and altered dopamine release levels suggesting a role for the STN in reward processes.

    In paper III, we investigated and identified age- and sex-dimorphisms in dopamine kinetics in the dorsal striatum of one of the most commonly used mouse lines worldwide, the C57/Bl6J. Our results point to the importance of taking these dimorphisms into account when utilizing the C57/Bl6J strain as model for neurological and neuropsychiatric disorders.

    List of papers
    1. Enhanced Sucrose and Cocaine Self-Administration and Cue-Induced Drug Seeking after Loss of VGLUT2 in Midbrain Dopamine Neurons in Mice
    Open this publication in new window or tab >>Enhanced Sucrose and Cocaine Self-Administration and Cue-Induced Drug Seeking after Loss of VGLUT2 in Midbrain Dopamine Neurons in Mice
    Show others...
    2011 (English)In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 31, no 35, p. 12593-12603Article in journal (Refereed) Published
    Abstract [en]

    The mesostriatal dopamine (DA) system contributes to several aspects of responses to rewarding substances and is implicated in conditions such as drug addiction and eating disorders. A subset of DA neurons has been shown to express the type 2 Vesicular glutamate transporter (Vglut2) and may therefore corelease glutamate. In the present study, we analyzed mice with a conditional deletion of Vglut2 in DA neurons (Vglut2(f/f;DAT-Cre)) to address the functional significance of the glutamate-DA cophenotype for responses to cocaine and food reinforcement. Biochemical parameters of striatal DA function were also examined by using DA receptor autoradiography, immediate-early gene quantitative in situ hybridization after cocaine challenge, and DA-selective in vivo chronoamperometry. Mice in which Vglut2 expression had been abrogated in DA neurons displayed enhanced operant self-administration of both high-sucrose food and intravenous cocaine. Furthermore, cocaine seeking maintained by drug-paired cues was increased by 76%, showing that reward-dependent plasticity is perturbed in these mice. In addition, several lines of evidence suggest that adaptive changes occurred in both the ventral and dorsal striatum in the absence of VGLUT2: DA receptor binding was increased, and basal mRNA levels of the DA-induced early genes Nur77 and c-fos were elevated as after cocaine induction. Furthermore, in vivo challenge of the DA system by potassium-evoked depolarization revealed less DA release in both striatal areas. This study demonstrates that absence of VGLUT2 in DA neurons leads to perturbations of reward consumption as well as reward-associated memory, features of particular relevance for addictive-like behavior.

    National Category
    Neurosciences
    Identifiers
    urn:nbn:se:uu:diva-158895 (URN)10.1523/JNEUROSCI.2397-11.2011 (DOI)000294451900022 ()
    Available from: 2011-09-19 Created: 2011-09-19 Last updated: 2018-01-12Bibliographically approved
    2. Limiting glutamate transmission in a Vglut2-expressing subpopulation of the subthalamic nucleus is sufficient to cause hyperlocomotion
    Open this publication in new window or tab >>Limiting glutamate transmission in a Vglut2-expressing subpopulation of the subthalamic nucleus is sufficient to cause hyperlocomotion
    Show others...
    2014 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 111, no 21, p. 7837-7842Article in journal (Refereed) Published
    Abstract [en]

    The subthalamic nucleus (STN) is a key area of the basal ganglia circuitry regulating movement. We identified a subpopulation of neurons within this structure that coexpresses Vglut2 and Pitx2, and by conditional targeting of this subpopulation we reduced Vglut2 expression levels in the STN by 40%, leaving Pitx2 expression intact. This reduction diminished, yet did not eliminate, glutamatergic transmission in the substantia nigra pars reticulata and entopeduncular nucleus, two major targets of the STN. The knockout mice displayed hyperlocomotion and decreased latency in the initiation of movement while preserving normal gait and balance. Spatial cognition, social function, and level of impulsive choice also remained undisturbed. Furthermore, these mice showed reduced dopamine transporter binding and slower dopamine clearance in vivo, suggesting that Vglut2-expressing cells in the STN regulate dopaminergic transmission. Our results demonstrate that altering the contribution of a limited population within the STN is sufficient to achieve results similar to STN lesions and high-frequency stimulation, but with fewer side effects.

