Revealing the neural mechanisms of amygdala-striatal control of stress-induced habits - The brain has two strategies for behavioral control. 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 contributes to maladaptive perseverative behavior, which characterizes numerous psychiatric conditions, including autism. Environmental factors, like chronic stress, and genetic alteration, can tip the balance between actions and habits. However, our knowledge of the brain mechanisms by which these factors influence habits is lacking, limiting our understanding of maladaptive behaviors in psychiatric conditions, and how to treat them effectively. Therefore, the broad goal of my research is to reveal specific neuronal mechanisms that allow genes and the environment to modulate behavioral control. Accumulating evidence suggests the dorsomedial striatum (DMS) is central for controlling goal-directed actions. Inhibition of the DMS, particularly Drd1+ direct pathway 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 is suppressed after chronic stress exposure. 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 Drd1+ control of goal-directed learning via BLA-DMS input. Through the proposed research, I will reveal how chronic stress changes the DMS Drd1+ neuronal activity associated with goal-directed learning, at the population and single-cell levels, and how BLA input facilitates this. I will accomplish this using cellular resolution in vivo calcium imaging with miniscopes, combined with projection- specific chemogenetic manipulation, in mice (Aim 1; K99). In my independent phase, I will apply these techniques 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 stress, and assess amygdala-striatal control, using cell-type specific in vivo calcium imaging with miniscopes, slice electrophysiology, and projection-specific optogenetic manipulations (Aim 2; R00). 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. I will conduct my K99 training in the Wassum Lab at UCLA, with the guidance of a remarkable mentoring team that has pioneered the open source miniscope technology. This environment will provide me with the necessary intellectual and technical training I need to launch my independent research program studying the mechanisms that allow environmental and genetic factors to modulate behavioral control strategies.
