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  • 101.
    Holmqvist, Tomas
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience, Physiology.
    Åkerman, Karl
    Kukkonen, Jyrki
    High specificity of human orexin receptors for orexins over Neuropeptide Y and other neuropeptides2001In: Neuroscience Letters, ISSN 0304-3940, Vol. 305, no 3, p. 177-180Article in journal (Refereed)
  • 102.
    Holmqvist, Tomas
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience, Physiology.
    Åkerman, Karl
    Kukkonen, Jyrki
    Orexin signaling in recombinant neuron-like cells2002In: FEBS Letters, ISSN 00145793, Vol. 526, no 1-3, p. 11-14Article in journal (Refereed)
  • 103.
    Holmqvist, Tomas
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience, Physiology.
    Östman, Marie
    Åkerman, Karl
    Kukkonen, Jyrki
    OX1 orexin receptors couple to adenylyl cyclase regulation via multiple mechanismsManuscript (Other academic)
  • 104. Huang, Yong-Qing
    et al.
    Li, Ya-Di
    Li, Guo-Kai
    Jin, Zhe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Ma, Jian
    The Evaluation of Basic Fibroblast Growth Factor and Fibroblastic Growth Factor Receptor 1 Levels in Saliva and Serum of Patients with Salivary Gland Tumor2012In: DNA and Cell Biology, ISSN 1044-5498, E-ISSN 1557-7430, Vol. 31, no 4, p. 520-523Article in journal (Refereed)
    Abstract [en]

    Basic fibroblast growth factor (FGF2) is a well-known endothelial mitogen that regulates endothelial cell proliferation, migration, differentiation, and survival. In the present study, we investigated the levels of FGF2 and fibroblastic growth factor receptor 1 (FGFR1) in saliva and serum of patients with salivary gland tumors. Saliva and serum samples were collected from 43 patients with salivary gland tumors and 40 healthy volunteers. The FGF2 and FGFR1 concentrations in saliva and serum samples were measured by enzyme-linked immunosorbent assay. We found that the levels of FGF2 and FGFR1 in saliva and serum from patients with salivary gland tumors were significantly higher than those from healthy control subjects. These results suggest that salivary FGF2 and FGFR1 can be used as potential biomarkers in the diagnosis of salivary gland tumors.

  • 105.
    Höglund, Erik
    et al.
    Norwegian Inst Water Res NIVA, Gaustadalleen 21, N-0349 Oslo, Norway.;Univ Agder, Ctr Coastal Res, Postboks 422, N-4604 Kristiansand, Norway..
    Overli, Oyvind
    Norwegian Univ Life Sci, Dept Anim & Agr Sci, POB 1432, As, Norway..
    Andersson, Madelene Å.
    Tech Univ Denmark, North Sea Ctr, Danish Inst Fisheries Res, Dept Marine Ecol & Aquaculture, POB 101, DK-9850 Hirtshals, Denmark..
    Silva, Patricia
    Norwegian Univ Life Sci, Dept Anim & Agr Sci, POB 1432, As, Norway.;Tech Univ Denmark, North Sea Ctr, Danish Inst Fisheries Res, Dept Marine Ecol & Aquaculture, POB 101, DK-9850 Hirtshals, Denmark..
    Laursen, Danielle Caroline
    Tech Univ Denmark, North Sea Ctr, Danish Inst Fisheries Res, Dept Marine Ecol & Aquaculture, POB 101, DK-9850 Hirtshals, Denmark..
    Moltesen, Maria M.
    Tech Univ Denmark, North Sea Ctr, Danish Inst Fisheries Res, Dept Marine Ecol & Aquaculture, POB 101, DK-9850 Hirtshals, Denmark.;Univ Copenhagen, Dept Biol, Sect Ecol & Evolut, Univ Pk 15,Bldg 3,4th Floor, DK-2100 Copenhagen O, Denmark..
    Krogdahl, Åshild
    Norwegian Univ Life Sci, Dept Basic Sci & Aquat Med, POB 8146 Dep, N-0033 Oslo, Norway..
    Schjolden, Joachim
    Norwegian Univ Life Sci, Dept Anim & Agr Sci, POB 1432, As, Norway..
    Winberg, Svante
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Vindas, Marco A.
    Uni Res AS, Uni Environm, NO-5020 Bergen, Norway..
    Mayer, Ian
    Norwegian Univ Life Sci, Dept Prod Anim Clin Sci, POB 8146 Dep, N-0033 Oslo, Norway..
    Hillestad, Marie
    BioMar AS, Nordre Gate 11, N-7011 Trondheim, Norway..
    Dietary L-tryptophan leaves a lasting impression on the brain and the stress response2017In: British Journal of Nutrition, ISSN 0007-1145, E-ISSN 1475-2662, Vol. 117, no 10, p. 1351-1357Article in journal (Refereed)
    Abstract [en]

    Comparative models suggest that effects of dietary tryptophan (Trp) on brain serotonin (5-hydroxytryptamine; 5-HT) neurochemistry and stress responsiveness are present throughout the vertebrate lineage. Moreover, hypothalamic 5-HT seems to play a central role in control of the neuroendocrine stress axis in all vertebrates. Still, recent fish studies suggest long-term effects of dietary Trp on stress responsiveness, which are independent of hypothalamic 5-HT. Here, we investigated if dietary Trp treatment may result in long-lasting effects on stress responsiveness, including changes in plasma cortisol levels and 5-HT neurochemistry in the telencephalon and hypothalamus of Atlantic salmon. Fish were fed diets containing one, two or three times the Trp content in normal feed for 1 week. Subsequently, fish were reintroduced to control feed and were exposed to acute crowding stress for 1 h, 8 and 21 d post Trp treatment. Generally, acute crowding resulted in lower plasma cortisol levels in fish treated with 3xTrp compared with 1xTrp- and 2xTrp-treated fish. The same general pattern was reflected in telencephalic 5-HTergic turnover, for which 3xTrp-treated fish showed decreased values compared with 2xTrp-treated fish. These long-term effects on post-stress plasma cortisol levels and concomitant 5-HT turnover in the telencephalon lends further support to the fact that the extrahypothalamic control of the neuroendocrine stress response is conserved within the vertebrate lineage. Moreover, they indicate that trophic/structural effects in the brain underlie the effects of dietary Trp treatment on stress reactivity.

  • 106.
    Jin, Yang
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    The Cross-Talk between GABA Signalling and Metabolic Hormones in the Brain and Pancreatic Islets2013Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    GABA is a well-known neurotransmitter that can be synthesized in the central nervous system (CNS) and, interestingly, also in pancreatic islets. Once released, GABA activates GABA-A channels tonically or transiently resulting in different physiological functions. The pancreatic islets are important micro-organs composed of mainly α, β and δ cells secreting the metabolic hormones, namely insulin, glucagon and somatosatin, respectively. When insulin is secreted from pancreatic β cells, it can enter the blood and travel to the target tissues including the brain where the insulin receptor is prominently expressed such as in the hippocampus. It has been suggested that insulin regulates hippocampal function and, thereby, possibly modulates cognition. However, how this comes about is not understood. On the other hand, GABA secreted from the pancreatic β cells can regulate the islet cells via the para or autocrine loop. Nevertheless, in order to elucidate the details of GABA effects on cellular function, more insight into the pharmacological characteristics of GABA-A receptors, the physiological concentration of GABA and activation types of the GABA-receptors are required. We, therefore, used the whole-cell and single-channel patch-clamp technique to record from cells in the hippocampal slice and pancreatic islets for studying the function of GABA-A receptors and how they are modified by hormones, GABA or drugs. RT-qPCR was utilized to profile the expression of GABA-A receptors in the intact tissues. We also initiated the patch-clamp combined single-cell RT-PCR in the intact rat and human islets to investigate the cell-specific function of GABA-A receptors.

