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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, 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: 2021-06-14Bibliographically approved
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  • 2. Abdelhak, Ahmed
    et al.
    Barba, Lorenzo
    Romoli, Michele
    Benkert, Pascal
    Conversi, Francesco
    D'Anna, Lucio
    Masvekar, Ruturaj R
    Bielekova, Bibiana
    Prudencio, Mercedes
    Petrucelli, Leonard
    Meschia, James F
    Erben, Young
    Furlan, Roberto
    De Lorenzo, Rebecca
    Mandelli, Alessandra
    Sutter, Raoul
    Hert, Lisa
    Epple, Varenka
    Marastoni, Damiano
    Sellner, Johann
    Steinacker, Petra
    Aamodt, Anne Hege
    Heggelund, Lars
    Dyrhol-Riise, Anne Margarita
    Virhammar, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Neurology.
    Fällmar, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Rostami, Elham
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Neurosurgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Acquired brain injury.
    Kumlien, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Neurology.
    Blennow, Kaj
    Zetterberg, Henrik
    Tumani, Hayrettin
    Sacco, Simona
    Green, Ari J
    Otto, Markus
    Kuhle, Jens
    Ornello, Raffaele
    Foschi, Matteo
    Abu-Rumeileh, Samir
    Prognostic performance of blood neurofilament light chain protein in hospitalized COVID-19 patients without major central nervous system manifestations: an individual participant data meta-analysis.2023In: Journal of Neurology, ISSN 0340-5354, E-ISSN 1432-1459, Vol. 270, no 7, p. 3315-3328Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND AIMS: To investigate the prognostic value of blood neurofilament light chain protein (NfL) levels in the acute phase of coronavirus disease 2019 (COVID-19).

    METHODS: We conducted an individual participant data (IPD) meta-analysis after screening on MEDLINE and Scopus to May 23rd 2022. We included studies with hospitalized adult COVID-19 patients without major COVID-19-associated central nervous system (CNS) manifestations and with a measurement of blood NfL in the acute phase as well as data regarding at least one clinical outcome including intensive care unit (ICU) admission, need of mechanical ventilation (MV) and death. We derived the age-adjusted measures NfL Z scores and conducted mixed-effects modelling to test associations between NfL Z scores and other variables, encompassing clinical outcomes. Summary receiver operating characteristic curves (SROCs) were used to calculate the area under the curve (AUC) for blood NfL.

    RESULTS: We identified 382 records, of which 7 studies were included with a total of 669 hospitalized COVID-19 cases (mean age 66.2 ± 15.0 years, 68.1% males). Median NfL Z score at admission was elevated compared to the age-corrected reference population (2.37, IQR: 1.13-3.06, referring to 99th percentile in healthy controls). NfL Z scores were significantly associated with disease duration and severity. Higher NfL Z scores were associated with a higher likelihood of ICU admission, need of MV, and death. SROCs revealed AUCs of 0.74, 0.80 and 0.71 for mortality, need of MV and ICU admission, respectively.

    CONCLUSIONS: Blood NfL levels were elevated in the acute phase of COVID-19 patients without major CNS manifestations and associated with clinical severity and poor outcome. The marker might ameliorate the performance of prognostic multivariable algorithms in COVID-19.

  • 3.
    Abu Hamdeh, Sami
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Rollman Waara, Erik
    BioArctic Neurosci AB, Stockholm, Sweden.
    Möller, Christer
    BioArctic Neurosci AB, Stockholm, Sweden.
    Söderberg, Linda
    BioArctic Neurosci AB, Stockholm, Sweden.
    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 injury2018In: Brain Pathology, ISSN 1015-6305, E-ISSN 1750-3639, Vol. 28, no 4, p. 451-462Article 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.

  • 4.
    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)
  • 5.
    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, 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.

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  • 6.
    Abu Hamdeh, Sami
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Enblad: Neurosurgery.
    Tenovuo, Olli
    Univ Turku, Turku Brain Injury Ctr, Turku, Finland; Turku Univ Hosp, Turku, Finland.
    Peul, Wilco
    Leiden Univ, HAGA, Neurosurg Ctr Holland, HMC, The Hague, Netherlands; Leiden Univ, LUMC, Neurosurg Ctr Holland, HMC, The Hague, Netherlands; Leiden Univ, HAGA, Neurosurg Ctr Holland, HMC, Leiden, Netherlands; Leiden Univ, LUMC, Neurosurg Ctr Holland, HMC, Leiden, Netherlands.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Enblad: Neurosurgery. Lund Univ, Skåne Univ Hosp, Dept Clin Sci Lund, Neurosurg, Lund, Sweden.
    "Omics" in traumatic brain injury: novel approaches to a complex disease2021In: Acta Neurochirurgica, ISSN 0001-6268, E-ISSN 0942-0940, Vol. 163, no 9, p. 2581-2594Article, review/survey (Refereed)
    Abstract [en]

    Background

    To date, there is neither any pharmacological treatment with efficacy in traumatic brain injury (TBI) nor any method to halt the disease progress. This is due to an incomplete understanding of the vast complexity of the biological cascades and failure to appreciate the diversity of secondary injury mechanisms in TBI. In recent years, techniques for high-throughput characterization and quantification of biological molecules that include genomics, proteomics, and metabolomics have evolved and referred to as omics.

    Methods

    In this narrative review, we highlight how omics technology can be applied to potentiate diagnostics and prognostication as well as to advance our understanding of injury mechanisms in TBI.

    Results

    The omics platforms provide possibilities to study function, dynamics, and alterations of molecular pathways of normal and TBI disease states. Through advanced bioinformatics, large datasets of molecular information from small biological samples can be analyzed in detail and provide valuable knowledge of pathophysiological mechanisms, to include in prognostic modeling when connected to clinically relevant data. In such a complex disease as TBI, omics enables broad categories of studies from gene compositions associated with susceptibility to secondary injury or poor outcome, to potential alterations in metabolites following TBI.

    Conclusion

    The field of omics in TBI research is rapidly evolving. The recent data and novel methods reviewed herein may form the basis for improved precision medicine approaches, development of pharmacological approaches, and individualization of therapeutic efforts by implementing mathematical “big data” predictive modeling in the near future.

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  • 7.
    Abzhandadze, Tamar
    et al.
    Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Gothenburg, Sweden.;Sahlgrens Univ Hosp, Dept Occupat Therapy & Physiotherapy, Gothenburg, Sweden..
    Lundström, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Landtblom: Neurology.
    Buvarp, Dongni
    Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Gothenburg, Sweden..
    Eriksson, Marie
    Umeå Univ, Dept Stat, USBE, Umeå, Sweden..
    Quinn, Terence J.
    Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland..
    Sunnerhagen, Katharina
    Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Gothenburg, Sweden.;Sahlgrens Univ Hosp, Neurocare, Gothenburg, Sweden..
    Development of a short-form Swedish version of the Montreal Cognitive Assessment (s-MoCA-SWE): protocol for a cross-sectional study2021In: BMJ Open, E-ISSN 2044-6055, Vol. 11, no 5, article id e049035Article in journal (Refereed)
    Abstract [en]

    Introduction Short forms of the Montreal Cognitive Assessment (MoCA) have allowed quick cognitive screening. However, none of the available short forms has been created or validated in a Swedish sample of patients with stroke. The aim is to develop a short-form Swedish version of the MoCA (s-MoCA-SWE) in a sample of patients with acute and subacute stroke. The specific objectives are: (1) to identify a subgroup of MoCA items that have the potential to form the s-MoCA-SWE; (2) to determine the optimal cut-off value of s-MoCA-SWE for predicting cognitive impairment and (3) and to compare the psychometric properties of s-MoCA-SWE with those of previously developed MoCA short forms. Methods and analysis This is a statistical analysis protocol for a cross-sectional study. The study sample will comprise patients from Vaststroke, a local stroke registry from Gothenburg, Sweden and Efficacy oF Fluoxetine-a randomisEd Controlled Trial in Stroke (EFFECTS), a randomised controlled trial in Sweden. The s-MoCA-SWE will be developed by using exploratory factor analysis and the boosted regression tree algorithm. The cut-off value of s-MoCA-SWE for impaired cognition will be determined based on binary logistic regression analysis. The psychometric properties of s-MoCA-SWE will be compared with those of other MoCA short forms by using cross-tabulation and area under the receiving operating characteristic curve analyses. Ethics and dissemination The Vaststroke study has received ethical approval from the Regional Ethical Review Board in Gothenburg (346-16) and the Swedish Ethical Review Authority (amendment 2019-04299). The handling of data generated within the framework of quality registers does not require written informed consent from patients. The EFFECTS study has received ethical approval from the Stockholm Ethics Committee (2013/1265-31/2 on 30 September 2013). All participants provided written consent. Results will be published in an international, peer-reviewed journal, presented at conferences and communicated to clinical practitioners in local meetings and seminars.

