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unpublished data using pathway-specific optogenetic circuit analyses have revealed that two parallel pathways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.