Responses to stress are regulated by a network of limbic forebrain structures, whereas dysfunction in these
neural systems following chronic conditions has been widely implicated in the pathogenesis of stress-related
psychiatric illness. To date, there is virtually no information accounting for central effectors of chronic stress-
induced endocrine and behavioral modifications, nor has there been any attempt to rescue normal function
after chronic stress. Work in the field implicates the medial prefrontal cortex in providing top-down inhibitory
control over hypothalamo-pituitary-adrenal (HPA) effector neurons in the paraventricular hypothalamic nucleus
(PVH) during acute stress, via a disynaptic pathway involving GABAergic neurons in the bed nuclei of the stria
terminalis (BST). However, no information is currently available regarding the neural circuit mechanisms in the
genesis of exaggerated HPA responses upon subsequent exposure to novel challenges (i.e., sensitization).
Additionally, our preliminary data suggest that BST plays a broader role in coordinating both endocrine and
behavioral coping responses during a variety of challenges (e.g., tail suspension, forced swim, shock probe
defensive burying tests), via dissociable pathways involving the PVH and periaqueductal gray area (PAG).
Therefore, our objective in this proposal is to manipulate these circuit elements to elucidate the mechanisms of
chronic stress-induced HPA sensitization and shift toward passive behavioral responses to subsequent
challenges. These studies will combine optogenetics and neurophysiology to build on our existing strengths in
anatomical and behavioral approaches to manipulate putative stress modulatory networks in rats. In Aim 1, we
will interrogate the divergent pathways from BST to PVH and PAG in mediating the maladaptive HPA and
behavioral changes following chronic variable stress exposure. Aim 2 will examine whether diminished
prefrontal control over descending pathways to BST and/ or PAG account for chronic stress-induced
maladaptive HPA and behavioral alterations. This work will advance our thinking of how different features of
stress responses are coordinated, and will provide a clearer picture of how dysfunction in modulatory brain
circuits may lead to chronic stress-related dysfunction of multiple systems as is common in psychiatric
illnesses such as depression.