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Principal Investigator: VADIM BOLSHAKOV
Organization: MCLEAN HOSPITAL
Fiscal Year: 2019
Award: $454,383
Funding agency: National Institute of Mental Health
DESCRIPTION (provided by applicant): The synaptic, neuronal and neural network mechanisms driving anxiety-like behaviors are not completely understood. Transient Receptor Potential channels (TRPC), belonging to the TRPC1/4/5 subfamily, are abundant in the brain areas implicated in control of innate fear responses, including the amygdala and the bed nucleus of the stria terminalis (BNST). Consistent with this expression pattern, we found recently that specific TRPC subunits belonging to this subfamily may contribute to anxiety mechanisms, possibly modulating the signal flow within specific neural circuits in the brain through activation of Gaq/11 protein-coupled receptors (specifically, Group I mGluR and CCK2 receptors). However, TRPC4 and TRPC5 subunits (members of the TRPC1/4/5 subfamily) can either form homomeric channels or heteromerize with the TRPC1 subunit, resulting in heterotetrameric TRPC channels with distinct biophysical and functional properties. These TRPCs can differentially regulate neuronal functions and, possibly, anxiety states, depending on their subunit composition. Combining genetic, behavioral, electrophysiological and optogenetic tools, we will explore the functional roles of distinct TRPC subunits and their combinations in structural components of the anxiety circuitry-the amygdala and BNST-and their contribution to control of anxiety-like behavioral responses. In our experiments, we will focus on the behavioral and functional analysis of mice lacking TRPC1, TRPC4 and TRPC5 (and combinations thereof) subunits. We will also study TrpC floxed mice in which TRPC subunits will be ablated specifically in subdivisions of the amygdala or BNST. In Aim 1, we will explore the roles of TRPC1/4/5 subfamily of TRPC channels in anxiety-like behaviors by probing anxiety levels in mice lacking different combinations of TRPC subunits. We will also investigate the effect of different TRPCs' ablation on synaptic functions, Gaq/11 protein-mediated signaling and neuronal spike output in intra-amygdala projections. We will then explore the role of TRPC channels in the function of local neuronal circuits in the amygdala (Aim 2). Specifically, we will examine whether the balance between excitation and inhibition in interdivisional projections in the amygdala is affected in neurons and interneurons in mutant mice. Finally (Aim 3), we will investigate the role of TRPC channels in regulation of synaptic and neuronal functions in the BNST, focusing on its two different subregions, the oval nucleus and anterodorsal BNST, known to exert opposing effects on anxiety. We will use optogenetic tools to achieve projection-specific activation of the fibers arising in the BLA and terminating in the BNST. We hypothesize that the ablation of TRPC1/4/5 subunits may modify the signal flow in the amygdala-BNST circuits, leading to the enhanced activation of adBNST and resulting in diminished anxiety-like responses, as adBNST activation was shown to be anxiolytic. These studies, illuminating the role of TRPC channels in anxiety-related behavioral processes, may contribute to our better understanding of how anxiety is regulated at the level of interacting components of the corresponding brain circuits.
Terms: <Ablation><Address><Affect><Amygdala><Amygdaloid Body><Amygdaloid Nucleus><Amygdaloid structure><Anti-Anxiety Agents><Anti-Anxiety Drugs><Anxiety><Anxiety Disorders><Anxiolytic Agents><Anxiolytics><Area><Automobile Driving><Aversive Stimulus><Bed Nucleus of Stria Terminalis><Beds><Behavioral><Biophysics><Brain><Brain Nervous System><CCK-B Receptor><CCK-BR><CCK2 Receptor><CCKRB><CKK-2 Receptor><Cell Body><Cell Communication and Signaling><Cell Nucleus><Cell Signaling><Cells><Cholecystokinin B Receptor><Cholecystokinin Type B Receptor><Cholecystokinin-2 Receptor><Connector Neuron><Coupled><Development><Electrophysiology><Electrophysiology (science)><Encephalon><Equilibrium><Exhibits><Fear><Fiber><Fright><GASR><Gastrin Receptors><Genes><Genetic><Goals><Intercalary Neuron><Intercalated Neurons><Interneurons><Internuncial Cell><Internuncial Neuron><Intracellular Communication and Signaling><KO mice><Knock-out><Knock-out Mice><Knockout><Knockout Mice><Knowledge><Lateral><Lead><LoxP-flanked allele><Mediating><Metabotropic Glutamate Receptors><Mice><Mice Mammals><Minor Tranquilizing Agents><Murine><Mus><Mutant Strains Mice><Nerve Cells><Nerve Unit><Neural Cell><Neural Transmission><Neurocyte><Neurons><Neurophysiology / Electrophysiology><Nucleus><Null Mouse><Output><Pattern><Pb element><Phobias><Process><Property><Proteins><Publishing><Receptor Protein><Regulation><Role><Signal Transduction><Signal Transduction Systems><Signaling><Slice><Specificity><Stria Terminalis Nucleus><Structure><Structure of terminal stria nuclei of preoptic region><Synapses><Synaptic><Synaptic Transmission><System><TRP channel><Translating><Whole-Cell Recordings><amygdaloid nuclear complex><antianxiety agent><antianxiety drugs><anxiety spectrum disorders><anxiety states><anxiety treatment><anxiety-like behavior><anxious><balance><balance function><behavior outcome><behavior response><behavioral outcome><behavioral response><biological signal transduction><biophysical characteristics><biophysical characterization><biophysical foundation><biophysical measurement><biophysical parameters><biophysical principles><biophysical properties><biophysical sciences><cartilage link protein><developmental><driving><electrophysiological><experiment><experimental research><experimental study><floxed><floxed allele><functional outcomes><generalized anxiety><heavy metal Pb><heavy metal lead><link protein><member><mouse mutant><neural><neural circuit><neural circuitry><neural network><neuronal><neuronal circuit><neuronal circuitry><new drug treatments><new drugs><new therapeutics><new therapy><next generation therapeutics><novel drug treatments><novel drugs><novel therapeutics><novel therapy><optogenetics><patch clamp><public health relevance><receptor><relating to nervous system><response><social role><synapse><synapse function><synaptic circuit><synaptic circuitry><synaptic function><tool>