Sex-dependent pain processing circuitry in classical Pavlovian fear conditioning

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Project Summary Sex differences in the development and prevalence of mental illnesses are widespread, suggesting that the factors that promote disease risk and resilience may be distinct in men and women. The neurobiological mechanisms underlying this possibility are poorly understood, however, because the vast majority of pre- clinical animal research has been conducted in males. In addition, the behavioral outcome measures used to understand learned fear have focused predominantly on passive, or freezing behavior. We recently identified an active, escape-like conditioned fear response in rats (“darting”) that occurred almost exclusively in females and was associated with an augmented response to the foot shock unconditioned stimulus. A better understanding of potentially sexually dimorphic mechanisms that drive this behavior could open new avenues for treatment of disorders that are more prevalent in women, like PTSD. We have collected preliminary data implicating the neural projections from the anterior cingulate (ACC) to ventrolateral periaqueductal gray (vlPAG) as a potentially novel, sex-dependent circuit that integrates sensory pain information into conditioned and unconditioned fear responses. We propose here to explore sex differences in this circuit at both the structural and functional level. First, we will use a retrograde tracer to perform a quantitative mapping of ACC- vlPAG projections, then we will characterize the post-synaptic vlPAG targets of ACC afferents using trans- synaptic viral approaches combined with fluorescent immunohistochemistry. Next, we will record ACC-vlPAG activity during fear conditioning using fiber photometry to correlate activity to stimulus presentation and behavioral responses, and finally test the causal role this circuit plays in driving darting using circuit-specific chemogenetic techniques. Together, these studies can provide insight into sex-dependent circuit mechanisms underlying individual differences in stress resilience and vulnerability.