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  • 8.
    Abzhandadze, Tamar
    et al.
    Univ Gothenburg, Inst Neurosci & Physiol, Sahlgrenska Acad, Gothenburg, Sweden.;Sahlgrens Univ Hosp, Dept Occupat Therapy & Physiotherapy, Gothenburg, Sweden.;Univ Gothenburg, Inst Neurosci & Physiol, Rehabil Med, Dubbsgatan 14,fl 3, SE-41345 Gothenburg, Sweden..
    Lundström, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Neurology.
    Buvarp, Dongni
    Univ Gothenburg, Inst Neurosci & Physiol, Sahlgrenska Acad, Gothenburg, Sweden..
    Eriksson, Marie
    Umeå Univ, Dept Stat, USBE, Umeå, Sweden..
    Quinn, Terence J.
    Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Scotland..
    Sunnerhagen, Katharina S.
    Univ Gothenburg, Inst Neurosci & Physiol, Sahlgrenska Acad, Gothenburg, Sweden.;Sahlgrens Univ Hosp, Neurocare, Rehabil Med, Gothenburg, Sweden..
    Development of a Swedish short version of the Montreal Cognitive Assessment for cognitive screening in patients with stroke2023In: Journal of Rehabilitation Medicine, ISSN 1650-1977, E-ISSN 1651-2081, Vol. 55, article id jrm4442Article in journal (Refereed)
    Abstract [en]

    Objective: The primary objective was to develop a Swedish short version of the Montreal Cognitive Assessment (s-MoCA-SWE) for use with patients with stroke. Secondary objectives were to iden-tify an optimal cut-off value for the s-MoCA-SWE to screen for cognitive impairment and to compare its sensitivity with that of previously developed short forms of the Montreal Cognitive Assessment.

    Design: Cross-sectional study.

    Subjects/patients: Patients admitted to stroke and rehabilitation units in hospitals across Sweden.

    Methods: Cognition was screened using the Mont-real Cognitive Assessment. Working versions of the s-MoCA-SWE were developed using supervised and unsupervised algorithms.

    Results: Data from 3,276 patients were analysed (40% female, mean age 71.5 years, 56% minor stroke at admission). The suggested s-MoCA-SWE compri-sed delayed recall, visuospatial/executive function, serial 7, fluency, and abstraction. The aggregated scores ranged from 0 to 16. A threshold for impai-red cognition & LE; 12 had a sensitivity of 97.41 (95% confidence interval, 96.64-98.03) and positive pre-dictive value of 90.30 (95% confidence interval 89.23-91.27). The s-MoCA-SWE had a higher abso-lute sensitivity than that of other short forms.

    Conclusion: The s-MoCA-SWE (threshold & LE; 12) can detect post-stroke cognitive issues. The high sensitivity makes it a potentially useful "rule-out" tool that may eliminate severe cognitive impair-ment in people with stoke.

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  • 9.
    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.

  • 10.
    Affatato, Oreste
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience.
    Beating of hammers2024Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    I've been investigating the connection between migraine and depression—two debilitating disorders with high comorbidity. My overarching goal is to unravel their pathophysiology and pinpoint associated risk factors to pave the way for more effective therapeutic interventions. The fruits of my labor is discussed in the introductory part of the thesis and comprises four first-author publications in international peer-reviewed journals.

    In the first two projects, I worked mostly on the comorbid aspects of migraine and depression. I conducted a meta-analysis on the efficacy of onabotulinumtoxinA injections as a treatment for those grappling with both migraine and depression. The findings were promising, showing not only the treatment's safety and effectiveness but also hinting at a shared pathophysiology between the two conditions. The second project delved into the structural brain anatomy, utilizing voxel-based magnetic resonance imaging measures to explore subcortical volumes in migraine and depression patients. The distinct patterns observed suggest a nuanced relationship at the subcortical level.

    Expanding beyond comorbidity, my research ventured into the occupational determinants of migraine, scrutinizing the impact of job-related factors on migraine prevalence. Leveraging data from the UK Biobank, the third project identified strong associations between migraine and specific job categories, setting the stage for future interventions and policies to enhance workers' well-being. Additionally, my exploration into the role of the cerebellum and brainstem in migraine pathophysiology, using the UK Biobank data, unveiled larger gray matter volumes in multiple cerebellar regions in individuals with migraines. This sheds light on potential mechanisms underlying migraine attacks, contributing significantly to our understanding and potential treatments for these challenging disorders.

    List of papers
    1. High efficacy of onabotulinumtoxinA treatment in patients with comorbid migraine and depression: a meta-analysis
    Open this publication in new window or tab >>High efficacy of onabotulinumtoxinA treatment in patients with comorbid migraine and depression: a meta-analysis
    Show others...
    2021 (English)In: Journal of Translational Medicine, ISSN 1479-5876, E-ISSN 1479-5876, Vol. 19, no 1, article id 133Article, review/survey (Refereed) Published
    Abstract [en]

    Background: Migraine and depression are highly prevalent and partly overlapping disorders that cause strong limitations in daily life. Patients tend to respond poorly to the therapies available for these diseases. OnabotulinumtoxinA has been proven to be an effective treatment for both migraine and depression. While many studies have addressed the effect of onabotulinumtoxinA in migraine or depression separately, a growing body of evidence suggests beneficial effects also for patients comorbid with migraine and depression. The current meta-analysis systematically investigates to what extent onabotulinumtoxinA is efficient in migraineurs with depression.

    Methods: A systematic literature search was performed based on PubMed, Scopus and Web of Science from the earliest date till October 30th, 2020. Mean, standard deviation (SD) and sample size have been used to evaluate improvement in depressive symptoms and migraine using random- effects empirical Bayes model.

    Results: Our search retrieved 259 studies, eight of which met the inclusion criteria. OnabotulinumtoxinA injections administered to patients with both chronic migraine and major depressive disorder led to mean reduction of - 8.94 points (CI [ - 10.04,- 7.84], p < 0.01) in the BDI scale, of - 5.90 points (CI [ - 9.92,- 1.88], p < 0.01) in the BDI-II scale and of - 6.19 points (CI [ - 9.52,- 2.86], p < 0.01) in the PHQ-9 scale, when evaluating depressive symptoms. In the case of the migraine-related symptoms, we found mean reductions of - 4.10 (CI [ - 7.31,- 0.89], p = 0.01) points in the HIT6 scale, - 32.05 (CI [ - 55.96,- 8.14], p = 0.01) in the MIDAS scale, - 1.7 (CI [ - 3.27,- 0.13], p = 0.03) points in the VAS scale and of - 6.27 (CI [ - 8.48,- 4.07], p < 0.01) migraine episodes per month. Comorbid patients showed slightly better improvements in BDI, HIT6 scores and migraine frequency compared to monomorbid patients. The latter group manifested better results in MIDAS and VAS scores.

    Conclusion: Treatment with onabotulinumtoxinA leads to a significant reduction of disease severity of both chronic migraine and major depressive disorder in patients comorbid with both diseases. Comparative analyses suggest an equivalent strong effect in monomorbid and comorbid patients, with beneficial effects specifically seen for certain migraine features.