    Keywords
    Parkinson disease, deep brain stimulation, vesicular transporter, optogenetics, striatum
    National Category
    Neurosciences
    Identifiers
    urn:nbn:se:uu:diva-227717 (URN)10.1073/pnas.1323499111 (DOI)000336411300073 ()
    Note

    N.S. and S.P. contributed equally to this work.

    Available from: 2014-06-30 Created: 2014-06-30 Last updated: 2018-01-11Bibliographically approved
    3. Age- and Sex-Dependence of Dopamine Release and Capacity for Recovery Identified in the Dorsal Striatum ofC57/Bl6J Mice
    Open this publication in new window or tab >>Age- and Sex-Dependence of Dopamine Release and Capacity for Recovery Identified in the Dorsal Striatum ofC57/Bl6J Mice
    2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 6, p. e99592-Article in journal (Refereed) Published
    Abstract [en]

    The dorsal striatum is the main input structure of the basal ganglia and the major target area of dopaminergic projections originating in the substantia nigra pars compacta. Heavily involved in the regulation of voluntary movement and habit formation, this structure is of strong importance in Parkinson's disease, obsessive-compulsive disorder, Tourette's syndrome and addiction. The C57/Bl6J mouse strain, the most commonly used strain in preclinical research today, is frequently used as a model organism for analysis of dopaminergic parameters implicated in human pathophysiology. Several components of the dopamine system have been shown to vary with age and sex, however knowledge of the contribution of these factors for dopamine release kinetics in the C57/Bl6J mouse strain is lacking. In the present study, we used an intracranial KCl-stimulation challenge paradigm to provoke release from dopaminergic terminals in the dorsal striatum of anaesthetized C57/Bl6J mice. By high-speed in vivo chronoamperometric recordings, we analyzed DA release parameters in male and female mice of two different ages. Our experiments demonstrate elevated DA amplitudes in adult compared to young mice of both sexes and higher DA amplitudes in females compared to males at both ages. Adult mice exhibited higher recovery capabilities after repeated stimulation than did young mice and also showed a lower variability in the kinetic parameters trise and t80 between stimulations. These results identified age- and sex- dimorphisms in DA release parameters and point to the importance of taking these dimorphisms into account when utilizing the C57/Bl6J mouse strain as model for neurological and neuropsychiatric disorders.

    National Category
    Neurosciences Basic Medicine
    Identifiers
    urn:nbn:se:uu:diva-229825 (URN)10.1371/journal.pone.0099592 (DOI)000338701300080 ()24925086 (PubMedID)
    Available from: 2014-08-14 Created: 2014-08-14 Last updated: 2018-01-11Bibliographically approved
    4. Selective targeting within the subthalamic nucleus alters responsiveness to sugar and regulates accumbal dopamine levels
    Open this publication in new window or tab >>Selective targeting within the subthalamic nucleus alters responsiveness to sugar and regulates accumbal dopamine levels
    (English)Manuscript (preprint) (Other academic)
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-229851 (URN)
    Available from: 2014-08-15 Created: 2014-08-15 Last updated: 2015-01-22
  • 36.
    Arvidsson, Emma
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Viereckel, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Mikulovic, Sanja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Wallén-Mackenzie, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Age- and Sex-Dependence of Dopamine Release and Capacity for Recovery Identified in the Dorsal Striatum ofC57/Bl6J Mice2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 6, p. e99592-Article in journal (Refereed)
    Abstract [en]

    The dorsal striatum is the main input structure of the basal ganglia and the major target area of dopaminergic projections originating in the substantia nigra pars compacta. Heavily involved in the regulation of voluntary movement and habit formation, this structure is of strong importance in Parkinson's disease, obsessive-compulsive disorder, Tourette's syndrome and addiction. The C57/Bl6J mouse strain, the most commonly used strain in preclinical research today, is frequently used as a model organism for analysis of dopaminergic parameters implicated in human pathophysiology. Several components of the dopamine system have been shown to vary with age and sex, however knowledge of the contribution of these factors for dopamine release kinetics in the C57/Bl6J mouse strain is lacking. In the present study, we used an intracranial KCl-stimulation challenge paradigm to provoke release from dopaminergic terminals in the dorsal striatum of anaesthetized C57/Bl6J mice. By high-speed in vivo chronoamperometric recordings, we analyzed DA release parameters in male and female mice of two different ages. Our experiments demonstrate elevated DA amplitudes in adult compared to young mice of both sexes and higher DA amplitudes in females compared to males at both ages. Adult mice exhibited higher recovery capabilities after repeated stimulation than did young mice and also showed a lower variability in the kinetic parameters trise and t80 between stimulations. These results identified age- and sex- dimorphisms in DA release parameters and point to the importance of taking these dimorphisms into account when utilizing the C57/Bl6J mouse strain as model for neurological and neuropsychiatric disorders.