    We have shown in acute rat hippocampal slices that 1 nM insulin “turns on” extrasynaptic GABA-A receptors in CA1 pyramidal neurons resulting in decreased frequency of action potential firing. The single-channel current amplitude is related to the GABA concentration resulting in a single-channel GABA affinity in the pM range. The benzodiazepines, flumazenil and zolpidem, are inverse agonists. The results demonstrated an unexpected hormonal control of the inhibitory channel subtype expressed and excitability of hippocampal neurons.

    In the intact rat islets, the GABA-evoked tonic currents were present in the α cells and may contribute to keeping the resting membrane potential of α cells population at hyperpolarized membrane potential and, thereby, making it more difficult to depolarize the cells. In the human, the GABA signaling system was compromised in islets from type 2 diabetic individuals, where the expression of genes encoding the α1, α2, β2 and β3 GABA-A receptor subunits were down-regulated. GABA originating within the islets evoked tonic currents in the α, β and δ cells. However, transient current was observed only in δ cells, which implies a rapid regulation of somatostatin secretion by GABA. The effects of SR95531 on hormone release revealed that activation of GABA-A receptors decreased both insulin and glucagon secretion. The data is important for understanding the mechanism underlying GABA regulation of hormones secretion in human islets.

    List of papers
    1. Insulin reduces neuronal excitability by turning on GABA(A) channels that generate tonic current
    Open this publication in new window or tab >>Insulin reduces neuronal excitability by turning on GABA(A) channels that generate tonic current
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    2011 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 1, p. e16188-Article in journal (Refereed) Published
    Abstract [en]

    Insulin signaling to the brain is important not only for metabolic homeostasis but also for higher brain functions such as cognition. GABA (γ-aminobutyric acid) decreases neuronal excitability by activating GABA(A) channels that generate phasic and tonic currents. The level of tonic inhibition in neurons varies. In the hippocampus, interneurons and dentate gyrus granule cells normally have significant tonic currents under basal conditions in contrast to the CA1 pyramidal neurons where it is minimal. Here we show in acute rat hippocampal slices that insulin (1 nM) "turns on" new extrasynaptic GABA(A) channels in CA1 pyramidal neurons resulting in decreased frequency of action potential firing. The channels are activated by more than million times lower GABA concentrations than synaptic channels, generate tonic currents and show outward rectification. The single-channel current amplitude is related to the GABA concentration resulting in a single-channel GABA affinity (EC(50)) in intact CA1 neurons of 17 pM with the maximal current amplitude reached with 1 nM GABA. They are inhibited by GABA(A) antagonists but have novel pharmacology as the benzodiazepine flumazenil and zolpidem are inverse agonists. The results show that tonic rather than synaptic conductances regulate basal neuronal excitability when significant tonic conductance is expressed and demonstrate an unexpected hormonal control of the inhibitory channel subtypes and excitability of hippocampal neurons. The insulin-induced new channels provide a specific target for rescuing cognition in health and disease.

    National Category
    Medical and Health Sciences
    Research subject
    Physiology
    Identifiers
    urn:nbn:se:uu:diva-148240 (URN)10.1371/journal.pone.0016188 (DOI)000286516500036 ()21264261 (PubMedID)
    Available from: 2011-03-03 Created: 2011-03-03 Last updated: 2017-12-11Bibliographically approved
    2. In Intact Islets Interstitial GABA Activates GABA(A) Receptors That Generate Tonic Currents in alpha-Cells
    Open this publication in new window or tab >>In Intact Islets Interstitial GABA Activates GABA(A) Receptors That Generate Tonic Currents in alpha-Cells
    Show others...
    2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 6, p. e67228-Article in journal (Refereed) Published
    Abstract [en]

    In the rat islets γ-aminobutyric acid (GABA) is produced by the β-cells and, at least, the α-cells express the GABAA receptors (GABAA channels). In this study, we examined in intact islets if the interstitial GABA activated the GABAA receptors. We used the patch-clamp technique to record whole-cell and single-channel currents and single-cell RT-PCR to identify the cell-type we recorded from, in the intact rat islets. We further identified which GABAA receptor subunits were expressed. We determined the cell-type of 43 cells we recorded from and of these 49%, 28% and 7% were α, β and δ-cells, respectively. In the remaining 16% of the cells, mRNA transcripts of more than one hormone gene were detected. The results show that in rat islets interstitial GABA activates tonic current in the α-cells but not in the β-cells. Seventeen different GABAA receptor subunits are expressed with high expression of α1, α2, α4, α6, β3, γ1, δ, ρ1, ρ2 and ρ3 subunits whereas no expression was detected for α5 or ε subunits. The abundance of the GABAA receptor subunits detected suggests that a number of GABAA receptor subtypes are formed in the islets. The single-channel and tonic currents were enhanced by pentobarbital and inhibited by the GABAA receptor antagonist SR-95531. The single-channel conductance ranged from 24 to 105 pS. Whether the single-channel conductance is related to subtypes of the GABAA receptor or variable interstitial GABA concentrations remains to be determined. Our results reveal that GABA is an extracellular signaling molecule in rat pancreatic islets and reaches concentration levels that activate GABAA receptors on the glucagon-releasing α-cells.

    National Category
    Physiology
    Identifiers
    urn:nbn:se:uu:diva-203228 (URN)10.1371/journal.pone.0067228 (DOI)000321738400122 ()23826240 (PubMedID)
    Available from: 2013-07-05 Created: 2013-07-05 Last updated: 2019-02-01Bibliographically approved
    3. gamma-Aminobutyric acid (GABA) signalling in human pancreatic islets is altered in type 2 diabetes
    Open this publication in new window or tab >>gamma-Aminobutyric acid (GABA) signalling in human pancreatic islets is altered in type 2 diabetes
    Show others...
    2012 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 55, no 7, p. 1985-1994Article in journal (Refereed) Published
    Abstract [en]

    gamma-Aminobutyric acid (GABA) is a signalling molecule in the interstitial space in pancreatic islets. We examined the expression and function of the GABA signalling system components in human pancreatic islets from normoglycaemic and type 2 diabetic individuals. Expression of GABA signalling system components was studied by microarray, quantitative PCR analysis, immunohistochemistry and patch-clamp experiments on cells in intact islets. Hormone release was measured from intact islets. The GABA signalling system was compromised in islets from type 2 diabetic individuals, where the expression of the genes encoding the alpha 1, alpha 2, beta 2 and beta 3 GABA(A) channel subunits was downregulated. GABA originating within the islets evoked tonic currents in the cells. The currents were enhanced by pentobarbital and inhibited by the GABA(A) receptor antagonist, SR95531. The effects of SR95531 on hormone release revealed that activation of GABA(A) channels (GABA(A) receptors) decreased both insulin and glucagon secretion. The GABA(B) receptor antagonist, CPG55845, increased insulin release in islets (16.7 mmol/l glucose) from normoglycaemic and type 2 diabetic individuals. Interstitial GABA activates GABA(A) channels and GABA(B) receptors and effectively modulates hormone release in islets from type 2 diabetic and normoglycaemic individuals.

    Keywords
    gamma-Aminobutyric acid, Gene expression, Human islets, Type 2 diabetes
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-178541 (URN)10.1007/s00125-012-2548-7 (DOI)000305215200017 ()
    Note

    De tre första författarna delar förstaförfattarskapet.

