Sunday, May 11, 2025
5/11/2025
Role of the circadian rhythm on endocannabinoid response to an acute stress - Project Summary Cardiovascular (CV) disease is the leading cause of death in the US. Night and rotating shift work, ~20% of the labor force, is associated with a greater incidence of both psychosocial stress and CV disease suggesting that wakefulness and activity when the body is optimized for sleep and recovery is harmful to one’s health. Acute stressors in the form of both heightened emotions in response to a psychosocial stress and moderate exercise can trigger a CV event, however, the underlying physiology remains unclear. Endocannabinoids (eCB) are lipid messengers that modulate the emotional and physiological response to stress and have also been demonstrated to regulate CV function. Colleagues and I have recently demonstrated a robust endogenous circadian rhythm in basal levels of circulating eCBs with a trough during the biological night. However, the circadian variation in eCB reactivity, change from baseline in response to an acute stress, remains unclear. A difference in eCB response and associated CV reactivity to an acute stress across the circadian system provides a plausible pathway that could underlie risks for development of CV disease in shift workers. Thus, I aim to test the hypotheses that changes of circulating eCBs in response to (a) an acute psychosocial stress and (b) a mild somatic stress (exercise) are dependent upon circadian phase and will correlate with changes in emotional and CV reactivity. The proposed research will take advantage of the opposite effects on mood of psychosocial stress (depressed mood) and exercise stress (improved mood) to further examine how eCB regulation of emotional processing is related to CV function. Additionally, as Black Americans have the highest age-adjusted CV disease mortality and persistently demonstrate differential responses to stress this proposal will test the hypothesis that Blacks compared to Whites will have attenuated eCB responses to psychosocial and somatic stressors. These aims will be achieved via a multi-day circadian protocol (dim lighting free of time cues) with sleep-wake cycles adjusted to recurring 18h cycles so that after numerous cycles all behaviors occur evenly across all circadian phases. Assessments include circadian phase and amplitude from salivary melatonin, circulating eCBs from blood plasma and mood from questionnaires. Relevant markers of CV function will include autonomic function and markers of hemostasis. This protocol will be performed in 40 healthy adults as an additional component to my primary mentor’s active project (R01HL142064, PI, Steven Shea). Elucidation of mechanisms that impact stress reactivity across the circadian system integrates my prior training and is a logical progression in my research career that will provide valuable information for evaluating the utility of evidence-based interventions. To achieve my long-term goal of becoming an independent scientist translating stress and circadian research between the laboratory and community, this K01 will provide further training in the following areas: 1) Standardization and assessment of stress protocols; 2) Advanced statistical training for examining the temporal order of stress markers; and 3) Knowledge on the etiology and prevention of sudden CV events and assessment of CV health.
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