Do opposing amygdala-striatal pathways enable chronic stress to promote habit formation?

PROJECT SUMMARY When making a decision we can use our understanding of available action-outcome relationships to prospectively evaluate the consequences of our potential actions and choose the one that is currently most beneficial. This goal- directed strategy is, thus, quite flexible, allowing us to readily adapt when circumstances change. For example,

when ordering dinner, you consider how nutritious and delicious each potential meal will be and will avoid options that you’ve just had for lunch or do not meet your current nutritional needs. But we don’t always think about the consequences of our behavior. Usually this is fine. Such habits are a way for our brain to efficiently execute routine

behaviors. But disrupted goal-directed learning and overreliance on habit can cause inadequate consideration of consequences, inflexibility, a lower threshold for compulsivity, and disrupted decision making. This can contribute to aspects of numerous diseases, including substance use disorder (SUD), obsessive-compulsive disorder,

obesity, schizophrenia, depression, anxiety, and autism. Chronic stress can attenuate goal-directed learning and tip the balance of behavioral control towards habit. This is one major avenue through which chronic stress can predispose one to SUD and other mental illnesses. But we know very little of how chronic stress promotes habit

formation. The overarching goal of this proposal is, thus, to expose the neuronal circuits through which chronic stress promotes premature habit formation. This work will help us to understand how chronic stress can promote maladaptive and pathological habits, which will be critical for understanding and treating SUD and mental illness.

Filling this gap is especially important because chronic stress contributes to mental health disparities in the US. Recent evidence from our team has suggested that central (CeA) and basolateral (BLA) amygdala projections to the dorsomedial striatum (DMS) may be critical conduits for stress-potentiated habit. Based on prior and our

preliminary data, our novel, comparative hypothesis is that BLADMS and CeADMS promote and oppose, respectively, goal-directed learning and associated neuronal activity in the DMS and that chronic stress amplifies CeADMS and attenuates BLADMS pathway activity to promote premature habit formation. We will test this

with a multifaceted approach including projection-specific optical neuronal activity monitoring and manipulation, cell-type specific, cellular resolution, microendoscopic calcium imaging with pathway-specific chemogenetic manipulations, a model of chronic stress, and theory-driven behavioral tools. We will expose how ensembles of

DMS neurons organize their activity during goal-directed and habit learning and how this is impacted by chronic stress. We will reveal the functions of two understudied amygdala-striatal pathways in goal-directed and habit learning and how they are influenced by chronic stress. More broadly, we will uncover neuronal circuitry through

which chronic stress promotes habit formation. This will provide a critical basic science foundation for our long- term goal of understanding of how chronic stress is a conduit to pathological habits.