PROJECT SUMMARY Maladaptive avoidance behaviors underlie several anxiety-related disorders, many of which are not treated appropriately. Surprisingly, the neural mechanisms that underlie avoidance are poorly understood. Here, I seek to expand on recent evidence from our laboratory which supports the idea that anatomical projections from the posterior paraventricular nucleus of the thalamus (pPVT) to the nucleus accumbens (pPVTNAc) drive active avoidance behavior. Specifically, I will test the hypothesis that dynamic modulation of inhibitory inputs onto pPVTNAc cells shapes the selection of defensive behaviors. This prediction is based on the notion that in an active avoidance behavioral task failure to perform avoidance is associated with the expression of freezing behavior (a defensive response elicited by imminent threats) and the concomitant attenuation of pPVTNAc activity, suggesting that these two events are related. The central amygdala (CeA), a region composed of GABAergic neurons, is critical for driving conditioned defensive responses to imminent threat, including freezing. Notably, recent anatomical evidence shows that the CeA sends projections to the pPVT (CeApPVT), making it a suitable candidate for mediating defensive transitions via the PVT. However, what role CeApPVT projections and GABAergic inhibition in general play in the selection of defensive behaviors has received little attention. Therefore, the objective of the proposed research is to independently assess the contribution of GABAergic transmission and the role of CeApPVT projections in the emergence and selection of defensive behaviors. My central hypothesis is that the CeA inhibits pPVTNAc neurons to suppress active avoidance and promote freezing. In preliminary studies we observed that GABAergic transmission onto pPVTNAc cells was suppressed during avoidance and increased during freezing. Additionally, we found that the CeA sends inhibitory projections to the pPVT. To expand on these observations, I have outlined the following research plan. In Aim 1, I will utilize the recently developed pharmacological tool DART in parallel with genetic knockout and overexpression techniques to provide two independent methods of suppressing and enhancing GABAergic signaling onto pPVTNAC cells. This will test the prediction that GABAergic inhibition of pPVTNAc neurons suppresses avoidance behaviors, and that in contrast disinhibition of this pathway promotes avoidance. In Aim 2, I will combine ex vivo electrophysiology with in vivo optogenetics and fiber photometry to determine whether CeA inhibition of the pPVT shapes the selection of defensive behaviors by inhibiting pPVTNAc cells. Execution of this proposal will allow me to learn, further develop, and master the use of relevant neuroscience techniques, such as AAV-mediated target vector delivery for the monitoring and manipulation of neural circuits, and in vivo optogenetics and fiber photometry. In addition, these finding...