    Available from: 2012-08-01 Created: 2012-07-31 Last updated: 2017-12-07Bibliographically approved
    4. In a cell-type specific manner, high-affinity GABA-A receptors participate in autocrine and paracrine GABA signaling in human pancreatic islets
    Open this publication in new window or tab >>In a cell-type specific manner, high-affinity GABA-A receptors participate in autocrine and paracrine GABA signaling in human pancreatic islets
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    γ-Aminobutyric acid (GABA), best known as the classical inhibitory neurotransmitter, is also produced and released by pancreatic islet cells. The hormone secreting α, β and δ- cells in human islets express GABA-A receptors that are activated by GABA. GABA signaling in the islets is thought to regulate hormone secretion but how it comes about is unclear. To-date the interstitial GABA concentration and cell-type specific GABA-A receptors have not been characterized. As a consequence, it is not clear how the interstitial GABA in the intact human islet regulates the specific cell-types. We have set- up single-cell RT-PCR combined whole-cell patch-clamp to investigate the functional role of GABA-A receptors in identified cell within intact human islets. GABA-activated tonic current is present in all α, β and δ-cells whereas only the δ-cells respond to GABA with large, transient currents. High-affinity GABA-A receptors activated with interstitial concentrations lower than 10 nM GABA are expressed in both α and β-cells. In the β- cells different subtypes of GABA-A receptors were identified based on single-channel kinetics, current-voltage relation and pharmacology. The data provides insight into the mechanisms underlying GABA regulation of different cell-types in intact human islet.

    National Category
    Medical and Health Sciences
    Research subject
    Physiology
    Identifiers
    urn:nbn:se:uu:diva-209530 (URN)
    Available from: 2013-10-21 Created: 2013-10-21 Last updated: 2013-11-22Bibliographically approved
    Download full text (pdf)
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  • 107.
    Jin, Yang
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Korol, Sergiy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Jin, Zhe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Laver, Derek
    University of Newcastle.
    Birnir, Bryndis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    In a cell-type specific manner, high-affinity GABA-A receptors participate in autocrine and paracrine GABA signaling in human pancreatic isletsManuscript (preprint) (Other academic)
    Abstract [en]

    γ-Aminobutyric acid (GABA), best known as the classical inhibitory neurotransmitter, is also produced and released by pancreatic islet cells. The hormone secreting α, β and δ- cells in human islets express GABA-A receptors that are activated by GABA. GABA signaling in the islets is thought to regulate hormone secretion but how it comes about is unclear. To-date the interstitial GABA concentration and cell-type specific GABA-A receptors have not been characterized. As a consequence, it is not clear how the interstitial GABA in the intact human islet regulates the specific cell-types. We have set- up single-cell RT-PCR combined whole-cell patch-clamp to investigate the functional role of GABA-A receptors in identified cell within intact human islets. GABA-activated tonic current is present in all α, β and δ-cells whereas only the δ-cells respond to GABA with large, transient currents. High-affinity GABA-A receptors activated with interstitial concentrations lower than 10 nM GABA are expressed in both α and β-cells. In the β- cells different subtypes of GABA-A receptors were identified based on single-channel kinetics, current-voltage relation and pharmacology. The data provides insight into the mechanisms underlying GABA regulation of different cell-types in intact human islet.

  • 108.
    Jin, Yang
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Korol, Sergiy V
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Jin, Zhe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Barg, Sebastian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Birnir, Bryndis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    In Intact Islets Interstitial GABA Activates GABA(A) Receptors That Generate Tonic Currents in alpha-Cells2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 6, p. e67228-Article in journal (Refereed)
    Abstract [en]

    In the rat islets γ-aminobutyric acid (GABA) is produced by the β-cells and, at least, the α-cells express the GABAA receptors (GABAA channels). In this study, we examined in intact islets if the interstitial GABA activated the GABAA receptors. We used the patch-clamp technique to record whole-cell and single-channel currents and single-cell RT-PCR to identify the cell-type we recorded from, in the intact rat islets. We further identified which GABAA receptor subunits were expressed. We determined the cell-type of 43 cells we recorded from and of these 49%, 28% and 7% were α, β and δ-cells, respectively. In the remaining 16% of the cells, mRNA transcripts of more than one hormone gene were detected. The results show that in rat islets interstitial GABA activates tonic current in the α-cells but not in the β-cells. Seventeen different GABAA receptor subunits are expressed with high expression of α1, α2, α4, α6, β3, γ1, δ, ρ1, ρ2 and ρ3 subunits whereas no expression was detected for α5 or ε subunits. The abundance of the GABAA receptor subunits detected suggests that a number of GABAA receptor subtypes are formed in the islets. The single-channel and tonic currents were enhanced by pentobarbital and inhibited by the GABAA receptor antagonist SR-95531. The single-channel conductance ranged from 24 to 105 pS. Whether the single-channel conductance is related to subtypes of the GABAA receptor or variable interstitial GABA concentrations remains to be determined. Our results reveal that GABA is an extracellular signaling molecule in rat pancreatic islets and reaches concentration levels that activate GABAA receptors on the glucagon-releasing α-cells.

    Download full text (pdf)
    fulltext
  • 109.
    Jin, Zhe
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Bazov, Igor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kononenko, Olga
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Korpi, Esa R
    Univ Helsinki, Inst Biomed, FIN-00014 Helsinki, Finland.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Birnir, Bryndis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Selective Changes of GABA(A) Channel Subunit mRNAs in the Hippocampus and Orbitofrontal Cortex but not in Prefrontal Cortex of Human Alcoholics2012In: Frontiers in Cellular Neuroscience, ISSN 1662-5102, E-ISSN 1662-5102, Vol. 5, article id 30Article in journal (Refereed)
    Abstract [en]

    Alcohol dependence is a common chronic relapsing disorder. The development of alcohol dependence has been associated with changes in brain GABA(A) channel-mediated neurotransmission and plasticity. We have examined mRNA expression of the GABA(A) channel subunit genes in three brain regions in individuals with or without alcohol dependence using quantitative real-time PCR assay. The levels of selective GABA(A) channel subunit mRNAs were altered in specific brain regions in alcoholic subjects. Significant increase in the α1, α4, α5, β1, and γ1 subunit mRNAs in the hippocampal dentate gyrus region, and decrease in the β2 and δ subunit mRNAs in the orbitofrontal cortex were identified whereas no changes in the dorsolateral prefrontal cortex were detected. The data increase our understanding of the role of GABA(A) channels in the development of alcohol dependence.

    Download full text (pdf)
    fulltext
  • 110.
    Jin, Zhe
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Bhandage, Amol K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Bazov, Igor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kononenko, Olga
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Korpi, Esa R.
    Birnir, Bryndis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Expression of specific ionotropic glutamate and GABA-A receptor subunits is decreased in central amygdala of alcoholics2014In: Frontiers in Cellular Neuroscience, ISSN 1662-5102, E-ISSN 1662-5102, Vol. 8, p. 288-Article in journal (Refereed)
    Abstract [en]

    The central amygdala (CeA) has a role for mediating fear and anxiety responses. It is also involved in emotional imbalance caused by alcohol abuse and dependence and in regulating relapse to alcohol abuse. Growing evidences suggest that excitatory glutamatergic and inhibitory gamma-aminobutyric acid-ergic (GABAergic) transmissions in the CeA are affected by chronic alcohol exposure. Human post-mortem CeA samples from male alcoholics (n = 9) and matched controls (n = 9) were assayed for the expression level of ionotropic glutamate and GABA-A receptors subunit mRNAs using quantitative real-time reverse transcription-PCB (RT-qPCR). Our data revealed that out of the 16 ionotropic glutamate receptor subunits, mRNAs encoding two AMPA P-amino-3-(3-hydroxy-5-methyl-isoxazol-4-y1)propanoic acid] receptor subunits GluA1 and GluA4; one kainate receptor subunit GluK2; one NMDA (N-methyl-D-aspartate) receptor subunit GluN2D and one delta receptor subunit GluD2 were significantly decreased in the CeA of alcoholics. In contrast, of the 19 GABA-A receptor subunits, only the mRNA encoding the a2 subunit was significantly down-regulated in the CeA of the alcoholics as compared with control subjects. Our findings imply that the down-regulation of specific ionotropic glutamate and GABA-A receptor subunits in the CeA of alcoholics may represent one of the molecular substrates underlying the new balance between excitatory and inhibitory neurotransmission in alcohol dependence.