    Place, publisher, year, edition, pages
    Springer NatureSpringer Nature, 2021
    Keywords
    OnabotulinumtoxinA, Botox, Migraine, Depression, Meta-analysis
    National Category
    Neurology
    Identifiers
    urn:nbn:se:uu:diva-442250 (URN)10.1186/s12967-021-02801-w (DOI)000636462700003 ()33789668 (PubMedID)
    Funder
    Swedish Research Council
    Available from: 2021-05-17 Created: 2021-05-17 Last updated: 2024-04-11Bibliographically approved
    2. Major sex differences in migraine prevalence among occupational categories: a cross-sectional study using UK Biobank
    Open this publication in new window or tab >>Major sex differences in migraine prevalence among occupational categories: a cross-sectional study using UK Biobank
    2021 (English)In: Journal of Headache and Pain, ISSN 1129-2369, E-ISSN 1129-2377, Vol. 22, no 1, article id 145Article in journal (Refereed) Published
    Abstract [en]

    Background Migraine represents one of the most prevalent neurological conditions worldwide. It is a disabling condition with high impact on the working situation of migraineurs. Interestingly, gender-related differences regarding an association of migraine with important occupational characteristics has been hardly studied. Methods The current study scrutinizes gender-specific differences in the prevalence of migraine across a broad spectrum of occupational categories, shedding also light on associations with important job-related features such as shift work, job satisfaction, and physical activity. The study included data from 415 712 participants from the UK Biobank cohort, using the official ICD10 diagnosis of migraine and other health conditions as selection criteria. Prevalence ratios of migraineurs compared to healthy controls among different occupational categories and job-related variables were estimated using log-binomial regression analyses. Statistical models were adjusted for important sociodemographic features such as age, BMI, ethnicity, education and neuroticism. To better highlight specific differences between men and women we stratified by sex. Results We detected a differential prevalence pattern of migraine in relation to different job categories between men and women. Especially in men, migraine appears to be more prevalent in highly physically demanding occupations (PR 1.38, 95% CI [0.93, 2.04]). Furthermore, migraine is also more prevalent in jobs that frequently involve shift or night shift work compared to healthy controls. Interestingly, this prevalence is especially high in women (shift work PR 1.45, 95% CI [1.14, 1.83], night shift work PR 1.46, 95% CI [0.93, 2.31]). Conclusion Our results show that migraine is genderdependently associated with physically demanding jobs and shift working.

    Place, publisher, year, edition, pages
    Springer NatureSpringer Nature, 2021
    Keywords
    Migraine, Occupation, Work, Job, Sex differences
    National Category
    Public Health, Global Health, Social Medicine and Epidemiology Neurosciences
    Identifiers
    urn:nbn:se:uu:diva-461712 (URN)10.1186/s10194-021-01356-x (DOI)000726269000002 ()34863088 (PubMedID)
    Funder
    Swedish Research Council
    Available from: 2022-01-31 Created: 2022-01-31 Last updated: 2024-04-11Bibliographically approved
    3. Assessing volumetric brain differences in migraine and depression patients: a UK Biobank study
    Open this publication in new window or tab >>Assessing volumetric brain differences in migraine and depression patients: a UK Biobank study
    Show others...
    2023 (English)In: BMC Neurology, E-ISSN 1471-2377, Vol. 23, no 1, article id 284Article in journal (Refereed) Published
    Abstract [en]

    Background: Migraine and depression are two of the most common and debilitating conditions. From a clinical perspective, they are mostly prevalent in women and manifest a partial overlapping symptomatology. Despite the high level of comorbidity, previous studies hardly investigated possible common patterns in brain volumetric differences compared to healthy subjects. Therefore, the current study investigates and compares the volumetric difference patterns in sub-cortical regions between participants with migraine or depression in comparison to healthy controls.

    Methods: The study included data from 43 930 participants of the large UK Biobank cohort. Using official ICD10 diagnosis, we selected 712 participants with migraine, 1 853 with depression and 23 942 healthy controls. We estimated mean volumetric difference between the groups for the different sub-cortical brain regions using generalized linear regression models, conditioning the model within the levels of BMI, age, sex, ethnical background, diastolic blood pressure, current tobacco smoking, alcohol intake frequency, Assessment Centre, Indices of Multiple Deprivation, comorbidities and total brain volume.

    Results: We detected larger overall volume of the caudate (mean difference: 66, 95% CI [-3, 135]) and of the thalamus (mean difference: 103 mm(3), 95% CI [-2, 208]) in migraineurs than healthy controls. We also observed that individuals with depression appear to have also larger overall (mean difference: 47 mm(3), 95% CI [-7, 100]) and gray matter (mean difference: 49 mm(3), 95% CI [2, 95]) putamen volumes than healthy controls, as well as larger amygdala volume (mean difference: 17 mm(3), 95% CI [-7, 40]).

    Conclusion: Migraineurs manifested larger overall volumes at the level of the nucleus caudate and of the thalamus, which might imply abnormal pain modulation and increased migraine susceptibility. Larger amygdala and putamen volumes in participants with depression than controls might be due to increased neuronal activity in these regions.

    Place, publisher, year, edition, pages
    BMC, 2023
    Keywords
    Migraine, Depression, Structural brain MRI, UK Biobank
    National Category
    Neurosciences Neurology
    Identifiers
    urn:nbn:se:uu:diva-509232 (URN)10.1186/s12883-023-03336-x (DOI)001040412700002 ()37507671 (PubMedID)
    Available from: 2023-08-22 Created: 2023-08-22 Last updated: 2024-04-11Bibliographically approved
    4. Volumetric Differences in Cerebellum and Brainstem in Patients with Migraine: A UK Biobank Study
    Open this publication in new window or tab >>Volumetric Differences in Cerebellum and Brainstem in Patients with Migraine: A UK Biobank Study
    2023 (English)In: Biomedicines, E-ISSN 2227-9059, Vol. 11, no 9, article id 2528Article in journal (Refereed) Published
    Abstract [en]

    Background: The cerebellum and the brainstem are two brain structures involved in pain processing and modulation that have also been associated with migraine pathophysiology. The aim of this study was to investigate possible associations between the morphology of the cerebellum and brainstem and migraine, focusing on gray matter differences in these brain areas.

    Methods: The analyses were based on data from 712 individuals with migraine and 45,681 healthy controls from the UK Biobank study. Generalized linear models were used to estimate the mean gray matter volumetric differences in the brainstem and the cerebellum. The models were adjusted for important biological covariates such as BMI, age, sex, total brain volume, diastolic blood pressure, alcohol intake frequency, current tobacco smoking, assessment center, material deprivation, ethnic background, and a wide variety of health conditions. Secondary analyses investigated volumetric correlation between cerebellar sub-regions.

    Results: We found larger gray matter volumes in the cerebellar sub-regions V (mean difference: 72 mm3, 95% CI [13, 132]), crus I (mean difference: 259 mm3, 95% CI [9, 510]), VIIIa (mean difference: 120 mm3, 95% CI [0.9, 238]), and X (mean difference: 14 mm3, 95% CI [1, 27]).

    Conclusions: Individuals with migraine show larger gray matter volumes in several cerebellar sub-regions than controls. These findings support the hypothesis that the cerebellum plays a role in the pathophysiology of migraine.

    Place, publisher, year, edition, pages
    MDPI, 2023
    Keywords
    migraine, cerebellum, brainstem, structural MRI, UK Biobank
    National Category
    Neurology Neurosciences
    Identifiers
    urn:nbn:se:uu:diva-514061 (URN)10.3390/biomedicines11092528 (DOI)001071288700001 ()37760969 (PubMedID)
    Available from: 2023-10-16 Created: 2023-10-16 Last updated: 2024-04-11Bibliographically approved
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  • 11.
    Affatato, Oreste
    et al.
    Uppsala University, WoMHeR (Centre for Women’s Mental Health during the Reproductive Lifespan). Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Dahlén, Amelia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Rukh, Gull
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience.
    Mwinyi, Jessica
    Uppsala University, WoMHeR (Centre for Women’s Mental Health during the Reproductive Lifespan). Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience.
    Assessing volumetric brain differences in migraine and depression patients: a UK Biobank study2023In: BMC Neurology, E-ISSN 1471-2377, Vol. 23, no 1, article id 284Article in journal (Refereed)
    Abstract [en]

    Background: Migraine and depression are two of the most common and debilitating conditions. From a clinical perspective, they are mostly prevalent in women and manifest a partial overlapping symptomatology. Despite the high level of comorbidity, previous studies hardly investigated possible common patterns in brain volumetric differences compared to healthy subjects. Therefore, the current study investigates and compares the volumetric difference patterns in sub-cortical regions between participants with migraine or depression in comparison to healthy controls.

