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HCN channels in the hippocampus regulate active coping behavior.
Fisher DW, Han Y, Lyman KA, Heuermann RJ, Bean LA, Ybarra N, Foote KM, Dong H, Nicholson DA, Chetkovich DM
(2018) J Neurochem 146: 753-766
MeSH Terms: Adaptation, Psychological, Animals, Avoidance Learning, Depression, Disease Models, Animal, Exploratory Behavior, Hippocampus, Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels, Male, Maze Learning, Membrane Proteins, Mice, Mice, Inbred C57BL, Mice, Transgenic, Microscopy, Electron, Peroxins, Pyramidal Cells, Swimming
Show Abstract · Added April 2, 2019
Active coping is an adaptive stress response that improves outcomes in medical and neuropsychiatric diseases. To date, most research into coping style has focused on neurotransmitter activity and little is known about the intrinsic excitability of neurons in the associated brain regions that facilitate coping. Previous studies have shown that HCN channels regulate neuronal excitability in pyramidal cells and that HCN channel current (I ) in the CA1 area increases with chronic mild stress. Reduction of I in the CA1 area leads to antidepressant-like behavior, and this region has been implicated in the regulation of coping style. We hypothesized that the antidepressant-like behavior achieved with CA1 knockdown of I is accompanied by increases in active coping. In this report, we found that global loss of TRIP8b, a necessary subunit for proper HCN channel localization in pyramidal cells, led to active coping behavior in numerous assays specific to coping style. We next employed a viral strategy using a dominant negative TRIP8b isoform to alter coping behavior by reducing HCN channel expression. This approach led to a robust reduction in I in CA1 pyramidal neurons and an increase in active coping. Together, these results establish that changes in HCN channel function in CA1 influences coping style.
© 2018 International Society for Neurochemistry.
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18 MeSH Terms
Acute blockade of the Caenorhabditis elegans dopamine transporter DAT-1 by the mammalian norepinephrine transporter inhibitor nisoxetine reveals the influence of genetic modifications of dopamine signaling in vivo.
Bermingham DP, Hardaway JA, Snarrenberg CL, Robinson SB, Folkes OM, Salimando GJ, Jinnah H, Blakely RD
(2016) Neurochem Int 98: 122-8
MeSH Terms: Animals, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Dopamine, Dopamine Plasma Membrane Transport Proteins, Dopamine Uptake Inhibitors, Fluoxetine, Gene Deletion, Mutation, Norepinephrine Plasma Membrane Transport Proteins, Paralysis, Plasmids, Signal Transduction, Swimming
Show Abstract · Added February 15, 2016
Modulation of neurotransmission by the catecholamine dopamine (DA) is conserved across phylogeny. In the nematode Caenorhabditis elegans, excess DA signaling triggers Swimming-Induced Paralysis (Swip), a phenotype first described in animals with loss of function mutations in the presynaptic DA transporter (dat-1). Swip has proven to be a phenotype suitable for the identification of novel dat-1 mutations as well as the identification of novel genes that impact DA signaling. Pharmacological manipulations can also induce Swip, though the reagents employed to date lack specificity and potency, limiting their use in evaluation of dat-1 expression and function. Our lab previously established the mammalian norepinephrine transporter (NET) inhibitor nisoxetine to be a potent antagonist of DA uptake conferred by DAT-1 following heterologous expression. Here we demonstrate the ability of low (μM) concentrations of nisoxetine to trigger Swip within minutes of incubation, with paralysis dependent on DA release and signaling, and non-additive with Swip triggered by dat-1 deletion. Using nisoxetine in combination with genetic mutations that impact DA release, we further demonstrate the utility of the drug for demonstrating contributions of presynaptic DA receptors and ion channels to Swip. Together, these findings reveal nisoxetine as a powerful reagent for monitoring multiple dimensions of DA signaling in vivo, thus providing a new resource that can be used to evaluate contributions of dat-1 and other genes linked to DA signaling without the potential for compensations that attend constitutive genetic mutations.
Copyright © 2016 Elsevier Ltd. All rights reserved.
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14 MeSH Terms
An open-source analytical platform for analysis of C. elegans swimming-induced paralysis.
