The Role of Amygdala GABAergic Transmission in Fear and AnxietyThe results of numerous studies have demonstrated that changes in fast glutamatergic transmissionin the amygdala play a major role in neural processes involved in the acquisition and extinction ofconditioned fear. However, there are converging lines of evidence suggesting that changes ingamma-aminobutyric acid (GABA) may also be involved in these processes. In humans, involvementof GABAergic transmission in the regulation of fear and anxiety is highlighted by the fact thatpatients suffering from anxiety disorders are commonly treated by the administration ofbenzodiazepines (BZs), which mediate their actions via GABAA receptors (GABAAR).The amygdala isparticularly rich in GABAARs which are known to be involved in the anxiolytic and anxiogenic effectsof GABA agonists and antagonists, respectively. At present, there is a void in research designed toinvestigate how the changes in amygdala GABAergic transmission influences emotional memoriesand behaviors associated with anxiety and fear. Recently, our lab reported learning-related changesin GABA-related genes and GABAAR levels in the amygdala after the acquisition and extinction ofPavlovian fear, a commonly used animal model of fear and anxiety disorders. Our findings showedthat the acquisition of fear induced a down regulation of genetic markers related to decreasedamygdala GABAergic function; whereas the acquisition of fear extinction produced an up regulationof GABAergic markers related to enhanced GABAergic transmission.This research proposal will employ a novel and powerful approach to investigating the role ofamygdala GABAergic transmission in fear and behavioral responses to pharmacological agents.Specifically, in Aim 1 of this proposal, we propose to examine the acquisition and extinction ofconditioned fear in mice with knocked down expression of 2-GABAAR, 5-GABAAR, or GAD67 in theamygdala using a vector-based RNA interference (RNAi) strategy to locally induce loss-of-function.We hypothesize that associated changes in GABAergic function will decrease the level of phasicand/or tonic inhibition, resulting in facilitated acquisition of fear and blunted extinction of fear.
In Aim2 of this proposal, we plan to examine the behavioral effects of BZ administration in mice withknocked down expression of 2-GABAAR, 5-GABAAR, or GAD67 in the amygdala. We hypothesizethat associated changes in amygdala GABAergic function will result in blunted anxiety-likebehavioral effects to BZ administration.A model system of inducing focal knocked down gene expression will provide a sizeable advantageover traditional transgenic and knockout approaches in determining the region-specific functiongenes in the amydala. The results of the current proposal will provide a better understanding of therole of GABAergic transmission in the amygdala may provide a better understanding of themechanisms that influence emotional memories and behaviors associated with anxiety and fear.Furthermore, an understand of the role of specific subtypes of GABAA receptors in anatomicallocalized areas of the brain will also have direct implications for the development of new therapeuticstrategies for the treatment of a myriad of psychiatric and neurological disorders characterized byGABAergic dysfunction and/or treated by BZs.
The Role of Amygdala GABAergic Transmission in Fear and Anxiety According to the National Institute of Mental Health, the excessive fear of specific objects or in the absence of external threat are hallmarks of a variety of disabling anxiety disorders that affect approximately 40 million American adults during the course of any given year. There is considerable evidence suggesting that alterations in GABAergic transmission might actually form the basis of vulnerability for some anxiety disorders. While GABAAR agonists exert anxiolytic effects by acting at a number of limbic areas, there is converging lines of evidence indicating that that the amygdala is a major site of action. Given effectiveness of GABAAR -acting agents and their current widespread use in the treatment of anxiety-related disorders, a fuller understanding of how GABAergic mechanisms control anxiety and fear circuits will advance our understanding of anxiety-related disorders. This grant proposes to use a novel and powerful genetic method to functionally dissect region-specific GABA(A) subtype function. This research proposal will employ a novel and powerful approach to investigating the role of amygdala GABAergic transmission in conditioned fear and behavioral responses to pharmacological agents. This model system of inducing focal knocked down gene expression will provide a sizeable advantage over traditional transgenic and knockout approaches in determining the region-specific function genes in the amydala. The results of the current proposal will provide a better understanding of the role of GABAergic transmission in the amygdala may provide a better understanding of the mechanisms that influence emotional memories and behaviors associated with anxiety and fear.
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