    Methods: The study included data from 43 930 participants of the large UK Biobank cohort. Using official ICD10 diagnosis, we selected 712 participants with migraine, 1 853 with depression and 23 942 healthy controls. We estimated mean volumetric difference between the groups for the different sub-cortical brain regions using generalized linear regression models, conditioning the model within the levels of BMI, age, sex, ethnical background, diastolic blood pressure, current tobacco smoking, alcohol intake frequency, Assessment Centre, Indices of Multiple Deprivation, comorbidities and total brain volume.

    Results: We detected larger overall volume of the caudate (mean difference: 66, 95% CI [-3, 135]) and of the thalamus (mean difference: 103 mm(3), 95% CI [-2, 208]) in migraineurs than healthy controls. We also observed that individuals with depression appear to have also larger overall (mean difference: 47 mm(3), 95% CI [-7, 100]) and gray matter (mean difference: 49 mm(3), 95% CI [2, 95]) putamen volumes than healthy controls, as well as larger amygdala volume (mean difference: 17 mm(3), 95% CI [-7, 40]).

    Conclusion: Migraineurs manifested larger overall volumes at the level of the nucleus caudate and of the thalamus, which might imply abnormal pain modulation and increased migraine susceptibility. Larger amygdala and putamen volumes in participants with depression than controls might be due to increased neuronal activity in these regions.

    Download full text (pdf)
    FULLTEXT01
  • 12.
    Affatato, Oreste
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Uppsala University, WoMHeR (Centre for Women’s Mental Health during the Reproductive Lifespan).
    Miguet, Maud
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. IM Sechenov First Moscow State Med Univ, Inst Translat Med & Biothechnol, Moscow, Russia..
    Mwinyi, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Uppsala University, WoMHeR (Centre for Women’s Mental Health during the Reproductive Lifespan).
    Major sex differences in migraine prevalence among occupational categories: a cross-sectional study using UK Biobank2021In: Journal of Headache and Pain, ISSN 1129-2369, E-ISSN 1129-2377, Vol. 22, no 1, article id 145Article in journal (Refereed)
    Abstract [en]

    Background Migraine represents one of the most prevalent neurological conditions worldwide. It is a disabling condition with high impact on the working situation of migraineurs. Interestingly, gender-related differences regarding an association of migraine with important occupational characteristics has been hardly studied. Methods The current study scrutinizes gender-specific differences in the prevalence of migraine across a broad spectrum of occupational categories, shedding also light on associations with important job-related features such as shift work, job satisfaction, and physical activity. The study included data from 415 712 participants from the UK Biobank cohort, using the official ICD10 diagnosis of migraine and other health conditions as selection criteria. Prevalence ratios of migraineurs compared to healthy controls among different occupational categories and job-related variables were estimated using log-binomial regression analyses. Statistical models were adjusted for important sociodemographic features such as age, BMI, ethnicity, education and neuroticism. To better highlight specific differences between men and women we stratified by sex. Results We detected a differential prevalence pattern of migraine in relation to different job categories between men and women. Especially in men, migraine appears to be more prevalent in highly physically demanding occupations (PR 1.38, 95% CI [0.93, 2.04]). Furthermore, migraine is also more prevalent in jobs that frequently involve shift or night shift work compared to healthy controls. Interestingly, this prevalence is especially high in women (shift work PR 1.45, 95% CI [1.14, 1.83], night shift work PR 1.46, 95% CI [0.93, 2.31]). Conclusion Our results show that migraine is genderdependently associated with physically demanding jobs and shift working.

    Download full text (pdf)
    FULLTEXT01
  • 13.
    Affatato, Oreste
    et al.
    Uppsala University, WoMHeR (Centre for Women’s Mental Health during the Reproductive Lifespan). Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience.
    Rukh, Gull
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience.
    Mwinyi, Jessica
    Uppsala University, WoMHeR (Centre for Women’s Mental Health during the Reproductive Lifespan). Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience.
    Volumetric Differences in Cerebellum and Brainstem in Patients with Migraine: A UK Biobank Study2023In: Biomedicines, E-ISSN 2227-9059, Vol. 11, no 9, article id 2528Article in journal (Refereed)
    Abstract [en]

    Background: The cerebellum and the brainstem are two brain structures involved in pain processing and modulation that have also been associated with migraine pathophysiology. The aim of this study was to investigate possible associations between the morphology of the cerebellum and brainstem and migraine, focusing on gray matter differences in these brain areas.

    Methods: The analyses were based on data from 712 individuals with migraine and 45,681 healthy controls from the UK Biobank study. Generalized linear models were used to estimate the mean gray matter volumetric differences in the brainstem and the cerebellum. The models were adjusted for important biological covariates such as BMI, age, sex, total brain volume, diastolic blood pressure, alcohol intake frequency, current tobacco smoking, assessment center, material deprivation, ethnic background, and a wide variety of health conditions. Secondary analyses investigated volumetric correlation between cerebellar sub-regions.

    Results: We found larger gray matter volumes in the cerebellar sub-regions V (mean difference: 72 mm3, 95% CI [13, 132]), crus I (mean difference: 259 mm3, 95% CI [9, 510]), VIIIa (mean difference: 120 mm3, 95% CI [0.9, 238]), and X (mean difference: 14 mm3, 95% CI [1, 27]).

    Conclusions: Individuals with migraine show larger gray matter volumes in several cerebellar sub-regions than controls. These findings support the hypothesis that the cerebellum plays a role in the pathophysiology of migraine.

    Download full text (pdf)
    FULLTEXT01
  • 14.
    Agalave, Nilesh M.
    et al.
    Karolinska Inst, Ctr Mol Med, Dept Physiol & Pharmacol, Stockholm, Sweden.;Univ Texas Dallas, Sch Behav & Brain Sci, Dept Neurosci, Neuroimmunol & Behav Grp, Richardson, TX 75083 USA..
    Rudjito, Resti
    Karolinska Inst, Ctr Mol Med, Dept Physiol & Pharmacol, Stockholm, Sweden..
    Farinotti, Alex Bersellini
    Karolinska Inst, Ctr Mol Med, Dept Physiol & Pharmacol, Stockholm, Sweden..
    Emami Khoonsari, Payam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry. Karolinska Inst, Ctr Mol Med, Dept Physiol & Pharmacol, Stockholm, Sweden..
    Sandor, Katalin
    Karolinska Inst, Ctr Mol Med, Dept Physiol & Pharmacol, Stockholm, Sweden..
    Nomura, Yuki
    Karolinska Inst, Ctr Mol Med, Dept Physiol & Pharmacol, Stockholm, Sweden..
    Szabo-Pardi, Thomas A.
    Univ Texas Dallas, Sch Behav & Brain Sci, Dept Neurosci, Neuroimmunol & Behav Grp, Richardson, TX 75083 USA..
    Urbina, Carlos Morado
    Karolinska Inst, Ctr Mol Med, Dept Physiol & Pharmacol, Stockholm, Sweden..
    Palada, Vinko
    Karolinska Inst, Ctr Mol Med, Dept Physiol & Pharmacol, Stockholm, Sweden..
    Price, Theodore J.
    Univ Texas Dallas, Sch Behav & Brain Sci, Dept Neurosci, Pain Neurobiol Res Grp, Richardson, TX 75083 USA..
    Harris, Helena Erlandsson
    Karolinska Inst, Ctr Mol Med, Dept Med, Stockholm, Sweden..
    Burton, Michael D.
    Univ Texas Dallas, Sch Behav & Brain Sci, Dept Neurosci, Neuroimmunol & Behav Grp, Richardson, TX 75083 USA..
    Kultima, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry. Karolinska Inst, Ctr Mol Med, Dept Physiol & Pharmacol, Stockholm, Sweden..
    Svensson, Camilla, I
    Karolinska Inst, Ctr Mol Med, Dept Physiol & Pharmacol, Stockholm, Sweden..
    Sex-dependent role of microglia in disulfide high mobility group box 1 protein-mediated mechanical hypersensitivity2021In: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 162, no 2, p. 446-458Article in journal (Refereed)
    Abstract [en]