Hardaway JA, Wang J, Fleming PA, Fleming KA, Whitaker SM, Nackenoff A, Snarrenberg CL, Hardie SL, Zhang B, Blakely RD
(2014) J Neurosci Methods 232: 58-62
MeSH Terms: Analysis of Variance, Animals, Animals, Genetically Modified, Antidepressive Agents, Tricyclic, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Dopamine Plasma Membrane Transport Proteins, Dose-Response Relationship, Drug, Electronic Data Processing, Imipramine, Mixed Function Oxygenases, Mutation, Paralysis, Receptors, Dopamine D2, Swimming
Show Abstract · Added May 21, 2014
BACKGROUND - The nematode Caenhorhabditis elegans offers great power for the identification and characterization of genes that regulate behavior. In support of this effort, analytical methods are required that provide dimensional analyses of subcomponents of behavior. Previously, we demonstrated that loss of the presynaptic dopamine (DA) transporter, dat-1, evokes DA-dependent Swimming-Induced Paralysis (Swip) (Mcdonald et al., 2007), a behavior compatible with forward genetic screens (Hardaway et al., 2012).
NEW METHOD - Here, we detail the development and implementation of SwimR, a set of tools that provide for an automated, kinetic analysis of C. elegans Swip. SwimR relies on open source programs that can be freely implemented and modified.
RESULTS - We show that SwimR can display time-dependent alterations of swimming behavior induced by drug-treatment, illustrating this capacity with the dat-1 blocker and tricyclic antidepressant imipramine (IMI). We demonstrate the capacity of SwimR to extract multiple kinetic parameters that are impractical to obtain in manual assays.
COMPARISON WITH EXISTING METHODS - Standard measurements of C. elegans swimming utilizes manual assessments of the number of animals exhibiting swimming versus paralysis. Our approach deconstructs the time course and rates of movement in an automated fashion, offering a significant increase in the information that can be obtained from swimming behavior.
CONCLUSIONS - The SwimR platform is a powerful tool for the deconstruction of worm thrashing behavior in the context of both genetic and pharmacological manipulations that can be used to segregate pathways that underlie nematode swimming mechanics.
Copyright © 2014 Elsevier B.V. All rights reserved.
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2 Members
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15 MeSH Terms
Involvement of sigma-1 receptors in the antidepressant-like effects of dextromethorphan.
Nguyen L, Robson MJ, Healy JR, Scandinaro AL, Matsumoto RR
(2014) PLoS One 9: e89985
MeSH Terms: Adrenergic alpha-Antagonists, Animals, Antidepressive Agents, Behavior, Animal, Cytochrome P-450 Enzyme Inhibitors, Cytochrome P-450 Enzyme System, Dextromethorphan, Dose-Response Relationship, Drug, Ethylenediamines, Excitatory Amino Acid Antagonists, Ketamine, Kinetics, Male, Mice, Piperazines, Protein Binding, Quinidine, Receptors, N-Methyl-D-Aspartate, Receptors, sigma, Swimming
Show Abstract · Added August 26, 2015
Dextromethorphan is an antitussive with a high margin of safety that has been hypothesized to display rapid-acting antidepressant activity based on pharmacodynamic similarities to the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine. In addition to binding to NMDA receptors, dextromethorphan binds to sigma-1 (σ1) receptors, which are believed to be protein targets for a potential new class of antidepressant medications. The purpose of this study was to determine whether dextromethorphan elicits antidepressant-like effects and the involvement of σ1 receptors in mediating its antidepressant-like actions. The antidepressant-like effects of dextromethorphan were assessed in male, Swiss Webster mice using the forced swim test. Next, σ1 receptor antagonists (BD1063 and BD1047) were evaluated in conjunction with dextromethorphan to determine the involvement of σ receptors in its antidepressant-like effects. Quinidine, a cytochrome P450 (CYP) 2D6 inhibitor, was also evaluated in conjunction with dextromethorphan to increase the bioavailability of dextromethorphan and reduce exposure to additional metabolites. Finally, saturation binding assays were performed to assess the manner in which dextromethorphan interacts at the σ1 receptor. Our results revealed dextromethorphan displays antidepressant-like effects in the forced swim test that can be attenuated by pretreatment with σ1 receptor antagonists, with BD1063 causing a shift to the right in the dextromethorphan dose response curve. Concomitant administration of quinidine potentiated the antidepressant-like effects of dextromethorphan. Saturation binding assays revealed that a Ki concentration of dextromethorphan reduces both the Kd and the Bmax of [(3)H](+)-pentazocine binding to σ1 receptors. Taken together, these data suggest that dextromethorphan exerts some of its antidepressant actions through σ1 receptors.
