The Role of Gamma-Aminobutyric Acid- (GABA-)ergic Long-Range Projections in Fear Inhibition

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Fear and anxiety-related disorders are one of the most prevalent psychiatric disorders worldwide, with an increasing tendency due to the Russo-Ukrainian war and Covid-19-related socio-economic and health-related consequences. The coordinated action of large-scale neuronal networks, that is, local circuit components that are linked together by long-range connections, is essential for proper brain functioning and the modulation of behavior. However, while the role of local inhibitory circuits in the amygdala, a key brain region for the modulation of fear, has been extensively characterized, the involvement of GABAergic long-range projections has been overlooked. To overcome this gap in knowledge, the current project aims to investigate whether inhibitory GABAergic long-range projections to the central amygdala directly influence fear- and anxiety-related behaviors.By utilizing Vesicular GABA Transporter (VGAT)-IRES-Cre mice and a combination of viral tracing methods, along with deep-tissue immunohistochemistry and 3D-whole-brain tissue clearing / imaging, this project will first screen the distribution of GABAergic long-range projection neurons to the central amygdala (Objective 1). To specifically understand how GABAergic long-range projection neurons mediate fear and its inhibition, the functionally relevant GABAergic long-range projections and their originating brain regions will be validated by means of Designer receptors exclusively activated by designer drugs and in vivo calcium imaging (Objective 2). To further characterize the molecular and cellular mechanisms through which the identified projections act to affect fear behavior, I will apply 3-D single cell imaging and fluorescence in situ hybridization chain reaction in order to find new pharmacological interventions (Objective 3).The project will advance our knowledge about the existence, properties, and possible functions of long-range projecting GABAergic neurons in the central amygdala and identify causal changes in neuronal activation patterns, which in turn represent the handle with which to dissect both the underlying molecular and therapeutic mechanisms.