    High mobility group box 1 protein (HMGB1) is increasingly regarded as an important player in the spinal regulation of chronic pain. Although it has been reported that HMGB1 induces spinal glial activation in a Toll-like receptor (TLR)4-dependent fashion, the aspect of sexual dimorphisms has not been thoroughly addressed. Here, we examined whether the action of TLR4-activating, partially reduced disulfide HMGB1 on microglia induces nociceptive behaviors in a sex-dependent manner. We found disulfide HMGB1 to equally increase microglial Iba1 immunoreactivity in lumbar spinal dorsal horn in male and female mice, but evoke higher cytokine and chemokine expression in primary microglial culture derived from males compared to females. Interestingly, TLR4 ablation in myeloid-derived cells, which include microglia, only protected male mice from developing HMGB1-induced mechanical hypersensitivity. Spinal administration of the glial inhibitor, minocycline, with disulfide HMGB1 also prevented pain-like behavior in male mice. To further explore sex difference, we examined the global spinal protein expression using liquid chromatography-mass spectrometry and found several antinociceptive and anti-inflammatory proteins to be upregulated in only male mice subjected to minocycline. One of the proteins elevated, alpha-1-antitrypsin, partially protected males but not females from developing HMGB1-induced pain. Targeting downstream proteins of alpha-1-antitrypsin failed to produce robust sex differences in pain-like behavior, suggesting that several proteins identified by liquid chromatography-mass spectrometry are required to modulate the effects. Taken together, the current study highlights the importance of mapping sex dimorphisms in pain mechanisms and point to processes potentially involved in the spinal antinociceptive effect of microglial inhibition in male mice.

  • 15.
    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.

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    fulltext
  • 16.
    Ahmad, Abdulbaghi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Child and Adolescent Psychiatry.
    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)
  • 17. 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)
  • 18.
    Ahmad, Abdulbaghi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Child and Adolescent Psychiatry.
    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)
  • 19.
    Ahmed, Mona
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    In vitro pharmacodynamic analysis on new small molecules acting on cholinergic enzymes as new therapeutic or molecular probes in dementia as well as in motor neuron disorders.2021Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    At present, more than 50 million people around the world have dementia. In fact, Alzheimer's disease (AD) is one of the leading causes, affecting up to 70% of all the cases. Dysfunction of the cholinergic system is a common feature in both AD and amyotrophic lateral sclerosis (ALS). The cholinergic system has three important enzymes, the acetylcholine (ACh) synthesizing enzyme choline acetyltransferase (ChAT), and the ACh hydrolyzing enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The aim of the study was to identify molecules with high affinity for these enzymes, that can be used as therapeutic compounds or as a molecular probe for diagnostics determination. Colorimetric and fluorometric assays were used to screen 126 compounds against ChAT, AChE and BChE to identify the hits. About 40 compounds were selected for enzyme kinetic inhibition analyses for determining the inhibition constant (Ki) and the mode of activity. Overall, several hits exhibited good affinity against ChAT with relatively low Ki values ranging between 1.2–10.8 μM. For AChE and BChE some of the hits showed high affinity and good inhibition in the screening step but not in the enzyme kinetic analyses. The reason for this discrepancy need to be assessed but it could be due to instability of some of the compounds in the solvent. Nonetheless, the next step concerning the promising hits would be to perform preclinical analyses on the compounds with low Ki, e.g. first in vitro in cell culture study and later on in the animal study. In conclusion, some results obtained from this study may provide useful information for the development of a new therapeutic or potential molecular probe in dementia as well as in motor neuron disorders such as ALS. 

  • 20.
    Aicardi, Christine
    et al.
    King’s College London.
    Akintoye, Simisola
    De Montfort University.
    Fothergill, B. Tyr
    De Montfort University.
    Guerrero, Manuel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics. Departament of Bioethics and Medical Humanities, University of Chile.
    Klinker, Gudrun
    Technical University Munich.
    Knight, William
    De Montfort University.
    Klüver, Lars
    The Danish Board of Technology.
    Morel, Yannick
    University of Maastricht.
    Morin, Fabrice O.
    Technical University Munich.
    Stahl, Bernd
    De Montfort University.
    Ulnicane, Inga
    De Montfort University.
    Ethical and Social Aspectos of Neurorobotics2020In: Science and Engineering Ethics, ISSN 1353-3452, E-ISSN 1471-5546Article in journal (Refereed)
    Abstract [en]

    The interdisciplinary field of neurorobotics looks to neuroscience to overcome limitations of modern robotics technology, to robotics to advance our understanding of the neural system's inner workings, and to information technology to develop tools that support those complementary endeavours. The development of these technologies is still at an early stage, which makes them an ideal candidate for proactive and anticipatory ethical reflection.

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    Ethical and Social Aspects of Neurorobotics
  • 21.
    Akerstedt, Torbjorn
    et al.
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.;Stockholm Univ, Stress Res Inst, Dept Psychol, Stockholm, Sweden.;Karolinska Inst, Clin Neurosci, S-17177 Stockholm, Sweden..
    Schwarz, Johanna
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.;Stockholm Univ, Stress Res Inst, Dept Psychol, Stockholm, Sweden..
    Theorell-Haglöw, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Lindberg, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    What do women mean by poor sleep?: A large population-based sample with polysomnographical indicators, inflammation, fatigue, depression, and anxiety2023In: Sleep Medicine, ISSN 1389-9457, E-ISSN 1878-5506, Vol. 109, p. 219-225Article in journal (Refereed)
    Abstract [en]

    Survey studies indicate that reports of disturbed sleep are prevalent and may be prospectively linked to several major diseases. However, it is not clear what self-reported disturbed sleep represents, since the link with objective sleep measures (polysomnography; PSG) seems very weak. The purpose of the present study was to try to investigate what combination of variables (PSG, inflammation, fatigue, anxiety, depression) that would characterize those who complain of disturbed sleep. This has never been done before. Participants were 319 women in a population-based sample, who gave ratings of sleep quality, fatigue, depression, and anxiety, then had their sleep recorded at home, and had blood drawn the following morning for analysis of immune parameters. Correlations and hierarchical multivariable regression analyses were applied to the data. For ratings of difficulties initiating sleep, the associations in the final step were beta =.22, (p <.001) for fatigue, beta = 0.22 (p <.001) for anxiety, and beta = 0.17 (p <.01) for sleep latency, with R-2 = 0.14. The rating of repeated awakenings was associated with fatigue (beta = 0.35, p <.001) and C-reactive protein (CRP) (beta = 0.12, p <.05), with R-2 = 0.19. The rating of early morning awakenings was associated with fatigue (beta = 0.31, p <.001), total sleep time (TST) (beta = -0.20, p <.01), and CRP (beta = 0.15, p <.05), with R-2 = 0.17. Interleukin-6 and Tumour Necrosis Factor were not associated with ratings of sleep problems. The results indicate that subjective fatigue, rather than objective sleep variables, is central in the perception of poor sleep, together with CRP.