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20 MeSH Terms
Spatial and temporal in vivo analysis of circulating and sessile immune cells in mosquitoes: hemocyte mitosis following infection.
King JG, Hillyer JF
(2013) BMC Biol 11: 55
MeSH Terms: Aging, Animals, Anopheles, Carbocyanines, Cell Adhesion, Cell Count, Cytoskeleton, Epidermal Cells, Escherichia coli, Escherichia coli Infections, Flight, Animal, Hemocytes, Immunity, Lymphocytes, Mitosis, Muscles, Organ Specificity, Phagocytosis, Spatio-Temporal Analysis, Swimming
Show Abstract · Added February 5, 2016
BACKGROUND - Mosquitoes respond to infection by mounting immune responses. The primary regulators of these immune responses are cells called hemocytes, which kill pathogens via phagocytosis and via the production of soluble antimicrobial factors. Mosquito hemocytes are circulated throughout the hemocoel (body cavity) by the swift flow of hemolymph (blood), and data show that some hemocytes also exist as sessile cells that are attached to tissues. The purpose of this study was to create a quantitative physical map of hemocyte distribution in the mosquito, Anopheles gambiae, and to describe the cellular immune response in an organismal context.
RESULTS - Using correlative imaging methods we found that the number of hemocytes in a mosquito decreases with age, but that regardless of age, approximately 75% of the hemocytes occur in circulation and 25% occur as sessile cells. Infection induces an increase in the number of hemocytes, and tubulin and nuclear staining showed that this increase is primarily due to mitosis and, more specifically, autonomous cell division, by circulating granulocytes. The majority of sessile hemocytes are present on the abdominal wall, although significant numbers of hemocytes are also present in the thorax, head, and several of the appendages. Within the abdominal wall, the areas of highest hemocyte density are the periostial regions (regions surrounding the valves of the heart, or ostia), which are ideal locations for pathogen capture as these are areas of high hemolymph flow.
CONCLUSIONS - These data describe the spatial and temporal distribution of mosquito hemocytes, and map the cellular response to infection throughout the hemocoel.
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20 MeSH Terms
Propulsive performance of a body with a traveling-wave surface.
Tian FB, Lu XY, Luo H
(2012) Phys Rev E Stat Nonlin Soft Matter Phys 86: 016304
MeSH Terms: Animals, Computer Simulation, Humans, Models, Biological, Rheology, Swimming
Show Abstract · Added May 29, 2014
A body with a traveling-wave surface (TWS) is investigated by solving the incompressible Navier-Stokes equation numerically to understand the mechanisms of a novel propulsive strategy. In this study, a virtual model of a foil with a flexible surface which performs a traveling-wave movement is used as a free swimming body. Based on the simulations by varying the traveling-wave Reynolds number and the amplitude and wave number of the TWS, some propulsive properties including the forward speed, the swimming efficiency, and the flow field are analyzed in detail. It is found that the mean forward velocity increases with the traveling-wave Reynolds number, the amplitude, and the wave number of the TWS. A weak wake behind the free swimming body is identified and the propulsive mechanisms are discussed. Moreover, the TWS is a "quiet" propulsive approach, which is an advantage when preying. The results obtained in this study provide a novel propulsion concept, which may also lead to an important design capability for underwater vehicles.
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6 MeSH Terms
Forward genetic analysis to identify determinants of dopamine signaling in Caenorhabditis elegans using swimming-induced paralysis.