  • 37.
    Arvidsson, Patrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg.
    Granlund, Mats
    Thyberg, Mikael
    How are the activity and participation aspects of the ICF used?: Examples from studies of people with intellectual disability2015In: NeuroRehabilitation (Reading, MA), ISSN 1053-8135, E-ISSN 1878-6448, Vol. 36, no 1, p. 45-49Article, review/survey (Refereed)
    Abstract [en]

    INTRODUCTION: Interdisciplinary differences regarding understanding the International Classification of Functioning, Disability and Health (ICF) concepts activity/participation may hinder its unifying purpose. In the ICF model, functioning (and disability) is described as a tripartite concept: 1) Body structures/functions, 2) Activities, and 3) Participation. Activities refer to an individual perspective on disability that does not tally with the basic structure of social models. OBJECTIVE: To review how activity and participation are actually used in studies of intellectual disability (ID). CONCLUSION: Based on 16 papers, four different usages of activity/participation were found. 1) Theoretical reference to tripartite ICF concept with attempts to use it. 2) Theoretical reference to tripartite ICF concept without actual use of activities. 3) "Atheoretical" approach with implicit focus on participation. 4) Theoretical reference to bipartite concept with corresponding use of terms. The highlighted studies have in common a focus on participation. However, the usage of the term "activity" differs both within and between studies. Such terminology will probably confuse interdisciplinary communication rather than facilitating it. Also, the use of an explicit underlying theory differs, from references to a tripartite to references to a bipartite concept of disability. This paper is focused on ID, but the discussed principles regarding the ICF and interdisciplinary disability theory are applicable to other diagnostic groups within rehabilitation practices.

  • 38. Arzberger, Thomas
    et al.
    Giese, Armin
    Edbauer, Dieter
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Ferrer, Isidro
    Special Issue: Research on Brain Bank Material - From Ethical Issues to Biomolecular Studies2015In: Journal of neural transmission, ISSN 0300-9564, E-ISSN 1435-1463, Vol. 122, no 7, p. 933-936Article in journal (Other academic)
  • 39.
    Axelson, Hans W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Human motor compensations for thixotropy-dependent changes in muscular resting tension after moderate joint movements2004In: Acta Physiologica Scandinavica, ISSN 0001-6772, E-ISSN 1365-201X, Vol. 182, no 3, p. 295-304Article in journal (Refereed)
    Abstract [en]

    AIM:

    This study on healthy subjects explores history-dependent changes in the resting tension of relaxed wrist muscles after moderate joint excursions and the motor control consequences of these changes during voluntary wrist joint position maintenance.

    METHODS:

    Integrated surface electromyogram (IEMG) was recorded from wrist extensor/flexor muscles. Angular position and torque were recorded from the wrist joint. Changes in wrist flexor muscle resting tension were sensed by a force transducer pressed against the tendons.

    RESULTS:

    Consecutive stepwise changes (7.5 degrees ) in wrist joint position (within the dorsiflexed range) were either imposed on relaxed subjects or actively performed while the subjects under visual guidance tried to mimic the passive movements. In relaxed subjects, passive joint torque resistance at a given steady dorsiflexed position either gradually declined or rose depending on the direction of the previous transition movements. In corresponding voluntary contraction experiments, the IEMG amplitude from position holding wrist extensors was found to vary in a similar way as the passive torque resistance. Further, there was a strong correlation between history-dependent changes in extensor IEMG amplitude and stress alterations exhibited by the relaxed antagonist flexors. The above described, slowly subsiding post-movement mechanical and motor adaptations were accelerated by brief forceful cocontractions of the forearm muscles.

    CONCLUSION:

    Moderate stepwise changes in joint position are sufficient to induce history-dependent after-effects in passive muscular resting tension, after-effects which during voluntary position holding are effectively compensated for by the motor control system.

