Project Summary A key aspect of stressor adaptation in humans and other mammals involves the selection of appropriate coping responses. The active coping response set allows for the maintenance of lower levels of glucocorticoid stress hormones and sympathetic activity, due in part to the actual or perceived agency over aversive stimuli, and when active responses are restricted, such as in the passive coping set, behavioral passivity increases and HPA and sympathetic responses are exaggerated. In this regard, elevations in HPA and autonomic systems resulting from over-biasing toward passive coping contribute to psychiatric and systemic disease pathogenesis. Our unpublished data using pathway-specific optogenetic circuit analyses have revealed that two parallel pathways from caudal and rostral prelimbic (cPL and rPL) cortex, innervating dorsolateral and ventrolateral subdivisions of periaqueductal gray (dlPAG and vlPAG), that promote active and prevent passive behaviors, respectively, in response to acute stressors. Based on these preliminary data, we will examine the hypotheses that one or both of these pathways are required to promote an active coping set, whereas their diminished influence under chronic stress conditions biases the animal toward a passive coping set. The first aim will determine how activity changes in PAG projector neurons in PL correlate with active and passive coping behavior following chronic stress compared to rats with no previous exposure. Aims 2 and 3 will utilize pathway specific optogenetic manipulations to evaluate whether inactivation of either cPL–dlPAG or rPL–vlPAG pathways under acute stress conditions increases passive behavior and exaggerated HPA and sympathetic activation. Conversely, we will evaluate whether increasing activity in either of these pathways in chronically stressed rats can rescue an active coping set involving increased active behavior, and attenuated HPA and sympathetic output. In the fourth aim, we will address the complementary relationship between each circuit’s function (i.e., cPL–dlPAG pathway promotes an active coping set; rPL–vlPAG pathway prevents a passive coping set), since these data implicate the predominance of one circuit over the other. Here, we will utilize an anterograde transsynaptic viral strategy to optogenetically test whether the cPL–dlPAG pathway engages vlPAG as a downstream mediator for restraining passive behavior and preventing exaggerated HPA and sympathetic activation under CVS conditions. These studies will advance a new framework for understanding the neural regulation of stress coping for translation to stress-related psychiatric diseases— by elucidating a novel circuitry and activity patterns of responses under acute and chronic conditions, and the expansion of the concepts of susceptibility and resilience to encompass behavioral, endocrine and physiological features.