Hardaway JA, Hardie SL, Whitaker SM, Baas SR, Zhang B, Bermingham DP, Lichtenstein AJ, Blakely RD
(2012) G3 (Bethesda) 2: 961-75
MeSH Terms: Adrenergic Uptake Inhibitors, Animals, Animals, Genetically Modified, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Dopamine, Dopamine Plasma Membrane Transport Proteins, Motor Activity, Mutation, Phenotype, Polymorphism, Single Nucleotide, Reserpine, Signal Transduction, Swimming
Show Abstract · Added July 19, 2013
Disrupted dopamine (DA) signaling is believed to contribute to the core features of multiple neuropsychiatric and neurodegenerative disorders. Essential features of DA neurotransmission are conserved in the nematode Caenorhabditis elegans, providing us with an opportunity to implement forward genetic approaches that may reveal novel, in vivo regulators of DA signaling. Previously, we identified a robust phenotype, termed Swimming-induced paralysis (Swip), that emerges in animals deficient in the plasma membrane DA transporter. Here, we report the use and quantitative analysis of Swip in the identification of mutant genes that control DA signaling. Two lines captured in our screen (vt21 and vt22) bear novel dat-1 alleles that disrupt expression and surface trafficking of transporter proteins in vitro and in vivo. Two additional lines, vt25 and vt29, lack transporter mutations but exhibit genetic, biochemical, and behavioral phenotypes consistent with distinct perturbations of DA signaling. Our studies validate the utility of the Swip screen, demonstrate the functional relevance of DA transporter structural elements, and reveal novel genomic loci that encode regulators of DA signaling.
1 Communities
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14 MeSH Terms
The involvement of FK506-binding protein 51 (FKBP5) in the behavioral and neuroendocrine effects of chronic social defeat stress.
Hartmann J, Wagner KV, Liebl C, Scharf SH, Wang XD, Wolf M, Hausch F, Rein T, Schmidt U, Touma C, Cheung-Flynn J, Cox MB, Smith DF, Holsboer F, Müller MB, Schmidt MV
(2012) Neuropharmacology 62: 332-9
MeSH Terms: Analysis of Variance, Animals, Corticosterone, Disease Models, Animal, Exploratory Behavior, Gene Expression Regulation, HSP90 Heat-Shock Proteins, Locomotion, Male, Maze Learning, Mice, Mice, Knockout, Neurosecretory Systems, Receptors, Glucocorticoid, Receptors, Mineralocorticoid, Stress, Psychological, Swimming, Tacrolimus Binding Proteins
Show Abstract · Added March 9, 2015
Chronic stress is increasingly considered to be a main risk factor for the development of a variety of psychiatric diseases such as depression. This is further supported by an impaired negative feedback of the hypothalamic-pituitary-adrenal (HPA) axis, which has been observed in the majority of depressed patients. The effects of glucocorticoids, the main hormonal endpoint of the HPA axis, are mediated via the glucocorticoid receptor (GR) and the mineralocorticoid receptor. The FK506-binding protein 51 (FKBP5), a co-chaperone of the Hsp90 and component of the chaperone-receptor heterocomplex, has been shown to reduce ligand sensitivity of the GR. This study aimed to investigate the function of FKBP5 as a possible mediator of the stress response system and its potential role in the development of stress-related diseases. Therefore, we assessed whether mice lacking the gene encoding FKBP5 (51KO mice) were less vulnerable to the adverse effects of three weeks of chronic social defeat stress. Mice were subsequently analyzed with regards to physiological, neuroendocrine, behavioral and mRNA expression alterations. Our results show a less vulnerable phenotype of 51KO mice with respect to physiological and neuroendocrine parameters compared to wild-type animals. 51KO mice demonstrated lower adrenal weights and basal corticosterone levels, a diminished response to a novel acute stimulus and an enhanced recovery, as well as more active stress-coping behavior. These results suggest an enhanced negative glucocorticoid feedback within the HPA axis of 51KO mice, possibly modulated by an increased sensitivity of the GR. This article is part of a Special Issue entitled 'Anxiety and Depression'.
Copyright © 2011 Elsevier Ltd. All rights reserved.
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18 MeSH Terms
Genetic, pharmacological and lesion analyses reveal a selective role for corticohippocampal GLUN2B in a novel repeated swim stress paradigm.