  • 40.
    Axelson, Hans W
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Hagbarth, K -E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Human motor control consequences of thixotropic changes in muscular short-range stiffness2001In: Journal of Physiology, ISSN 0022-3751, E-ISSN 1469-7793, Vol. 535, no Pt 1, p. 279-288Article in journal (Refereed)
    Abstract [en]
    1. The primary aim of the present study was to explore whether in healthy subjects the muscle contractions required for unrestrained voluntary wrist dorsiflexions are adjusted in strength to thixotropy-dependent variations in the short-range stiffness encountered in measurements of passive torque resistance to imposed wrist dorsiflexions.
    2. After a period of rest, only the first movement in a series of passive wrist dorsiflexions of moderate amplitude exhibited clear signs of short-range stiffness in the torque response. During analogous types of voluntary movements, the extensor EMG during the first movement after rest showed a steep initial rise of activity, which apparently served to compensate for the short-range stiffness.
    3. The passive torque resistance to minute repetitive wrist dorsiflexions (within the range of short-range stiffness) was markedly reduced after various types of mechanical agitation. During analogous low-amplitude voluntary wrist dorsiflexions the extensor EMG signals were weaker after than before agitation.
    4. Mechanical agitation also led to enhancement of passive dorsiflexion movements induced by weak constant torque pulses. In an analogous way, the movement-generating capacity of weak voluntary extensor activations (as determined by EMG recordings) was greatly enhanced by mechanical agitation.
    5. The signals from a force transducer probe pressed against the wrist flexor tendons - during passive wrist dorsiflexions - revealed short-range stiffness responses which highly resembled those observed in the torque measurements, suggesting that the latter to a large extent emanated from the stretched, relaxed flexor muscles. During repetitive stereotyped voluntary wrist dorsiflexions, a close correspondence was observed between the degree of short-range stiffness as sensed by the wrist flexor tension transducer and the strength of the initial extensor activation required for movement generation.
    6. The results provide evidence that the central nervous system in its control of voluntary movements takes account of and compensates for the history-dependent degree of inherent short-range stiffness of the muscles antagonistic to the prime movers.
  • 41.
    Axelson, Hans
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Winkler, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Flygt, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Djupsjö, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Hånell, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Plasticity of the contralateral motor cortex following focal traumatic brain injury in the rat2013In: Restorative Neurology and Neuroscience, ISSN 0922-6028, E-ISSN 1878-3627, Vol. 31, no 1, p. 73-85Article in journal (Refereed)
    Abstract [en]

    Purpose: Recovery is limited following traumatic brain injury (TBI) since injured axons regenerate poorly and replacement of lost cells is minimal. Behavioral improvements could instead be due to plasticity of uninjured brain regions. We hypothesized that plasticity of the uninjured hemisphere occurs contralateral to a focal TBI in the adult rat. Thus, we performed cortical mapping of the cortex contralateral to the TBI using intracortical microstimulation (ICMS). Methods: A focal TBI was induced using the weight-drop technique (n = 5) and sham-injured animals were used as controls (n = 4). At five weeks post-injury, ICMS was used to map the motor area contralateral to the injury. Motor responses were detected by visual inspection and electromyography (EMG). Results: In sham- and brain-injured animals, numerous fore- and hindlimb motor responses contralateral to the stimulation (ipsilateral to the injury) were obtained. Compared to sham-injured controls, there was a markedly increased (p < 0.05) number of fore- and hindlimb responses ipsilateral to the stimulation after TBI. Conclusion: Following focal TBI in the rat, our data suggest reorganization of cortical and/or subcortical regions in the uninjured hemisphere contralateral to a focal TBI leading to an altered responsiveness to ICMS. Although we cannot exclude that these changes are maladaptive, it is plausible that this plasticity process positively influences motor recovery after TBI.

  • 42.
    Babateen, Omar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Korol, Sergiy V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Jin, Zhe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Bhandage, Amol K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Ahemaiti, Aikeremu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Birnir, Bryndis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Liraglutide modulates GABAergic signaling in rat hippocampal CA3 pyramidal neurons predominantly by presynaptic mechanism2017In: BMC Pharmacology & Toxicology, E-ISSN 2050-6511, Vol. 18, article id 83Article in journal (Refereed)
    Abstract [en]

    Background

    γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the brain where it regulates activity of neuronal networks. The receptor for glucagon-like peptide-1 (GLP-1) is expressed in the hippocampus, which is the center for memory and learning. In this study we examined effects of liraglutide, a GLP-1 analog, on GABA signaling in CA3 hippocampal pyramidal neurons.