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  • 22.
    Akgül, Özge
    et al.
    Izmir Democracy Univ, Dept Psychol, Fac Arts & Sci, Izmir, Turkiye..
    Fide, Ezgi
    Dokuz Eylul Univ, Dept Neurosci, Izmir, Turkiye..
    Özel, Fatih
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Physiology and Environmental Toxicology.
    Alptekin, Köksal
    Dokuz Eylul Univ, Dept Neurosci, Izmir, Turkiye.;Dokuz Eylul Univ, Fac Med, Dept Psychiat, Izmir, Turkiye..
    Bora, Emre
    Dokuz Eylul Univ, Dept Neurosci, Izmir, Turkiye.;Dokuz Eylul Univ, Fac Med, Dept Psychiat, Izmir, Turkiye..
    Akdede, Berna Binnur
    Dokuz Eylul Univ, Dept Neurosci, Izmir, Turkiye.;Dokuz Eylul Univ, Fac Med, Dept Psychiat, Izmir, Turkiye..
    Yener, Görsev
    Dokuz Eylul Univ, Dept Neurosci, Izmir, Turkiye.;Izmir Univ Econ, Fac Med, Dept Anat, Izmir, Turkiye.;Izmir Int Biomed & Genome Inst, Izmir, Turkiye..
    Reduced Reward Processing in Schizophrenia: A Comprehensive EEG Event-Related Oscillation Study2024In: Brain Topography, ISSN 0896-0267, E-ISSN 1573-6792, Vol. 37, no 1, p. 126-137Article in journal (Refereed)
    Abstract [en]

    It is well known that abnormal reward processing is a characteristic feature of various psychopathologies including schizophrenia (SZ). Reduced reward anticipation has been suggested as a core symptom of SZ. The present study aims to evaluate the event-related oscillations (EROs) delta, theta, alpha, beta, and gamma in patients with SZ during the Monetary Incentive Delay (MID) task, which elicits the neural activity of reward processing. Twenty-one patients with SZ and twenty-two demographically matched healthy controls were included in the study. EROs were compared between groups and correlation analyses were conducted to determine a possible relationship between clinical scores and ERO values. Compared with healthy controls, the SZ group had reduced (1) delta and theta amplitudes in the reward condition (2) total beta and non-incentive cue-related beta amplitudes, and (3) incentive cue-related frontal gamma amplitudes. These reductions can be interpreted as impaired dopaminergic neurotransmission and disrupted cognitive functioning in the reward processing of SZ. In contrast, SZ patients showed higher incentive cue-related theta and occipital gamma amplitudes compared to controls. These increments may reflect negative symptoms in SZ. Moreover, theta amplitudes showed a negative correlation with Calgary Depression Scale for Schizophrenia scores and a positive correlation with attentional impulsivity. This is the first study showing the impairments of SZ patients in EROs from delta to gamma frequency bands compared with healthy controls during reward anticipation. Being the first comprehensive study, our results can be interpreted as providing evidence for disrupted brain dynamics in the reward processing of SZ studied by EROs. It may become possible to help patients' wellness by improving our understanding of reward processing in schizophrenia and developing innovative rehabilitation treatments based on these findings.

  • 23.
    Akram, Mehwish
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Univ Punjab, Sch Biol Sci, Quaid E Azam Campus, Lahore 54590, Pakistan.
    Rashid, Naeem
    Univ Punjab, Sch Biol Sci, Quaid E Azam Campus, Lahore 54590, Pakistan.
    Inwardly Rectifying Potassium Channels in Drosophila Regulate the Sleep/Wake Behaviour through PDF-Neurons2019In: PAKISTAN JOURNAL OF ZOOLOGY, ISSN 0030-9923, Vol. 51, no 2, p. 709-715Article in journal (Refereed)
    Abstract [en]

    Potassium channels are important modulators of cell function depending on the cell type of where they are expressed. They are involved in regulation of cell membrane resting potential, potassium homeostasis and control a variety of cellular functions including metabolism. In this study we determined that a regulator of Pigment dispersing factor, PDF-immunoreactive neurons in the Drosophila melanogaster adult brain, is an inwardly rectifying potassium channel, IRK1. Knocking down the potassium channels specifically on PDF expressing neurons using UAS-GAL4 RNA(1) system resulted in altered axonal projections of lateral neurons (LNv) towards the dorsal neurons (DN). Moreover, it was observed that lack of the potassium channels also caused a robust increase in sleep and reduction in the fly's active period during the day. We observed that the normal circadian control of the morning and evening anticipation is also dependant on these potassium channels. The flies deficient in IRK1 channels didn't show an evening anticipation peak. Another interesting disclosure during this study was the inability of PDF- Tri neurons to undergo programmed cell death in the absence of inwardly rectifying potassium channels. Hence, IRK1, though poorly expressed in the Drosophila central nervous system, plays an important role in the normal functioning of PDF expressing neurons. Further studies are needed to elaborate the physiological roles of Drosophila potassium channels which may lead to a better understanding of human Kir channels related to pathological conditions and diseases.

  • 24.
    Akula, Srinivas
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology and Immunology. Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, BOX 7011, SE-75007 Uppsala, Sweden..
    Hellman, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology and Immunology.
    Aviles, Francesc Xavier
    Univ Autonoma Barcelona, Inst Biotecnol & Biomed IBB, Barcelona, Spain.;Univ Autonoma Barcelona, Dept Bioquim & Biol Mol, Barcelona, Spain..
    Wernersson, Sara
    Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, BOX 7011, SE-75007 Uppsala, Sweden..
    Analysis of the mast cell expressed carboxypeptidase A3 and its structural and evolutionary relationship to other vertebrate carboxypeptidases2022In: Developmental and Comparative Immunology, ISSN 0145-305X, E-ISSN 1879-0089, Vol. 127, article id 104273Article in journal (Refereed)
    Abstract [en]

    Metallo-carboxypeptidases are exopeptidases with diverse expression and function, found in all kingdoms of life from bacteria to mammals. One of them, the carboxypeptidase A3 (CPA3), has become an important component of the mammalian immune system by its expression in mast cells. Mast cells (MCs) are highly specialized sentinel cells, which store large amounts of bioactive mediators, including CPA3, in very abundant cytoplasmic granules. Clinical studies have found an increased CPA3 expression in asthma but the physiological role as well as the evolutionary origin of CPA3 remains largely unexplored. CPA3 belongs to the M14A subfamily of metallocarboxypeptidases, which among others also includes the digestive enzymes CPA1, CPA2, CPB1 and CPO. To study the appearance of CPA3 during vertebrate evolution, we here performed bioinformatic analyses of homologous genes and gene loci from a broad panel of metazoan animals from invertebrates to mammals. The phylogenetic analysis indicated that CPA3 appeared at the base of tetrapod evolution in a branch closer to CPB1 than to other CPAs. Indeed, CPA3 and CPB1 are also located in the same locus, on chromosome 3 in humans. The presence of CPA3 only in tetrapods and not in fishes, suggested that CPA3 could have appeared by a gene duplication from CPB1 during early tetrapod evolution. However, the apparent loss of CPA3 in several tetrapod lineages, e.g. in birds and monotremes, indicates a complex evolution of the CPA3 gene. Interestingly, in the lack of CPA3 in fishes, zebrafish MCs express instead CPA5 for which the most closely related human carboxypeptidase is CPA1, which has a similar cleavage specificity as CPA3. Collectively, these findings clarify and add to our understanding of the evolution of hematopoietic proteases expressed by mast cells.

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  • 25.
    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)
  • 26.
    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.

  • 27.
    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)
  • 28.
    Alam, Aftab
    et al.
    Univ Cambridge, Dept Clin Neurosci, Cambridge, England..
    Singh, Tanya
    Cardiff Univ, Sch Biosci, Cardiff, Wales.;Cardiff Univ, Neurosci & Mental Hlth Innovat Inst, Cardiff, Wales..
    Kayhanian, Saeed
    Univ Cambridge, Dept Clin Neurosci, Cambridge, England.;Univ Cambridge, Cambridge Biomed Campus, Cambridge CB2 0QQ, England..
    Tjerkaski, Jonathan
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden..
    Garcia, Nuria Marco
    Univ Cambridge, Dept Clin Neurosci, Cambridge, England..
    Carpenter, Keri L. H.
    Univ Cambridge, Dept Clin Neurosci, Cambridge, England..
    Patani, Rickie
    UCL, Inst Neurol, Queen Sq, London, England..
    Lindblad, Caroline
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Acquired brain injury. Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden..
    Thelin, Eric P. P.
    Univ Cambridge, Dept Clin Neurosci, Cambridge, England.;Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Neurol, Stockholm, Sweden..
    Syed, Yasir Ahmed
    Cardiff Univ, Sch Biosci, Cardiff, Wales.;Cardiff Univ, Neurosci & Mental Hlth Innovat Inst, Cardiff, Wales..
    Helmy, Adel
    Univ Cambridge, Dept Clin Neurosci, Cambridge, England..
    Modeling the Inflammatory Response of Traumatic Brain Injury Using Human Induced Pluripotent Stem Cell Derived Microglia2023In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 40, no 19-20, p. 2164-2173Article in journal (Refereed)
    Abstract [en]

