Thalamic inputs modulate anxiety-related representations in the hippocampus

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Project Abstract Almost one third of adult Americans suffer from an anxiety disorder, carrying an enormous personal, societal, and financial burden. Difficulty advancing novel more effective treatments for anxiety disorders is because they are complex circuit-based conditions, resulting from dysfunction in several distributed regions, connections, and cell types that generate normal adaptive behavior. Thus, a fundamental understanding of how neural circuits become disrupted to generate maladaptive behavior is crucial if we hope to generate impactful treatments. Recent work has revealed the hippocampus (HPC), which has classically been implicated in learning, for its role in encoding emotionally charged environments and generating appropriate behavioral responses. More specifically, emerging evidence from our lab has identified HPC neurons in the ventral pole that project to the hypothalamus encode anxiogenic environments and bidirectionally modulate avoidance behavior. Yet how and which inputs are involved in the generation of anxiety-related representations in the ventral HPC remain unknown. Using a whole-brain cell-type specific anatomical screen, we identified the anterior portion of the paraventricular nucleus of the thalamus (PVT), an area implicated in the processing of salient emotional stimuli, as a putative source of anxiety-related information to the HPC. Here, I will use a combination of cutting-edge optical, pharmacological, and computational tools to dissect and characterize the thalamic-hippocampal encoding of anxiogenic contexts and control of anxiety- related behaviors. Experiments done here will provide the first studies to interrogate how HPC encodes anxiogenic contexts and the thalamic contribution in classical tests of anxiety. All in all, this study will provide crucial insight into how circuits generate excessive avoidance (i.e., anxiety-related behavior) for new therapeutic interventions for anxiety-related disorders. All proposed experiments are well established techniques in the lab and part of a globally prestigious neuroscience community, including prominent leading experts of circuit function, at The University of California, San Francisco. Consequently, I am poised and positioned in an ideal world-class environment for completing a successful and impactful doctoral dissertation.