Summary
Cardiovascular disease is the leading cause of death worldwide and psychosocial stress is a significant
predictor of disease incidence and severity. However, the specific neurobiological mechanisms that mediate
the cardiovascular consequences of stress are largely unknown. Therefore, the current proposal will determine
how the cortical circuits responsible for cognitive appraisal of stress regulate physiological stress responses.
Recent studies in rats identified a population of cells in the infralimbic (IL) region of the medial prefrontal cortex
that integrate endocrine and autonomic responses to stress in a sexually-divergent manner. Further,
stimulation of IL glutamate neurons and chronic stress interact sex-specifically to affect cardiac structure and
function. While the activity of excitatory IL projection neurons is critical for regulating the deleterious effects of
chronic stress, the pathways used by these cells to modulate reactivity of autonomic and endocrine systems
remain to be determined. Preliminary data indicate that IL projections to the posterior hypothalamus (PH)
reduce male stress responses but enhance female stress responses. These excitatory IL projections target
both inhibitory GABAergic and excitatory glutamatergic neurons in the male and female PH. Further, chronic
variable stress upregulates PH gene expression related to glutamate and GABA signaling in males but not
females. Altogether, these findings led to the hypothesis that sex-specific IL glutamatergic signaling to the PH
differentially engages glutamatergic and GABAergic cells to regulate cardiovascular and endocrine stress
reactivity, as well as the consequences of chronic stress on vascular stiffness and cardiac hypertrophy. This
hypothesis will be tested in 3 aims. First, circuit signaling will be examined with patch-clamp slice
electrophysiology in male and female rats. Specific experiments will determine how IL glutamate signaling
targets genetically-defined postsynaptic PH GABAergic and glutamatergic cells as well as chronic stress-
induced circuit plasticity. Second, in vivo optogenetic activation of IL synapses in the PH following chronic
variable stress will interface with measures of heart rate, blood pressure, and neuroendocrine stress
responses. This approach will isolate circuit effects to normalize or exacerbate stress reactivity. Third, a
combinatorial viral approach will be used to retrogradely inhibit IL projections to the PH with Cre-dependent
tetanus toxin. In addition to cardiovascular telemetry and hypothalamic-pituitary-adrenal hormones, cardiac
hypertrophy and microvascular function will be assessed in chronically-stressed male and female rats to
determine circuit regulation of stress-induced cardiac and vascular dysfunction. Collectively, these experiments
will determine specific circuit and cellular pathways linking cognitive appraisal with physiological stress
responses. Further, this investigation is poised to not only increase understanding of brain-body interactions
and sex-based health disparities, but also identify potential targets to mitigate cardiovascular risk.