  • 111.
    Jin, Zhe
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Bhandage, Amol K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Bazov, Igor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kononenko, Olga
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Korpi, Esa R
    Birnir, Bryndis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Selective increases of AMPA, NMDA, and kainate receptor subunit mRNAs in the hippocampus and orbitofrontal cortex but not in prefrontal cortex of human alcoholics2014In: Frontiers in Cellular Neuroscience, ISSN 1662-5102, E-ISSN 1662-5102, Vol. 8, p. 11-Article in journal (Refereed)
    Abstract [en]

    Glutamate is the main excitatory transmitter in the human brain. Drugs that affect the glutamatergic signaling will alter neuronal excitability. Ethanol inhibits glutamate receptors. We examined the expression level of glutamate receptor subunit mRNAs in human post-mortem samples from alcoholics and compared the results to brain samples from control subjects. RNA from hippocampal dentate gyrus (HP-DG), orbitofrontal cortex (OFC), and dorso-lateral prefrontal cortex (DL-PFC) samples from 21 controls and 19 individuals with chronic alcohol dependence were included in the study. Total RNA was assayed using quantitative RT-PCR. Out of the 16 glutamate receptor subunits, mRNAs encoding two AMPA [2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid] receptor subunits GluA2 and GluA3; three kainate receptor subunits GluK2, GluK3 and GluK5 and five NMDA (N-methyl-D-aspartate) receptor subunits GluN1, GluN2A, GluN2C, GluN2D, and GluN3A were significantly increased in the HP-DG region in alcoholics. In the OFC, mRNA encoding the NMDA receptor subunit GluN3A was increased, whereas in the DL-PFC, no differences in mRNA levels were observed. Our laboratory has previously shown that the expression of genes encoding inhibitory GABA-A receptors is altered in the HP-DG and OFC of alcoholics (Jin et al., 2011). Whether the changes in one neurotransmitter system drives changes in the other or if they change independently is currently not known. The results demonstrate that excessive long-term alcohol consumption is associated with altered expression of genes encoding glutamate receptors in a brain region-specific manner. It is an intriguing possibility that genetic predisposition to alcoholism may contribute to these gene expression changes.

  • 112.
    Jin, Zhe
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Jin, Yang
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Birnir, Bryndis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    GABA-activated single-channel and tonic currents in rat brain slices2011In: Journal of Visualized Experiments, ISSN 1940-087X, E-ISSN 1940-087X, no 53Article in journal (Refereed)
    Abstract [en]

    The GABA(A) channels are present in all neurons and are located both at synapses and outside of synapses where they generate phasic and tonic currents, respectively. The GABA(A) channel is a pentameric GABA-gated chloride channel. The channel subunits are grouped into 8 families (α1-6, β1-3, γ1-3, δ, ε, θ, π and ρ). Two alphas, two betas and one 3(rd) subunit form the functional channel. By combining studies of sub-type specific GABA-activated single-channel molecules with studies including all populations of GABA(A) channels in the neuron it becomes possible to understand the basic mechanism of neuronal inhibition and how it is modulated by pharmacological agents. We use the patch-clamp technique to study the functional properties of the GABA(A) channels in alive neurons in hippocampal brain slices and record the single-channel and whole-cell currents. We further examine how the channels are affected by different GABA concentrations, other drugs and intra and extracellular factors. For detailed theoretical and practical description of the patch-clamp method please see The Single-Channel Recordings edited by B Sakman and E Neher.

  • 113.
    Jin, Zhe
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Jin, Yang
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Kumar-Mendu, Suresh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Degerman, Eva
    Groop, Leif
    Birnir, Bryndis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Insulin reduces neuronal excitability by turning on GABA(A) channels that generate tonic current2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 1, p. e16188-Article in journal (Refereed)
    Abstract [en]

    Insulin signaling to the brain is important not only for metabolic homeostasis but also for higher brain functions such as cognition. GABA (γ-aminobutyric acid) decreases neuronal excitability by activating GABA(A) channels that generate phasic and tonic currents. The level of tonic inhibition in neurons varies. In the hippocampus, interneurons and dentate gyrus granule cells normally have significant tonic currents under basal conditions in contrast to the CA1 pyramidal neurons where it is minimal. Here we show in acute rat hippocampal slices that insulin (1 nM) "turns on" new extrasynaptic GABA(A) channels in CA1 pyramidal neurons resulting in decreased frequency of action potential firing. The channels are activated by more than million times lower GABA concentrations than synaptic channels, generate tonic currents and show outward rectification. The single-channel current amplitude is related to the GABA concentration resulting in a single-channel GABA affinity (EC(50)) in intact CA1 neurons of 17 pM with the maximal current amplitude reached with 1 nM GABA. They are inhibited by GABA(A) antagonists but have novel pharmacology as the benzodiazepine flumazenil and zolpidem are inverse agonists. The results show that tonic rather than synaptic conductances regulate basal neuronal excitability when significant tonic conductance is expressed and demonstrate an unexpected hormonal control of the inhibitory channel subtypes and excitability of hippocampal neurons. The insulin-induced new channels provide a specific target for rescuing cognition in health and disease.

  • 114.
    Jin, Zhe
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Korol, Sergiy V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Birnir, Bryndis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Insulin modulates GABA(A) receptor-mediated inhibition in rat amygdala neurons2014In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 211, no S696, p. 83-83, article id P39Article in journal (Other academic)
  • 115.
    Jin, Zhe
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Korol, Sergiy V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Jin, Yang
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Birnir, Bryndis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Insulin modulates GABAA receptor-mediated neuronal inhibition in rat hippocampus and amygdala2015In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 215, p. 90-90Article in journal (Other academic)
  • 116.
    Jin, Zhe
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Mendu, Suresh Kumar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Bhandage, Amol K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Birnir, Bryndis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    GABA is an efficient immunomodulator molecule2012In: Nerve-Driven Immunity: Neurotransmitters and Neuropeptides in the Immune System / [ed] Mia Levite, Wien: Springer, 2012, 1st, p. 163-173Chapter in book (Refereed)
  • 117.
    Jin, Zhe
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Mendu, Suresh Kumar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Birnir, Bryndis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    GABA is an effective immunomodulatory molecule2013In: Amino Acids, ISSN 0939-4451, E-ISSN 1438-2199, Vol. 45, no 1, p. 87-94Article in journal (Refereed)
    Abstract [en]

    In recent years, it has become clear that there is an extensive cross-talk between the nervous and the immune system. Somewhat surprisingly, the immune cells themselves do express components of the neuronal neurotransmitters systems. What role the neurotransmitters, their ion channels, receptors and transporters have in immune function and regulation is an emerging field of study. Several recent studies have shown that the immune system is capable of synthesizing and releasing the classical neurotransmitter GABA (γ-aminobutyric acid). GABA has a number of effects on the immune cells such as activation or suppression of cytokine secretion, modification of cell proliferation and GABA can even affect migration of the cells. The immune cells encounter GABA when released by the immune cells themselves or when the immune cells enter the brain. In addition, GABA can also be found in tissues like the lymph nodes, the islets of Langerhans and GABA is in high enough concentration in blood to activate, e.g., GABA-A channels. GABA appears to have a role in autoimmune diseases like multiple sclerosis, type 1 diabetes, and rheumatoid arthritis and may modulate the immune response to infections. In the near future, it will be important to work out what specific effects GABA has on the function of the different types of immune cells and determine the underlying mechanisms. In this review, we discuss some of the recent findings revealing the role of GABA as an immunomodulator.

  • 118.
    Johansson, Lisa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Ekholm, Marie E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Kukkonen, Jyrki P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Regulation of OX1 orexin/hypocretin receptor-coupling to phospholipase C by Ca2+ influx2007In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 150, no 1, p. 97-104Article in journal (Refereed)
    Abstract [en]

    Background and purpose: Orexin (OX) receptors induce Ca2+ elevations via both receptor-operated Ca2+ channels (ROCs) and the "conventional" phospholipase C (PLC)-Ca2+ release-store-operated Ca2+ channel (SOC) pathways. In this study we assessed the ability of these different Ca2+ influx pathways to amplify OX, receptor signalling to PLC in response to stimulation with the physiological ligand orexin-A.

