Grant: Project Grant

Anxiety disorders are the most common form of mental illness. They are underrecognized and existing treatments are inadequate. Yet, anxiety behaviors can be both adaptive and maladaptive in certain circumstances, and what defines an anxiety disorder is the inability to shift between a behavioral state in which potential harm is avoided to one in which the individual engages with an environment despite uncertain threat. Accordingly, individuals with anxiety disorders lead increasingly circumscribed lives to avoid potential threat. We have identified a novel brain circuit in mouse involving the Anterior Cingulate Cortex (ACC) and the Zona Incerta (ZI) that controls the transition between these states and promotes the exploration of potentially threatening environments. This is important, because optimal appraisal of threat to then explore environments is critical to survival, and the ACC is a cortical node that is well established in anxiety and threat appraisal. The Zona Incerta, in turn, is a novel anxiety-related target in the midbrain that is an integrative hub and critical in rapid selection of behavioral responses such as locomotion to escape or to explore. The proposal first aims to test the necessity and sufficiency of the ACC ZI circuit in the exploration of potentially threatening spaces and the sex specific sensitivity of this circuit to stress. Second, the physiology of this circuit will be studied using calcium imaging in the ACC to identify how neurons that project to the ZI differ from those that do not under both naïve conditions and under stress. Finally, using in vivo electrophysiology we will identify how ACC-ZI projections impact local networks within the ZI as well as their downstream projections to mesencephalic locomotor regions required for anti-anxiety exploratory behavior. This project will provide a new lens from which to design treatments for anxiety.