Endocannabinoid regulation of ventral hippocampus-nucleus accumbens circuit and consequences for stress-mediated behaviors

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Summary: Post-traumatic stress disorder and other anxiety disorders are the most common mental illnesses in the United States, affecting nearly one third of Americans at some point in their life. However, this growing public health concern is met with limited efficacious pharmacotherapies despite billions of dollars invested in drug development. Research has begun to focus on the neural processes mediating stress susceptibility as a potential target for therapeutics; as such, the endocannabinoid system has recently emerged as a central regulator of stress responsivity, avoidance behaviors, fear generalization, and aversive learning processes, and is thus a compelling candidate for future drug development. Augmentation of endocannabinoid signaling has been shown to reduce stress-induced avoidance and promote stress resilience. Here, we aim to understand which neural circuits drive endocannabinoid-mediated protection of deleterious stress effects. Recent evidence has implicated the ventral hippocampus (vHIPP)-nucleus accumbens (NAc) circuit in mediating stress susceptibility, and we have collected data confirming that endocannabinoids regulate vHIPP-NAc synapses. In this proposal, we will combine approach/avoidance behavioral paradigms, with optical tools for recording (fiber photometry) and manipulating (INTERSECT viral approach) endocannabinoid signaling to elucidate the role of circuit-specific endocannabinoid signaling in mediating stress adaptations. Together, this proposal will give me the technical and theoretical training to answer complex questions about the neural basis of behavior and its dysregulation in stress-induced disorders. In Aim 1, I will characterize what sort of stimuli induce endocannabinoid release in vivo at vHIPP-NAc synapses using a novel endocannabinoid sensor in conjunction with fiber photometry. These studies allow for temporal dynamics and activity-dependent mechanism mediating stress-induced endocannabinoid release, in vivo, for the first time. In Aim 2, I will define cell-type specific endocannabinoid regulation of vHIPP-NAc circuitry using whole cell patch clamp electrophysiology and transgenic reporter mice to identify discrete neuronal populations; this will provide cell-type specific assessment of how endocannabinoids mediate neural activity in the NAc. Finally, in Aim 3, I will selectively delete components of the endocannabinoid system from vHIPP-NAc circuit. This will allow us to define the sufficiency and necessity of endocannabinoid signaling in various aspects of stress-responsive avoidance behaviors. Through these novel findings, we will learn about the mechanisms that mediate dysfunctional stress responding and how the endocannabinoid system may present a therapeutic target to develop more specific drugs to treat psychiatric disorders.