    Experimental approach: PLC activity was assessed in CHO cells stably expressing human OX1 receptors.

    Key results: Inhibition of total Ca2+ influx by reduction of the extracellular [Ca2+] to 1 mu M effectively inhibited the receptor-stimulated PLC activity at low orexin-A concentrations (by 93% at 1 nM), and this effect was gradually reduced by higher orexin-A concentrations. A similar but weaker inhibitory effect (84% at 1 nM) was obtained on depolarization to similar to 0 mV, which disrupts most of the driving force for Ca2+ entry. The inhibitor of the OX, receptor-activated ROCs, tetraethylammonium chloride (TEA), was somewhat less effective than the reduction in extracellular [Ca2+] at inhibiting PLC activation, probably because it only partially blocks ROCs. The partial inhibitor of both ROCs and SOCs, Mg2+, and the SOC inhibitors, dextromethorphan, SKF-96365 (1-[beta-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenethyl]-1H-imidazole HCl) and 2-APB (2-aminoethoxydiphenyl borate), inhibited PLC activity at low concentrations of orexin-A, but were not as effective as TEA.

    Conclusions and implications: Both ROCs and SOCs markedly amplify the OX1 receptor-induced PLC response, but ROCS are more central for this response. These data indicate the crucial role of ROCs in orexin receptor signalling.

  • 119. Jutfelt, F.
    et al.
    Sundin, Josefin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Raby, G. D.
    Krang, A. S.
    Clark, T. D.
    Two-Current Choice Flumes for Testing Avoidance and Preference in Aquatic Animals2017In: Integrative and Comparative Biology, ISSN 1540-7063, E-ISSN 1557-7023, Vol. 57, p. E82-E82Article in journal (Other academic)
  • 120.
    Kairisalo, Minna
    et al.
    Minerva.
    Korhonen, Laura
    Minerva.
    Sepp, Mari
    Tallinn University of Technology.
    Pruunsild, Priit
    Tallinn University of Technology.
    Kukkonen, Jyrki P
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Kivinen, Jenny
    Minerva.
    Timmusk, Tõnis
    Tallinn University of Technology.
    Blomgren, Klas
    University of Gothenburg.
    Lindholm, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    NF-κB-dependent regulation of brain-derived neurotrophic factor in hippocampal neurons by X-linked inhibitor of apoptosis protein2009In: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 30, no 6, p. 958-966Article in journal (Refereed)
    Abstract [en]

    X chromosome-linked inhibitor of apoptosis protein (XIAP) is an anti-apoptotic protein enhancing cell survival. Brain-derived neurotrophic factor (BDNF) also promotes neuronal viability but the links between XIAP and BDNF have remained unclear. We show here that the overexpression of XIAP increases BDNF in transgenic mice and cultured rat hippocampal neurons, whereas downregulation of XIAP by silencing RNA decreased BDNF. XIAP also stimulated BDNF signaling, as shown by increased phosphorylation of the TrkB receptor and the downstream molecule, cAMP response element-binding protein. The mechanism involved nuclear factor-κB (NF-κB) activation and blocking of NF-κB signaling inhibited the increased activities of BDNF promoters I and IV by XIAP. In neuronal cultures XIAP also upregulated interleukin (IL)-6, which is an NF-κB-responsive gene. The addition of IL-6 elevated whereas incubation with IL-6-blocking antibodies reduced BDNF in the neurons. BDNF itself activated NF-κB in the neurons at higher concentrations. The data show that XIAP has trophic effects on hippocampal neurons by increasing BDNF and TrkB activity. The results reveal a cytokine network in the brain involving BDNF, IL-6 and XIAP interconnected via the NF-κB system.

  • 121.
    Koeck, Barbara
    et al.
    Univ Gothenburg, Dept Biol & Environm Sci, Gothenburg, Sweden;Univ Glasgow, Inst Biodivers Anim Hlth & Comparat Med, Coll Med Vet & Life Sci, Graham Kerr Bldg, Glasgow G12 8QQ, Lanark, Scotland.
    Zavorka, Libor
    Univ Gothenburg, Dept Biol & Environm Sci, Gothenburg, Sweden;Univ Toulouse, Lab Evolut & Diversite Biol EDB UMR 5174, CNRS, Toulouse, France.
    Aldven, David
    Univ Gothenburg, Dept Biol & Environm Sci, Gothenburg, Sweden.
    Naslund, Joacim
    Univ Gothenburg, Dept Biol & Environm Sci, Gothenburg, Sweden;Univ Stockholm, Dept Zool, Stockholm, Sweden.
    Arlinghaus, Robert
    Leibniz Inst Freshwater Ecol & Inland Fisheries, Dept Biol & Ecol Fishes, Berlin, Germany;Humboldt Univ, Div Integrat Fisheries Management, Fac Life Sci, Berlin, Germany.
    Thörnqvist, Per-Ove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Winberg, Svante
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Bjornsson, Bjorn Thrandur
    Univ Gothenburg, Dept Biol & Environm Sci, Gothenburg, Sweden.
    Johnsson, Jorgen I.
    Univ Gothenburg, Dept Biol & Environm Sci, Gothenburg, Sweden.
    Angling selects against active and stress-resilient phenotypes in rainbow trout2019In: Canadian Journal of Fisheries and Aquatic Sciences, ISSN 0706-652X, E-ISSN 1205-7533, Vol. 76, no 2, p. 320-333Article in journal (Refereed)
    Abstract [en]

    Selection induced by human harvest can lead to different patterns of phenotypic change than selection induced by natural predation and could be a major driving force of evolution of wild populations. The vulnerability of individuals to angling depends on the individual decision to ingest the bait, possibly mediated by their neuroendocrine response towards the associated stimulus. To investigate the mechanisms behind individual vulnerability to angling, we conducted angling experiments in replicated ponds and quantified individual behavioral traits and neuroendocrine stress responsiveness in two salmonid species, rainbow trout (Oncorhynchus mykiss) and brown trout (Salmo trutta). We discovered a phenotypic syndrome in rainbow trout, but not in brown trout, where lower serotonergic and dopaminergic brain activity and cortisol levels (i.e., lower stress responsiveness) in response to a standardized experimental stressor were associated with higher activity, forming a proactive phenotype that showed increased vulnerability to angling. Our results show that angling targets the most stress-resilient and active phenotypes of rainbow trout, supporting the suggestion that fishing-induced phenotypic selection may lead to an increased representation of stress-responsive and low-activity phenotypes in harvested populations.

  • 122.
    Kolm, Niclas
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Evolution, Animal Ecology.
    Gonzalez-Voyer, Alejandro
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Evolution, Animal Ecology.
    Brelin, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Winberg, Svante
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Evidence for small scale variation in the vertebrate brain: mating strategy and sex affect brain size and structure in wild brown trout (Salmo trutta)2009In: Journal of Evolutionary Biology, ISSN 1010-061X, E-ISSN 1420-9101, Vol. 22, no 12, p. 2524-2531Article in journal (Refereed)
    Abstract [en]

    The basis for our knowledge of brain evolution in vertebrates rests heavily on empirical evidence from comparative studies at the species level. However, little is still known about the natural levels of variation and the evolutionary causes of differences in brain size and brain structure within-species, even though selection at this level is an important initial generator of macroevolutionary patterns across species. Here, we examine how early life-history decisions and sex are related to brain size and brain structure in wild populations using the existing natural variation in mating strategies among wild brown trout (Salmo trutta). By comparing the brains of precocious fish that remain in the river and sexually mature at a small size with those of migratory fish that migrate to the sea and sexually mature at a much larger size, we show, for the first time in any vertebrate, strong differences in relative brain size and brain structure across mating strategies. Precocious fish have larger brain size (when controlling for body size) but migratory fish have a larger cerebellum, the structure in charge of motor coordination. Moreover, we demonstrate sex-specific differences in brain structure as female precocious fish have a larger brain than male precocious fish while males of both strategies have a larger telencephalon, the cognitive control centre, than females. The differences in brain size and structure across mating strategies and sexes thus suggest the possibility for fine scale adaptive evolution of the vertebrate brain in relation to different life histories.

