Network dynamics of vHip-amygdala-mPFC circuit in innate and learned anxiety

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DESCRIPTION (provided by applicant): Anxiety disorders include a broad repertoire of behaviors with differing etiologies. For instance, generalized anxiety disorder (GAD) is a state of innate and chronic fear, whereas post-traumatic stress disorder (PTSD) is an anxious response to learned fear that is acquired and cue dependent. The main goal of this proposal is to identify the differing ways in which implicated brain regions process these two types of anxiety. Research has identified the basolateral complex of the amygdala (BLA), the medial prefrontal cortex (mPFC) and the ventral portion of the hippocampus (vHip) as important for various aspects of anxiety processing. The proposed work will dissociate the behavior-driven dynamics of the network formed by these three areas during learned versus innate anxiety. The vHip, BLA and mPFC are directly connected, suggesting that they form a network, the interactions of which could constitute the basis for learned and chronic anxiety phenotypes. Indeed, the vHip and BLA have convergent inputs to the mPFC, which has been suggested as a means of integrating anxiety and context information in the cortex. Separate studies have demonstrated that in innate anxiety paradigms, the vHip and mPFC increase their communication, whereas conditioned fear increases synchrony between the hippocampus and BLA. In contrast, the mPFC and amygdala are thought to act in concert during extinction of learned fear. However, data is lacking on how the mPFC, BLA and vHip integrate or differentiate innate versus learned anxiety. Therefore, we aim to study the network dynamics of this circuit using chronic multisite recordings in vivo in conjunction with behavioral assays probing both types of anxiety. We will test the hypothesis that there are dissociable levels of cooperation between the vHip, BLA and mPFC as a function of the anxiety provoking scenario that is experienced. In addition, behavior and electrophysiological recordings will be used to test the idea that disruption of 5HT1A receptor signaling, an established model of hippocampal dependent anxiety, will enhance innate anxiety via increased vHip-mPFC coupling, while leaving intact amygdala-hippocampal signaling as well as learned anxiety. Given the prevalence of anxiety disorders in the United States and worldwide, as well as their high mortality and high cost to society, the translational nature of this proposal is undoubtedly beneficial to public heath. In particular, by examining the changing ways in which the ventral hippocampus, amygdala and medial prefrontal cortex interact during different anxiogenic scenarios, we aim to provide a network-level approach for differentiating between learned and innate anxiety in humans. The ultimate goal of this work is to create a framework for etiology-tailored therapies of anxiety.