Revealing the neural mechanisms of amygdala-striatal control of stress-induced habits - PROJECT SUMMARY: Updates: I am moving to a new position at Temple University Lewis Katz School of Medicine as an independent, tenure-track Assistant Professor in the Department of Neural Science. Here, I will conduct the R00 phase experiments and develop my own independent research program. The overall aims of the R00 phase have not changed from the K99 proposal. The brain has two strategies for controlling behavior. Goal-directed actions that rely on prospective consideration of their outcomes and consequences, and habits, reflexive responses performed without forethought of their consequences. Overreliance on habit can lead to maladaptive perseverative behavior, which contributes to numerous psychiatric conditions, including autism spectrum disorders. Environmental factors, like stress, and genetic alteration, can tip the balance between actions and habits. However, our knowledge of the mechanisms by which these factors influence habits is lacking, limiting our understanding of maladaptive behaviors in psychiatric conditions, and how to treat them. Therefore, the broad goal of my research is to reveal specific neuronal mechanisms that allow gene x environment interactions to disrupt behavioral strategy. Accumulating evidence suggests the dorsomedial striatum (DMS) is central for controlling goal-directed actions. Inhibition of the DMS, particularly D1+ neurons, disrupts goal-directed control, resulting in a bias toward habits. The basolateral amygdala (BLA) is a known hub for stress responsivity in the brain and projects onto DMS Drd1+ neurons. My postdoctoral work has revealed that BLA-DMS activity supports goal-directed learning and its suppression is necessary for premature habit formation. Further, I found that activation of BLA-DMS projections in stressed animals is sufficient to restore goal-directed control. This led me to the intriguing hypothesis that chronic stress dysregulates DMS D1+ control of goal-directed learning via BLA-DMS input. In my K99 phase, I found that indeed, suppression of DMS D1+ activity is necessary for chronic stress to promote premature habits. In my independent phase, I will apply these findings to a mouse model of 16p11.2 microdeletion, a genetic alteration associated with autism and that is known to dysregulate striatal function. Specifically, I will examine the vulnerability to premature habits of 16p11.2 mice, normally and after sub-threshold stress, and assess amygdala-striatal control, using cell-type specific in vivo calcium imaging with miniscopes, slice electrophysiology, and projection-specific chemogenetic manipulations. My findings will provide a mechanistic understanding of habitual control normally, after stress, and in a model of autism-associated genetic alteration. This will facilitate future work into the molecular and cellular mechanisms of this phenomenon and ultimately serve my goal of improving treatment approaches for psychiatric conditions.