  • 123.
    Korol, Sergiy V.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Jin, Zhe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Babateen, Omar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Birnir, Bryndis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    GLP-1 and Exendin-4 Transiently Enhance GABA(A) Receptor-Mediated Synaptic and Tonic Currents in Rat Hippocampal CA3 Pyramidal Neurons2015In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 64, no 1, p. 79-89Article in journal (Refereed)
    Abstract [en]

    GLP-1 is a hormone that stimulates insulin secretion. Receptors for GLP-1 are also found in the brain, including the hippocampus, the centre for memory and learning. Diabetes mellitus is a risk factor for decreased memory functions. We studied effects of GLP-1 and exendin-4, a GLP-1 receptor agonist, on γ-aminobutyric acid (GABA) signaling in hippocampal CA3 pyramidal neurons. GABA is the main inhibitory neurotransmitter and decreases neuronal excitability. GLP-1 (0.01 – 1 nmol/L) transiently enhanced synaptic and tonic currents and the effects were blocked by exendin(9–39). Ten pmol/L GLP-1 increased both the spontaneous inhibitory postsynaptic current (sIPSC) amplitudes and frequency by a factor of 1.8. In 0.1, 1 nmol/L GLP-1 or 10, 50 or 100 nmol/L exendin-4, only the sIPSC frequency increased. The tonic current was enhanced by 0.01 – 1 nmol/L GLP-1 and by 0.5 – 100 nmol/L exendin-4. When action potentials were inhibited by tetrodotoxin (TTX), IPSCs decreased and currents were no longer potentiated by GLP-1 or exendin-4. In contrast, although the tonic current decreased in TTX, it was still enhanced by GLP-1 or exendin-4. The results demonstrate GLP-1 receptor regulation of hippocampal function and are consistent with GLP-1 receptor agonists enhancing GABAA signaling by pre- and postsynaptic mechanisms.

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  • 124.
    Korol, Sergiy V.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Jin, Zhe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Babateen, Omar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Birnir, Bryndis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Modulation of GABAA receptor-mediated synaptic and tonic currents in the rat hippocampus by GLP-1, exendin-4 and diazepam2015In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 215, p. 89-90Article in journal (Other academic)
  • 125.
    Korol, Sergiy V.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Jin, Zhe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Babateen, Omar M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Birnir, Bryndis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    GABA(A) receptor-mediated currents in the hippocampus are transiently enhanced by glucagon-like peptide-1 receptor (GLP-1R) agonists2014In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 211, no S696, p. 83-83, article id P38Article in journal (Other academic)
  • 126.
    Korol, Sergiy V.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Jin, Zhe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Birnir, Bryndis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    The GLP-1 Receptor Agonist Exendin-4 and Diazepam Differentially Regulate GABAA Receptor-Mediated Tonic Currents in Rat Hippocampal CA3 Pyramidal Neurons2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 4, article id e0124765Article in journal (Refereed)
    Abstract [en]

    Glucagon-like peptide-1 (GLP-1) is a metabolic hormone that is secreted in a glucose-dependent manner and enhances insulin secretion. GLP-1 receptors are also found in the brain where their signalling affects neuronal activity. We have previously shown that the GLP-1 receptor agonists, GLP-1 and exendin-4 enhanced GABA-activated synaptic and tonic currents in rat hippocampal CA3 pyramidal neurons. The hippocampus is the centre for memory and learning and is important for cognition. Here we examined if exendin-4 similarly enhanced the GABA-activated currents in the presence of the benzodiazepine diazepam. In whole-cell recordings in rat brain slices, diazepam (1 μM), an allosteric positive modulator of GABAA receptors, alone enhanced the spontaneous inhibitory postsynaptic current (sIPSC) amplitude and frequency by a factor of 1.3 and 1.6, respectively, and doubled the tonic GABAA current normally recorded in the CA3 pyramidal cells. Importantly, in the presence of exendin-4 (10 nM) plus diazepam (1 μM), only the tonic but not the sIPSC currents transiently increased as compared to currents recorded in the presence of diazepam alone. The results suggest that exendin-4 potentiates a subpopulation of extrasynaptic GABAA receptors in the CA3 pyramidal neurons.

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  • 127.
    Korol, Sergiy V
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Jin, Zhe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Jin, Yang
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Bhandage, Amol K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Tengholm, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Gandasi, Nikhil R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Barg, Sebastian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Espes, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Laver, Derek
    University of Newcastle, Callaghan, Australia.
    Birnir, Bryndis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Functional Characterization of Native, High-Affinity GABAA Receptors in Human Pancreatic β Cells2018In: EBioMedicine, E-ISSN 2352-3964, Vol. 30Article in journal (Refereed)
    Abstract [en]

    In human pancreatic islets, the neurotransmitter γ-aminobutyric acid (GABA) is an extracellular signaling molecule synthesized by and released from the insulin-secreting β cells. The effective, physiological GABA concentration range within human islets is unknown. Here we use native GABAA receptors in human islet β cells as biological sensors and reveal that 100-1000nM GABA elicit the maximal opening frequency of the single-channels. In saturating GABA, the channels desensitized and stopped working. GABA modulated insulin exocytosis and glucose-stimulated insulin secretion. GABAA receptor currents were enhanced by the benzodiazepine diazepam, the anesthetic propofol and the incretin glucagon-like peptide-1 (GLP-1) but not affected by the hypnotic zolpidem. In type 2 diabetes (T2D) islets, single-channel analysis revealed higher GABA affinity of the receptors. The findings reveal unique GABAA receptors signaling in human islets β cells that is GABA concentration-dependent, differentially regulated by drugs, modulates insulin secretion and is altered in T2D.

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  • 128.
    Korol, Sergiy V.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Tafreshiha, Atieh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Bhandage, Amol K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Birnir, Bryndis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Jin, Zhe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Insulin enhances GABAA receptor-mediated inhibitory currents in rat central amygdala neurons2018In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 671, p. 76-81Article in journal (Refereed)
    Abstract [en]

    Insulin, a pancreatic hormone, can access the central nervous system, activate insulin receptors distributed in selective brain regions and affect various cellular functions such as neurotransmission. We have previously shown that physiologically relevant concentration of insulin potentiates the GABAA receptor-mediated tonic inhibition and reduces excitability of rat hippocampal CA1 neurons. The central nucleus of the amygdala (CeA) comprises heterogeneous neuronal populations that can respond to hormonal stimulus. Using quantitative PCR and immunofluorescent labeling, we report that the mRNA and protein of the insulin receptor are abundantly expressed in the rat CeA. The insulin receptor mRNA is also detected in the CeA from post-mortem human brain samples. Furthermore, our whole-cell patch-clamp recordings show that the application of insulin (5 and 50 nM) selectively enhances the frequency and amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs) in rat CeA neurons. Our findings reveal that GABAergic synaptic transmission is a target in the CeA for insulin receptor signaling that may underlie insulin modulation of emotion- and feeding-related behaviors.