Kiselycznyk C, Svenningsson P, Delpire E, Holmes A
(2011) Neuroscience 193: 259-68
MeSH Terms: Analysis of Variance, Animals, Cerebral Cortex, Corticosterone, Dark Adaptation, Disease Models, Animal, Excitatory Amino Acid Antagonists, Exploratory Behavior, Feeding Behavior, Fever, Food Preferences, Hindlimb Suspension, Hippocampus, Immobility Response, Tonic, Mice, Mice, Inbred C57BL, Mice, Transgenic, Neural Pathways, Phenols, Piperidines, Radioimmunoassay, Receptors, AMPA, Receptors, N-Methyl-D-Aspartate, Stress, Psychological, Sucrose, Swimming, Time Factors
Show Abstract · Added November 25, 2014
Glutamate and N-methyl-d-aspartate receptor (NMDAR) dysfunction is strongly implicated in the pathophysiology of mood and anxiety disorders. Treatment with NMDAR antagonists has antidepressant efficacy in treatment-resistant depressives. In preclinical rodent models, NMDAR antagonist administration reduces anxiety- and stress-related behaviors in concert with increases in prefrontal cortical (PFC) dendritic spinogenesis and synaptic proteins. While these effects have been attributed to actions at the NMDAR GluN2B subunit, the precise role of cortical GluN2B in mediating emotional behaviors and stress-responsivity is not fully understood. Here, we employed a novel mutant model in which the GluN2B subunit is postnatally deleted in principal neurons in the cortex and the dorsal CA1 subregion of the hippocampus. GluN2BKO mice were phenotyped on a battery of tests for anxiety-related (light/dark exploration, stress-induced hyperthermia) and antidepressant-sensitive (sucrose preference, novelty-induced hypophagia, single-trial forced swim) behaviors. A novel repeated inescapable forced swim paradigm (riFS) was developed to assess behavioral responses to repeated stress in the GluN2BKO mice. For comparison, non-mutant C57BL/6J mice were tested for single-trial forced swim behavior after systemic Ro 25-6981 treatment and for riFS behavior after lesions of the ventromedial prefrontal cortex. riFS-induced alterations in corticolimbic GluN2B expression were also examined in C57BL/6J mice. We found that GluN2BKO mice reduced "despair-like" behavior in the riFS procedure, as compared to GluN2BFLOX controls. By contrast, GluN2BKO mice showed minimal alterations on anxiety-like or antidepressant-sensitive assays, including the single-trial forced swim test. In C57BL/6J mice, induction of "despair-like" responses in the riFS test was attenuated by vmPFC lesions, and was associated with changes in limbic GluN2B expression. Collectively, these data suggest that cortical GluN2B plays a major role in modulating adaptive responses to stress. Current findings provide further support for GluN2B as a key mechanism underlying stress responsivity, and a novel pharmacotherapeutic target for stress-related neuropsychiatric disorders.
Published by Elsevier Ltd.
1 Communities
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27 MeSH Terms
Behavioral analysis of Ste20 kinase SPAK knockout mice.
Geng Y, Byun N, Delpire E
(2010) Behav Brain Res 208: 377-82
MeSH Terms: Acoustic Stimulation, Adaptation, Physiological, Animals, Behavior, Animal, Exploratory Behavior, Functional Laterality, Hindlimb Suspension, Hyperalgesia, Mice, Mice, Knockout, Muscle Strength, Pain Measurement, Pain Threshold, Phenotype, Protein-Serine-Threonine Kinases, Psychomotor Performance, Reflex, Startle, Statistics, Nonparametric, Swimming
Show Abstract · Added November 25, 2014
SPAK/STK39 is a mammalian protein kinase involved in the regulation of inorganic ion transport mechanisms known to modulate GABAergic neurotransmission in the both central and the peripheral nervous systems. We have previously shown that disruption of the gene encoding SPAK by homologous recombination in mouse embryonic stem cells results in viable mice that lack expression of the kinase. With the exception of reduced fertility, these mice do not exhibit an overt adverse phenotype. In the present study, we examine the neurological phenotype of these mice by subjecting them to an array of behavioral tests. We show that SPAK knockout mice displayed a higher nociceptive threshold than their wild-type counterparts on the hot plate and tail flick assays. SPAK knockout mice also exhibited a strong locomotor phenotype evidenced by significant deficits on the rotarod and decreased activity in open-field tests. In contrast, balance and proprioception was not affected. Finally, they demonstrated an increased anxiety-like phenotype, spending significantly longer periods of time in the dark area of the light/dark box and increased thigmotaxis in the open-field chamber. These results suggest that the kinase plays an important role in CNS function, consistent with SPAK regulating ion transport mechanisms directly involved in inhibitory neurotransmission.
Copyright 2009 Elsevier B.V. All rights reserved.
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19 MeSH Terms