Thursday, April 18, 2024
4/18/2024
PROJECT SUMMARY/ABSTRACT Avoidance is a hallmark symptom contributing to the deleterious impact of many anxiety disorders. Despite this, there are major gaps in our understanding of the neural circuits underlying avoidant behavior. A mechanistic account of this key symptom would advance progress toward brain-based innovations for the treatment of pathological anxiety. Signaled active avoidance (SAA) is a behavioral procedure for rats in which a highly persistent avoidance response is triggered by a conditioned stimulus (CS) associated with an aversive unconditioned stimulus (US). Because the avoidance response prevents US delivery, acquisition of SAA causes the US to transition from an imminent threat early in training to a remote threat later in training, once the response has become more frequent. Ethologically inspired models for aversive emotion suggest that this change in threat imminence is consistent with a shift from fear to anxiety, indicating that SAA expression is mediated by an anxiety-like state. The overarching hypothesis of this proposal is that neural circuits of anxiety-like behavior play a central role in SAA. Previous work implicates the bed nucleus of the stria terminalis (BNST) in anxiety. To generate preliminary data for the overarching hypothesis of this proposal, an initial experiment was conducted using an inhibitory DREADD (designer receptor exclusively activated by designer drugs) to inactivate BNST neurons in rats performing SAA. This manipulation demonstrated that BNST is necessary for the maintenance of the avoidance response. The proposed studies will build on this result by dissecting the function of a circuit mechanism for active avoidance, comprised of BNST and key regions that provide it with synaptic input (prefrontal cortex, basal amygdala). Given that avoidant coping is a behavioral disturbance common to many anxiety disorders, this work has clear relevance to public health. Discovery of an avoidance circuitry could provide a novel target for innovative therapeutic interventions for pathological anxiety. The goal of this work is to generate rigorous preclinical data that accelerates clinical advancement.
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