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    Insulin enhances GABAA receptor-mediated inhibitory currents in rat central amygdala neurons
  • 129.
    Kotrschal, Alexander
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology.
    Lievens, Eva J. P.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology.
    Dahlbom, Josefin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Bundsen, Andreas
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology.
    Semenova, Svetlana
    Sundvik, Maria
    Maklakov, Alexei A.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology.
    Winberg, Svante
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Panula, Pertti
    Kolm, Niclas
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology.
    Artificial Selection on Relative Brain Size Reveals a Positive Genetic Correlation Between Brain Size and Proactive Personality in the Guppy2014In: Evolution, ISSN 0014-3820, E-ISSN 1558-5646, Vol. 68, no 4, p. 1139-1149Article in journal (Refereed)
    Abstract [en]

    Animal personalities range from individuals that are shy, cautious, and easily stressed (a "reactive" personality type) to individuals that are bold, innovative, and quick to learn novel tasks, but also prone to routine formation (a "proactive" personality type). Although personality differences should have important consequences for fitness, their underlying mechanisms remain poorly understood. Here, we investigated how genetic variation in brain size affects personality. We put selection lines of large- and small-brained guppies (Poecilia reticulata), with known differences in cognitive ability, through three standard personality assays. First, we found that large-brained animals were faster to habituate to, and more exploratory in, open field tests. Large-brained females were also bolder. Second, large-brained animals excreted less cortisol in a stressful situation (confinement). Third, large-brained animals were slower to feed from a novel food source, which we interpret as being caused by reduced behavioral flexibility rather than lack of innovation in the large-brained lines. Overall, the results point toward a more proactive personality type in large-brained animals. Thus, this study provides the first experimental evidence linking brain size and personality, an interaction that may affect important fitness-related aspects of ecology such as dispersal and niche exploration.

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  • 130.
    Krjukova, Jelena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Holmqvist, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Danis, Alexander
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Åkerman, Karil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Kukkonen, Jyrki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Phospholipase C activator m-3M3FBS affects Ca2+ homeostasis independently of phospholipase C activation2004In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 143, no 1, p. 3-7Article in journal (Refereed)
    Abstract [en]

    In this study, we have investigated responses to the phospholipase C (PLC) activator m-3M3FBS in SH-SY5Y human neuroblastoma cells. As measured using fura-2, m-3M3FBS caused a slowly developing - full response was obtained within 4-6 min - Ca(2+) elevation both in the presence and absence of extracellular Ca(2+), indicating Ca(2+) release from intracellular stores, putatively from endoplasmic reticulum and mitochondria. PLC activity was also measured using two methods, the classical ion-exchange separation and the more novel fluorescent real-time method. In the time frame in which m-3M3FBS caused Ca(2+) elevation (up to 7 min), no PLC activation was detected. Instead, more than 20 min were required to see any inositol phosphate generation in response to m-3M3FBS. m-3M3FBS also interfered with store-operated Ca(2+) influx and Ca(2+) extrusion. In conclusion, m-3M3FBS cannot be considered either potent or specific PLC activator.

  • 131.
    Kukkonen, Jyrki P
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    An easy ratiometric compensation for the extracellular Ca2+ indicator-caused fluorescence artifact2009In: Analytical Biochemistry, ISSN 0003-2697, E-ISSN 1096-0309, Vol. 390, no 2, p. 212-214Article in journal (Refereed)
    Abstract [en]

    Measurement of intracellular Ca(2+) dynamics is one of the most central real-time assays for cellular signaling. Ratiometric methods reduce the need for internal calibration and also effectively compensate for most artifacts when used in imaging. However, ratiometric calculation cannot compensate for extracellularly leaked (and fluorescent) Ca(2+) indicator and will instead indicate erroneous Ca(2+) concentration. This frequently occurs in systems where extracellular indicator is accumulated such as fluorescence spectrophotometers and plate readers. Here I present a method that, for the first time, fully compensates for this phenomenon. The method uses a single-step internal calibration together with a predefined ratiometric calibration protocol.

  • 132.
    Landis, Susanne H.
    et al.
    Helmholtz Ctr Ocean Res Kiel GEOMAR, Evolutionary Ecol Marine Fishes, D-24105 Kiel, Germany..
    Sundin, Josefin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Rosenqvist, Gunilla
    Norwegian Univ Sci & Technol, Dept Biol, Ctr Biodivers Dynam, N-7491 Trondheim, Norway..
    Poirier, Maude
    Helmholtz Ctr Ocean Res Kiel GEOMAR, Evolutionary Ecol Marine Fishes, D-24105 Kiel, Germany..
    Jorgensen, Guro Oistensen
    Norwegian Univ Sci & Technol, Dept Biol, Ctr Biodivers Dynam, N-7491 Trondheim, Norway..
    Roth, Olivia
    Helmholtz Ctr Ocean Res Kiel GEOMAR, Evolutionary Ecol Marine Fishes, D-24105 Kiel, Germany..
    Female pipefish can detect the immune status of their mates2015In: Behavioral Ecology and Sociobiology, ISSN 0340-5443, E-ISSN 1432-0762, Vol. 69, no 12, p. 1917-1923Article in journal (Refereed)
    Abstract [en]

    Given the ubiquity of the parasites and their important fitness consequences on mate and offspring condition, selection for the ability to distinguish healthy from parasitized potential mates is a key process to enhance Darwinian fitness. In this study, we experimentally evaluated how the immunological experience of two potential partners influences mate choice, using the sex-role-reversed pipefish Syngnathus typhle. We exposed S. typhle to immune challenges with heat-killed Vibrio bacteria and investigated whether the activation of the immune system determined mate preferences. Our results demonstrate that the immune status of the potential partners influenced female mate preference, such that females that were exposed to an immune challenge became choosy and favored unchallenged males. Males, however, did not show any preferences for female immune status. In this context, we discuss mate choice decisions and behavioral plasticity as a complex result of immune challenge, severity of infection, as well as trans-generational effects.

  • 133. Larsen, Martin H.
    et al.
    Johnsson, Jorgen I.
    Winberg, Svante
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Wilson, Alexander D. M.
    Hammenstig, David
    Thörnqvist, Per-Ove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Midwood, Jonathan D.
    Aarestrup, Kim
    Hoglund, Erik
    Effects of Emergence Time and Early Social Rearing Environment on Behaviour of Atlantic Salmon: Consequences for Juvenile Fitness and Smolt Migration2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 3, article id e0119127Article in journal (Refereed)
    Abstract [en]

    Consistent individual differences in behaviour have been well documented in a variety of animal taxa, but surprisingly little is known about the fitness and life-history consequences of such individual variation. In wild salmonids, the timing of fry emergence from gravel spawning nests has been suggested to be coupled with individual behavioural traits. Here, we further investigate the link between timing of spawning nest emergence and behaviour of Atlantic salmon (Salmo salar), test effects of social rearing environment on behavioural traits in fish with different emergence times, and assess whether behavioural traits measured in the laboratory predict growth, survival, and migration status in the wild. Atlantic salmon fry were sorted with respect to emergence time from artificial spawning nest into three groups: early, intermediate, and late. These emergence groups were hatchery-reared separately or in co-culture for four months to test effects of social rearing environment on behavioural traits. Twenty fish from each of the six treatment groups were then subjected to three individual-based behavioural tests: basal locomotor activity, boldness, and escape response. Following behavioural characterization, the fish were released into a near-natural experimental stream. Results showed differences in escape behaviour between emergence groups in a net restraining test, but the social rearing environment did not affect individual behavioural expression. Emergence time and social environment had no significant effects on survival, growth, and migration status in the stream, although migration propensity was 1.4 to 1.9 times higher for early emerging individuals that were reared separately. In addition, despite individuals showing considerable variation in behaviour across treatment groups, this was not translated into differences in growth, survival, and migration status. Hence, our study adds to the view that fitness (i.e., growth and survival) and life-history predictions from laboratory measures of behaviour should be made with caution and ideally tested in nature.