    The neuroinflammatory response after traumatic brain injury (TBI) is implicated as a key mediator of secondary injury in both the acute and chronic periods after primary injury. Microglia are the key innate immune cell in the central nervous system, responding to injury with the release of cytokines and chemokines. In this context, we aimed to characterize the downstream cytokine response of human induced pluripotent stem cell (iPSC)-derived microglia when stimulated with five separate cytokines identified after human TBI. The iPSC-derived microglia were exposed to interleukin (IL)-1 & beta;, IL-4, IL-6, IL-10, and tumor necrosis factor (TNF) in the concentration ranges identified in clinical TBI studies. The downstream cytokine response was measured against a panel of 37 separate cytokines over a 72h time-course. The secretome revealed concentration-, time- and combined concentration and time-dependent downstream responses. TNF appeared to be the strongest inducer of downstream cytokine changes (51), followed by IL-1 & beta; (26) and IL-4 (19). IL-10 (11) and IL-6 (10) produced fewer responses. We also compare these responses with our previous studies of iPSC-derived neuronal and astrocyte cultures and the in vivo human TBI cytokine response. Notably, we found microglial culture to induce both a wider range of downstream cytokine responses and a greater fold change in concentration for those downstream responses, compared with astrocyte and neuronal cultures. In summary, we present a dataset for human microglial cytokine responses specific to the secretome found in the clinical context of TBI. This reductionist approach complements our previous datasets for astrocyte and neuronal responses and will provide a platform to enable future studies to unravel the complex neuroinflammatory network activated after TBI.

  • 29.
    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)
  • 30. 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.

  • 31.
    Aldskogius, Håkan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Kozlova: Regenerative neurobiology.
    Kozlova, Elena N.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Kozlova: Regenerative neurobiology.
    Dorsal Root Injury: A Model for Exploring Pathophysiology and Therapeutic Strategies in Spinal Cord Injury2021In: Cells, E-ISSN 2073-4409, Vol. 10, no 9, article id 2185Article, review/survey (Refereed)
    Abstract [en]

    Unraveling the cellular and molecular mechanisms of spinal cord injury is fundamental for our possibility to develop successful therapeutic approaches. These approaches need to address the issues of the emergence of a non-permissive environment for axonal growth in the spinal cord, in combination with a failure of injured neurons to mount an effective regeneration program. Experimental in vivo models are of critical importance for exploring the potential clinical relevance of mechanistic findings and therapeutic innovations. However, the highly complex organization of the spinal cord, comprising multiple types of neurons, which form local neural networks, as well as short and long-ranging ascending or descending pathways, complicates detailed dissection of mechanistic processes, as well as identification/verification of therapeutic targets. Inducing different types of dorsal root injury at specific proximo-distal locations provide opportunities to distinguish key components underlying spinal cord regeneration failure. Crushing or cutting the dorsal root allows detailed analysis of the regeneration program of the sensory neurons, as well as of the glial response at the dorsal root-spinal cord interface without direct trauma to the spinal cord. At the same time, a lesion at this interface creates a localized injury of the spinal cord itself, but with an initial neuronal injury affecting only the axons of dorsal root ganglion neurons, and still a glial cell response closely resembling the one seen after direct spinal cord injury. In this review, we provide examples of previous research on dorsal root injury models and how these models can help future exploration of mechanisms and potential therapies for spinal cord injury repair.

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  • 32. 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].

  • 33.
    Alm, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Blom Johansson: Speech-Language Pathology.
    Streptococcal infection as a major historical cause of stuttering: data, mechanisms, and current importance2020In: Frontiers in Human Neuroscience, E-ISSN 1662-5161, Vol. 14, article id 569519Article in journal (Refereed)
    Abstract [en]

    Stuttering is one of the most well-known speech disorders, but the underlying neurological mechanisms are debated. In addition to genetic factors, there are also major non-genetic contributions. It is here proposed that infection with group A beta-hemolytic streptococcus (GAS) was a major underlying cause of stuttering until the mid-1900s when penicillin was introduced in 1943. The main mechanism proposed is an autoimmune reaction from tonsillitis, targeting specific molecules, for example within the basal ganglia. It is here also proposed that GAS infections may have continued to cause stuttering to some extent, to the present date, though more rarely. If so, early diagnosis of such cases would be of importance. Childhood cases with sudden onset of stuttering after throat infection may be particularly important to assess for possible GAS infection. The support for this hypothesis primarily comes from three lines of argument. First, medical record data from the 1930s strongly indicates that there was one type of medical event in particular that preceded the onset of childhood stuttering with unexpected frequency: diseases related to GAS throat infections. In particular, this included tonsillitis and scarlet fever, but also rheumatic fever. Rheumatic fever is a childhood autoimmune sequela of GAS infection, which was a relatively widespread medical problem until the early 1960s. Second, available reports of changes of the childhood prevalence of stuttering indicate striking parallels between stuttering and the incidence of rheumatic fever, with: (1) decline from the early 1900s; (2) marked decline from the introduction of penicillin in the mid 1940s; and (3) reaching a more stable level in the 1960s. The correlations between the data for stuttering and rheumatic fever after the introduction of penicillin are very high, at about 0.95. Third, there are established biological mechanisms linking GAS tonsillitis to immunological effects on the brain. Also, a small number of more recent case reports have provided further support for the hypothesis linking stuttering to GAS infection. Overall, it is proposed that the available data provides strong evidence for the hypothesis that GAS infection was a major cause of stuttering until the mid-1900s, interacting with genetic predisposition.

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  • 34.
    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)
  • 35.
    Alm, Per A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Blom Johansson: Speech-Language Pathology.
    Stuttering: A Disorder of Energy Supply to Neurons?2021In: Frontiers in Human Neuroscience, E-ISSN 1662-5161, Vol. 15, article id 662204Article in journal (Refereed)
    Abstract [en]

    Stuttering is a disorder characterized by intermittent loss of volitional control of speech movements. This hypothesis and theory article focuses on the proposal that stuttering may be related to an impairment of the energy supply to neurons. Findings from electroencephalography (EEG), brain imaging, genetics, and biochemistry are reviewed: (1) Analyses of the EEG spectra at rest have repeatedly reported reduced power in the beta band, which is compatible with indications of reduced metabolism. (2) Studies of the absolute level of regional cerebral blood flow (rCBF) show conflicting findings, with two studies reporting reduced rCBF in the frontal lobe, and two studies, based on a different method, reporting no group differences. This contradiction has not yet been resolved. (3) The pattern of reduction in the studies reporting reduced rCBF corresponds to the regional pattern of the glycolytic index (GI; Vaishnavi et al., 2010). High regional GI indicates high reliance on non-oxidative metabolism, i.e., glycolysis. (4) Variants of the gene ARNT2 have been associated with stuttering. This gene is primarily expressed in the brain, with a pattern roughly corresponding to the pattern of regional GI. A central function of the ARNT2 protein is to act as one part of a sensor system indicating low levels of oxygen in brain tissue and to activate appropriate responses, including activation of glycolysis. (5) It has been established that genes related to the functions of the lysosomes are implicated in some cases of stuttering. It is possible that these gene variants result in a reduced peak rate of energy supply to neurons. (6) Lastly, there are indications of interactions between the metabolic system and the dopamine system: for example, it is known that acute hypoxia results in an elevated tonic level of dopamine in the synapses. Will mild chronic limitations of energy supply also result in elevated levels of dopamine? The indications of such interaction effects suggest that the metabolic theory of stuttering should be explored in parallel with the exploration of the dopaminergic theory.

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  • 36.
    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.

  • 37.
    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.

