Scott A. Heldt, Ph.D. - US grants

[unreadable] DESCRIPTION (provided by candidate): Past Pavlovian conditioning procedures have demonstrated that changes in fast glutamatergic transmission play an important role in the formation of emotional memories associated with the acquisition, retention, and extinction of fear. However, there are converging lines of evidence suggesting that changes in GABAergic transmission may also be involved in these processes. The research in the current application will help in understanding how GABAergic systems influence these processes. This will be accomplished by: (1) identifying and quantifying the expression of mRNAs encoding various GABA related genes which may play a role in the molecular processes involved in the acquisition, retrieval, and extinction of conditioned fear, (2) examining training-induce changes in the expression of GABA-related genes and examining changes in GABA(A) binding in the amygdala after the acquisition, retrieval, and extinction of Pavlovian fear, and (3), examining the function of amygdala alpha 1-GABA(A) receptors in the acquisition, retrieval, and extinction of conditioned fear in alpha l-GABA(A) inducible knockout mice. [unreadable] [unreadable]

Project Summary The Role of Amygdala GABAergic Transmission in Fear and Anxiety The results of numerous studies have demonstrated that changes in fast glutamatergic transmission in the amygdala play a major role in neural processes involved in the acquisition and extinction of conditioned fear. However, there are converging lines of evidence suggesting that changes in gamma-aminobutyric acid (GABA) may also be involved in these processes. In humans, involvement of GABAergic transmission in the regulation of fear and anxiety is highlighted by the fact that patients suffering from anxiety disorders are commonly treated by the administration of benzodiazepines (BZs), which mediate their actions via GABAA receptors (GABAAR).The amygdala is particularly rich in GABAARs which are known to be involved in the anxiolytic and anxiogenic effects of GABA agonists and antagonists, respectively. At present, there is a void in research designed to investigate how the changes in amygdala GABAergic transmission influences emotional memories and behaviors associated with anxiety and fear. Recently, our lab reported learning-related changes in GABA-related genes and GABAAR levels in the amygdala after the acquisition and extinction of Pavlovian fear, a commonly used animal model of fear and anxiety disorders. Our findings showed that the acquisition of fear induced a down regulation of genetic markers related to decreased amygdala GABAergic function;whereas the acquisition of fear extinction produced an up regulation of GABAergic markers related to enhanced GABAergic transmission. This research proposal will employ a novel and powerful approach to investigating the role of amygdala 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 of conditioned fear in mice with knocked down expression of [unreadable]2-GABAAR, [unreadable]5-GABAAR, or GAD67 in the amygdala 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 phasic and/or tonic inhibition, resulting in facilitated acquisition of fear and blunted extinction of fear. In Aim 2 of this proposal, we plan to examine the behavioral effects of BZ administration in mice with knocked down expression of [unreadable]2-GABAAR, [unreadable]5-GABAAR, or GAD67 in the amygdala. We hypothesize that associated changes in amygdala GABAergic function will result in blunted anxiety-like behavioral effects to BZ administration. A 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. Furthermore, an understand of the role of specific subtypes of GABAA receptors in anatomical localized areas of the brain will also have direct implications for the development of new therapeutic strategies for the treatment of a myriad of psychiatric and neurological disorders characterized by GABAergic dysfunction and/or treated by BZs.