Examining the neuronal mechanisms underlying stress-accelerated habit

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The brain has two strategies for behavioral control. Goal-directed actions which rely on prospective consideration of potential outcomes and consequences, and habits, reflexive behaviors executed without forethought of their consequences. Overreliance on habit causes maladaptive compulsive behavior that characterizes substance use disorder and other psychiatric conditions. Stress is a major predisposing factor to substance use disorder and can also cause an overreliance on habit. However, our understanding of the brain mechanisms by which stress influences habits is lacking, limiting our understanding of how stress promotes maladaptive compulsive behavior in substance use disorder. Therefore, the broad goal of this project is to reveal the neuronal mechanisms by which stress promotes habit formation. Accumulating evidence suggests that the dorsomedial striatum, part of the basal ganglia, is responsible for controlling goal-directed actions. Inhibition of the dorsomedial striatum, particularly Drd1+ direct pathway neurons, disrupts goal-directed control, resulting in a bias toward habits. The central amygdala (CeA), a majority inhibitory nucleus, is known to be a hub for stress-responsivity in the brain. Until recently, it was thought that the CeA and dorsal striatum are not directly connected. However, modern tracing techniques have revealed direct projections between these two regions, which I have found are biased towards the dorsomedial striatum. Interestingly, in my graduate work I discovered that CeA projections to other parts of the basal ganglia convey information about aversive stimuli. This led me to the intriguing hypothesis that amygdala-striatal projections convey information about stress to block goal-directed actions, biasing behavior toward habits. Through the proposed research I will reveal the mechanistic role of central amygdala-striatal projections in the context of stress-potentiated habit formation. I will accomplish this using a multifaceted approach of cutting-edge neuroscience techniques in mice. In Aim 1, I will apply in vivo fiber photometry imaging and optogenetic manipulation during a sophisticated behavioral paradigm to determine the temporal dynamics and sufficiency of central amygdala-striatal projections in controlling habits after stress. In Aim 2, I will reveal the endogenous activity dynamics of dorsomedial Drd1+ striatal ensembles during habit formation and how this activity is altered by stress and differs in the absence of CeA input using chemogenetics. The resulting findings will provide a mechanistic understanding of habit formation in both the normal context and after stress exposure. This will facilitate future work into the molecular and cellular mechanisms of this phenomenon and serve my goal of improving treatment approaches for substance use disorder and other stress-related conditions. I will conduct this project in the Wassum Lab at UCLA, with the guidance of a remarkable mentoring team. This environment will provide me with exceptional intellectual and technical training in systems and behavioral neuroscience, fully preparing me for an independent research career studying the role of stress in addiction.