    Methods

    We used patch-clamp electrophysiology to record synaptic and tonic GABA-activated currents in CA3 pyramidal neurons in rat hippocampal brain slices.

    Results

    We examined the effects of liraglutide on the neurons at concentrations ranging from one nM to one μM. Significant changes of the spontaneous inhibitory postsynaptic currents (sIPSCs) were only recorded with 100 nM liraglutide and then in just ≈50% of the neurons tested at this concentration. In neurons affected by liraglutide both the sIPSC frequency and the most probable amplitudes increased. When the action potential firing was inhibited by tetrodotoxin (TTX) the frequency and amplitude of IPSCs in TTX and in TTX plus 100 nM liraglutide were similar.

    Conclusions

    The results demonstrate that liraglutide regulation of GABA signaling of CA3 pyramidal neurons is predominantly presynaptic and more limited than has been observed for GLP-1 and exendin-4 in hippocampal neurons.

  • 43. Backstrom, Tobias
    et al.
    Heynen, Martina
    Brannas, Eva
    Nilsson, Jan
    Winberg, Svante
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Magnhagen, Carin
    Social stress effects on pigmentation and monoamines in Arctic charr2015In: Behavioural Brain Research, ISSN 0166-4328, E-ISSN 1872-7549, Vol. 291, p. 103-107Article in journal (Refereed)
    Abstract [en]

    Pigmentation often signals status and in general melanin-based pigmentation is indicative of aggression and stress resilience in vertebrates. This is evident in the salmonids Atlantic salmon (Salmo salar) and rainbow trout (Oncorhynchus mykiss) where more melanin spotted individuals are more stress resilient. However, in the salmonid Arctic charr (Salvelinus alpinus) it seems as if it is carotenoid-based pigmentation that signals aggression and stress resilience. In our study, social stress effects on carotenoid-based spots, and behavioural and physiological stress responses were investigated. Socially stressed individuals have more spots, and behavioural stress responses were associated with spots. Some of the results concerning physiological stress responses, such as plasma cortisol levels and monoaminergic activity, are associated with spottiness. Further, the earlier proposed lateralization of spots, with left side connected to stress responsiveness and right side to aggression, is to some extent validated although not conclusively. In conclusion, this study provides further evidence that more stressed charr have more carotenoid spots, and for the first time monoaminergic activity is shown to be connected with carotenoid pigmentation.

  • 44.
    Backstrom, Tobias
    et al.
    Univ Koblenz Landau, Inst Integrated Nat Sci, Koblenz, Germany..
    Winberg, Svante
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Serotonin Coordinates Responses to Social Stress: What We Can Learn from Fish2017In: Frontiers in Neuroscience, ISSN 1662-4548, E-ISSN 1662-453X, Vol. 11, article id 595Article, review/survey (Refereed)
    Abstract [en]

    Social interaction is stressful and subordinate individuals are often subjected to chronic stress, which greatly affects both their behavior and physiology. In teleost fish the social position of an individual may have long-term effects, such as effects on migration, age of sexual maturation or even sex. The brain serotonergic system plays a key role in coordinating autonomic, behavioral and neuroendocrine stress responses. Social subordination results in a chronic activation of the brain serotonergic system an effect, which seems to be central in the subordinate phenotype. However, behavioral effects of short-term acute activation of the serotonergic system are less obvious. As in other vertebrates, divergent stress coping styles, often referred to as proactive and reactive, has been described in teleosts. As demonstrated by selective breeding, stress coping styles appear to be partly heritable. However, teleost fish are characterized by plasticity, stress coping style being affected by social experience. Again, the brain serotonergic system appears to play an important role. Studies comparing brain gene expression of fish of different social rank and/or displaying divergent stress coping styles have identified several novel factors that seem important for controlling aggressive behavior and stress coping, e.g., histamine and hypocretin/orexin. These may also interact with brain monoaminergic systems, including serotonin.