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  • 134. Laursen, Danielle Caroline
    et al.
    Olsén, Hanna L.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    de Lourdes Ruiz-Gomez, Maria
    Winberg, Svante
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Höglund, Erik
    Behavioural responses to hypoxia provide a non-invasive method for distinguishing between stress coping styles in fish2011In: Applied Animal Behaviour Science, ISSN 0168-1591, E-ISSN 1872-9045, Vol. 132, no 3-4, p. 211-216Article in journal (Refereed)
    Abstract [en]

    Two divergent behavioural and physiological response patterns to challenges have been identified in mammals and birds, frequently termed the proactive and reactive coping styles. In recent years, individually distinct coping styles have also been observed in several species of fish. These individual differences may result in suboptimal production and compromised welfare in aquaculture. An approach to overcome these problems could be to sort fish and optimise rearing conditions according to coping style. It has been previously demonstrated that the proactive and reactive coping styles in fish can be characterised by contrasting behavioural responses to hypoxia. Two rainbow trout (Oncorhynchus mykiss) strains, bred for a low- (LR) and high- (HR) cortisol response to a standardized stressor, are suggested to resemble the proactive and reactive coping styles respectively. Therefore, these fish provided an opportunity for verifying a method for sorting fish with respect to coping style by exposure to hypoxia. Groups consisting of 24 individually tagged fish, 12 HR and 12 LR were exposed to hypoxia in a two choice system. The system consisted of a "home" tank provided with cover connected to a second brightly "illuminated" tank via a closable doorway. During the experiment, the doorway between the two tanks was opened and hypoxic conditions were gradually induced in the "home" tank by bubbling with nitrogen. The latency time to move away from hypoxic conditions to normoxic conditions in the second tank was recorded for each individual. The oxygen saturation in each tank was measured every 30 min. The experiment consisted of two trials. Each trial was carried out in two sessions, switching the "home" tank and "illuminated" tank between Sessions 1 and 2. The results indicated that the response to hypoxia differed significantly between LR and HR individuals in both Session 1 (P < 0.05) and Session 2 (P <= 0.001). Furthermore, a higher number of HR individuals left hypoxic conditions compared to LR individuals in both Session 1 (P = 0.001) and Session 2 (P <= 0.001). Taken together, the findings of the present study demonstrate a repeatable difference in behavioural response to hypoxia between the two strains. The method presented could be utilized as a non-invasive method for sorting fish according to stress coping style.

  • 135.
    Lee, Yu-Jen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Motion Vision Processing in Fly Lobula Plate Tangential Cells2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Flies are highly visually guided animals. In this thesis, I have used hoverflies as a model for studying motion vision. Flies process motion vision in three visual ganglia: the lamina, the medulla, and the lobula complex. In the posterior part of lobula complex, there are around 60 lobula plate tangential cells (LPTCs). Most of LPTCs have large receptive fields where the local direction sensitivity suggests that they function as matched filters to specific types of optic flow. LPTCs connect to descending or neck motor neurons that control wing and head movements, respectively. Therefore, in this thesis I have focused on the electrophysiological responses of LPTCs to gain understanding of visual behaviors in flies.

    The elementary motion detector (EMD) is a model that can explain the formation of local motion sensitivity. However, responses to higher order motion, where the direction of luminance change is uncorrelated with the direction of movement, cannot be predicted by classic EMDs. Nevertheless, behavior shows that flies can see and track bars with higher order motion cues. I showed (Paper I) that several LPTCs also respond to higher order motion.

    Many insects, including flies, release octopamine during flight. Therefore, adding octopamine receptor agonists can mimic physical activity. Our study (Paper II) investigated the effect of octopamine on three adaptation components. We found that the contrast gain reduction showed a frequency dependent increase after octopamine stimulation. Since the contrast gain is non-directional, it is likely presynaptic to the LPTC. We therefore believe that octopamine acts on the delay filter in the EMD.

    In the third paper we describe a novel LPTC. The centrifugal stationary inhibited flicker excited (cSIFE) is excited by flicker and inhibited by stationary patterns. Neither of these responses can be predicted by EMD models. Therefore, we provide a new type of motion detector that can explain cSIFE’s responses (Paper III).

    During bar tracking, self-generated optic flow may counteract the steering effect by inducing a contradictory optomotor response. Behavior shows that during bar fixation, flies ignore background optic flow. Our study (Paper IV) focus on the different receptive fields of two LPTCs, and relate these to the bar fixation behavior. In the neuron with a small and fronto-dorsal receptive field, we find a higher correlation with bar motion than with background motion. In contrast, the neuron with a larger receptive field shows a higher correlation with background motion.

    List of papers
    1. Higher-order motion sensitivity in fly visual circuits
    Open this publication in new window or tab >>Higher-order motion sensitivity in fly visual circuits
    2012 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, no 22, p. 8758-8763Article in journal (Refereed) Published
    Abstract [en]

    In higher-order motion stimuli, the direction of object motion does not follow the direction of luminance change. Such stimuli could be generated by the wing movements of a flying butterfly and further complicated by its motion in and out of shadows. Human subjects readily perceive the direction of higher-order motion, although this stands in stark contrast to prevailing motion vision models. Flies and humans compute motion in similar ways, and because flies behaviorally track bars containing higher-order motion cues, they become an attractive model system for investigating the neurophysiology underlying higher-order motion sensitivity. We here use intracellular electrophysiology of motion-vision-sensitive neurons in the hoverfly lobula plate to quantify responses to stimuli containing higher-order motion. We show that motion sensitivity can be broken down into two separate streams, directionally coding for elementary motion and figure motion, respectively, and that responses to Fourier and theta motion can be predicted from these. The sensitivity is affected both by the stimulus' time course and by the neuron's underlying receptive field. Responses to preferred-direction theta motion are sexually dimorphic and particularly robust along the visual midline.

    Keywords
    elementary motion detector, neural delays, sexual dimorphism, bar motion
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-176824 (URN)10.1073/pnas.1203081109 (DOI)000304881700079 ()
    Available from: 2012-06-27 Created: 2012-06-26 Last updated: 2017-12-07Bibliographically approved
    2. Octopaminergic modulation of contrast sensitivity
    Open this publication in new window or tab >>Octopaminergic modulation of contrast sensitivity
    2012 (English)In: Frontiers in Integrative Neuroscience, ISSN 1662-5145, E-ISSN 1662-5145, Vol. 6, no Article 55Article in journal (Refereed) Published
    Abstract [en]

    Sensory systems adapt to prolonged stimulation by decreasing their response to continuous stimuli. Whereas visual motion adaptation has traditionally been studied in immobilized animals, recent work indicates that the animal's behavioral state influences the response properties of higher-order motion vision-sensitive neurons. During insect flight octopamine is released, and pharmacological octopaminergic activation can induce a fictive locomotor state. In the insect optic ganglia, lobula plate tangential cells (LPTCs) spatially pool input from local elementary motion detectors (EMDs) that correlate luminosity changes from two spatially discrete inputs after delaying the signal from one. The LPTC velocity optimum thereby depends on the spatial separation of the inputs and on the EMD's delay properties. Recently it was shown that behavioral activity increases the LPTC velocity optimum, with modeling suggesting this to originate in the EMD's temporal delay filters. However, behavior induces an additional post-EMD effect: the LPTC membrane conductance increases in flying flies. To physiologically investigate the degree to which activity causes presynaptic and postsynaptic effects, we conducted intracellular recordings of Eristalis horizontal system (HS) neurons. We constructed contrast response functions before and after adaptation at different temporal frequencies, with and without the octopamine receptor agonist chlordimeform (CDM). We extracted three motion adaptation components, where two are likely to be generated presynaptically of the LPTCs, and one within them. We found that CDM affected the early, EMD-associated contrast gain reduction, temporal frequency dependently. However, a CDM-induced change of the HS membrane conductance disappeared during and after visual stimulation. This suggests that physical activity mainly affects motion adaptation presynaptically of LPTCs, whereas post-EMD effects have a minimal effect.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-181382 (URN)10.3389/fnint.2012.00055 (DOI)22876224 (PubMedID)