  • 38.
    Alm, Per A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Blom Johansson: Speech-Language Pathology.
    The Dopamine System and Automatization of Movement Sequences: A Review With Relevance for Speech and Stuttering2021In: Frontiers in Human Neuroscience, E-ISSN 1662-5161, Vol. 15, article id 661880Article, review/survey (Refereed)
    Abstract [en]

    The last decades of research have gradually elucidated the complex functions of the dopamine system in the vertebrate brain. The multiple roles of dopamine in motor function, learning, attention, motivation, and the emotions have been difficult to reconcile. A broad and detailed understanding of the physiology of cerebral dopamine is of importance in understanding a range of human disorders. One of the core functions of dopamine involves the basal ganglia and the learning and execution of automatized sequences of movements. Speech is one of the most complex and highly automatized sequential motor behaviors, though the exact roles that the basal ganglia and dopamine play in speech have been difficult to determine. Stuttering is a speech disorder that has been hypothesized to be related to the functions of the basal ganglia and dopamine. The aim of this review was to provide an overview of the current understanding of the cerebral dopamine system, in particular the mechanisms related to motor learning and the execution of movement sequences. The primary aim was not to review research on speech and stuttering, but to provide a platform of neurophysiological mechanisms, which may be utilized for further research and theoretical development on speech, speech disorders, and other behavioral disorders. Stuttering and speech are discussed here only briefly. The review indicates that a primary mechanism for the automatization of movement sequences is the merging of isolated movements into chunks that can be executed as units. In turn, chunks can be utilized hierarchically, as building blocks of longer chunks. It is likely that these mechanisms apply also to speech, so that frequent syllables and words are produced as motor chunks. It is further indicated that the main learning principle for sequence learning is reinforcement learning, with the phasic release of dopamine as the primary teaching signal indicating successful sequences. It is proposed that the dynamics of the dopamine system constitute the main neural basis underlying the situational variability of stuttering.

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  • 39.
    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
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    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: 2023-06-28Bibliographically 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
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    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 ()28028735 (PubMedID)
    Funder
    Swedish Research Council, 2011-4519Marianne and Marcus Wallenberg FoundationThe Swedish Brain FoundationSwedish Society of Medicine
    Available from: 2017-12-15 Created: 2017-12-15 Last updated: 2022-01-29Bibliographically 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
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    (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, 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: 2023-08-28Bibliographically approved
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  • 40.
    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, 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

    Download full text (pdf)
    fulltext
  • 41.
    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)
  • 42. 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.

  • 43.
    Al-Sabri, Mohamed H.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Nikpour, Maryam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience. Department of Medical Sciences, Uppsala University, BMC, Husargatan 3, 750 03, Uppsala, Sweden.
    Clemensson, Laura Emily
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Attwood, Misty M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Williams, Michael J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Rask-Andersen, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mwinyi, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    The regulatory role of AP-2 beta in monoaminergic neurotransmitter systems: insights on its signalling pathway, linked disorders and theragnostic potential2022In: Cell & Bioscience, ISSN 2045-3701, Vol. 12, no 1, article id 151Article, review/survey (Refereed)
    Abstract [en]

    Monoaminergic neurotransmitter systems play a central role in neuronal function and behaviour. Dysregulation of these systems gives rise to neuropsychiatric and neurodegenerative disorders with high prevalence and societal burden, collectively termed monoamine neurotransmitter disorders (MNDs). Despite extensive research, the transcriptional regulation of monoaminergic neurotransmitter systems is not fully explored. Interestingly, certain drugs that act on these systems have been shown to modulate central levels of the transcription factor AP-2 beta (AP-2 beta, gene: TFAP2B). AP-2 beta regulates multiple key genes within these systems and thereby its levels correlate with monoamine neurotransmitters measures; yet, its signalling pathways are not well understood. Moreover, although dysregulation of TFAP2B has been associated with MNDs, the underlying mechanisms for these associations remain elusive. In this context, this review addresses AP-2 beta, considering its basic structural aspects, regulation and signalling pathways in the controlling of monoaminergic neurotransmitter systems, and possible mechanisms underpinning associated MNDS. It also underscores the significance of AP-2 beta as a potential diagnostic biomarker and its potential and limitations as a therapeutic target for specific MNDs as well as possible pharmaceutical interventions for targeting it. In essence, this review emphasizes the role of AP-2 beta as a key regulator of the monoaminergic neurotransmitter systems and its importance for understanding the pathogenesis and improving the management of MNDs.

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  • 44.
    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.

  • 45.
    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.

  • 46.
    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)
  • 47.
    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)
  • 48.
    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, E-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.

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  • 49.
    Amorim, Felippe E.
    et al.
    Univ Fed Rio de Janeiro, Inst Med Biochem Leopoldo de Meis, BR-21941902 Rio De Janeiro, Brazil..
    Chapot, Renata L.
    Univ Fed Rio de Janeiro, Inst Med Biochem Leopoldo de Meis, BR-21941902 Rio De Janeiro, Brazil..
    Moulin, Thiago
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Lee, Jonathan L. C.
    Univ Birmingham, Sch Psychol, Birmingham B15 2TT, W Midlands, England..
    Amaral, Olavo B.
    Univ Fed Rio de Janeiro, Inst Med Biochem Leopoldo de Meis, BR-21941902 Rio De Janeiro, Brazil..
    Memory destabilization during reconsolidation: a consequence of homeostatic plasticity?2021In: Learning & memory (Cold Spring Harbor, N.Y.), ISSN 1072-0502, E-ISSN 1549-5485, Vol. 28, no 10, p. 371-389Article in journal (Refereed)
    Abstract [en]

    Remembering is not a static process: When retrieved, a memory can be destabilized and become prone to modifications. This phenomenon has been demonstrated in a number of brain regions, but the neuronal mechanisms that rule memory destabilization and its boundary conditions remain elusive. Using two distinct computational models that combine Hebbian plasticity and synaptic downscaling, we show that homeostatic plasticity can function as a destabilization mechanism, accounting for behavioral results of protein synthesis inhibition upon reactivation with different re-exposure times. Furthermore, by performing systematic reviews, we identify a series of overlapping molecular mechanisms between memory destabilization and synaptic downscaling, although direct experimental links between both phenomena remain scarce. In light of these results, we propose a theoretical framework where memory destabilization can emerge as an epiphenomenon of homeostatic adaptations prompted by memory retrieval.

  • 50. Andersen, Søren S. L.
    Real time large scale in vivo observations reveal intrinsic synchrony, plasticity and growth cone dynamics of midline crossing axons at the ventral floor plate of the zebrafish spinal cord2019In: Journal of Integrative Neuroscience, ISSN 0219-6352, E-ISSN 1757-448X, Vol. 18, no 4, p. 351-368Article in journal (Refereed)
    Abstract [en]

    How axons are wiring the vertebrate spinal cord has in particular been studied at the ventral floor plate using fixed samples or looking at single growing axons with various microscopy techniques. Thereby may remain hidden important live organismal scale information concerning dynamics and concurrent timing of the many axons simultaneously crossing the floor plate. Here then, applying light-sheet microscopy, axonal growth and guidance at the floor plate are followed in vivo in real time at high resolution along several hundred micrometers of the zebrafish spinal cord by using an interneuron expressing GFP as a model axon. The commissural axons are observed crossing the ventral floor plate midline perpendicularly at about 20 microns/h and in a manner dependent on the Robo3 receptor. Commissural growth rate reaches a minimum at the midline, confirming previous observations. Ipsilateral axons extend concurrently, at three to six times higher growth rates. At guidance points, commissural axons are seen to decrease their growth rate and growth cones increase in size. Commissural filopodia appear to interact with the nascent neural network, and thereby trigger immediate plastic and reversible sinusoidal-shaped bending movements of neighboring commissural shafts. A simple protocol isolating single neuronal cells from the spinal cord is developed to facilitate further molecular characterization. The recordings show the strikingly stereotyped spatio-temporal control that governs midline crossing. The live observations give renewed perspective on the mechanisms of axonal guidance in the spinal cord that provide for a discussion of the current distinction between diffusible long-range versus substrate-bound short-range guidance cues.

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