  • 45.
    Bakalkin, Georgy
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Yakovleva, Tatiana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    The dynorphin/kappa-opioid receptor system: molecular and epigenetic adaptations in emotional circuitry of alcoholics2016In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 26, p. S152-S152Article in journal (Other academic)
  • 46.
    Bakall, Benjamin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Mayordomo, Raquel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Hallböök, Finn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Wadelius, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Analysis of subcellular location of bestrophin in transfected RPE cell lines2000In: Gene Function and Disease, ISSN 1438-7506, E-ISSN 1438-826X, Vol. 1, no 3-4, p. 128-133Article in journal (Refereed)
    Abstract [en]

    Best macular dystrophy is an autosomal dominant disease leading to macular degeneration and subsequent impaired vision. The disease has juvenile onset and affects the retinal pigment epithelium and adjacent photoreceptors. There are histopathological similarities between Best macular dystrophy (BMD) and age-related macular degeneration (AMD) with accumulation of lipofuscin in the outer retina. Recently, we identified the gene VMD2 causing Best macular dystrophy. The VMD2 gene has unknown function and there are no similarities between the VMD2 product, called bestrophin, and other proteins with known function. In order to gain more knowledge about the function of bestrophin we investigated its subcellular localization. DNA constructs encoding the bestrophin protein fused to the green fluorescent protein (GFP) or a c-myc tag were transiently expressed in COS-7 cells or retinal pigment epithelium cells. The observed pattern of bestrophin fusion protein was spotted and mainly perinuclear, well corresponding to the endoplasmic reticulum (ER), which was also suggested when counterstaining with an ER probe. Probes for other organelles had a different localization pattern compared to bestrophin. In conclusion, the results indicate that bestrophin is located to the endoplasmic reticulum.

  • 47.
    Balciuniene, J
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Emilsson, L
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Oreland, L
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Pettersson, U
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Jazin, Elena
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Investigation of the functional effect of monoamine oxidase polymorphisms in human brain2002In: Human Genetics, ISSN 0340-6717, E-ISSN 1432-1203, Vol. 110, no 1, p. 1-7Article in journal (Refereed)
  • 48. Balciuniene, J
    et al.
    Syvänen, A-C
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    McLeod, H L
    Pettersson, U
    Jazin, E E
    Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Department of Evolution, Genomics and Systematics, Evolutionary Biology. Evolutionsbiologi.
    The geographic distribution of monoamine oxidase haplotypes supports a bottleneck during the dispersion of modern humans from Africa.2001In: J Mol Evol, ISSN 0022-2844, Vol. 52, no 2, p. 157-63Article in journal (Other scientific)
  • 49.
    Banduseela, Varuna C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Ochala, Julien
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Chen, Yi-Wen
    Göransson, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Norman, Holly
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Radell, Peter
    Eriksson, Lars I.
    Hoffman, Eric P.
    Larsson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Gene expression and muscle fiber function in a porcine ICU model2009In: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 39, no 3, p. 141-159Article in journal (Refereed)
    Abstract [en]

    Skeletal muscle wasting and impaired muscle function in response to mechanical ventilation and immobilization in intensive care unit (ICU) patients are clinically challenging partly due to 1) the poorly understood intricate cellular and molecular networks and 2) the unavailability of an animal model mimicking this condition. By employing a unique porcine model mimicking the conditions in the ICU with long-term mechanical ventilation and immobilization, we have analyzed the expression profile of skeletal muscle biopsies taken at three time points during a 5-day period. Among the differentially regulated transcripts, extracellular matrix, energy metabolism, sarcomeric and LIM protein mRNA levels were downregulated, while ubiquitin proteasome system, cathepsins, oxidative stress responsive genes and heat shock proteins (HSP) mRNAs were upregulated. Despite 5 days of immobilization and mechanical ventilation single muscle fiber cross-sectional areas as well as the maximum force generating capacity at the single muscle fiber level were preserved. It is proposed that HSP induction in skeletal muscle is an inherent, primary, but temporary protective mechanism against protein degradation. To our knowledge, this is the first study that isolates the effect of immobilization and mechanical ventilation in an ICU condition from various other cofactors.

  • 50.
    Barg, Sebastian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Gandasi, Nikhil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Quantitative analysis of t-SNARE and Ca2+-channel clusters near secretory granules2010In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 53, no Suppl. 1, p. S46-S46Article in journal (Other academic)
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