Revealing the neural circuitry underlying the permissive role of orexin on peripheral chemoreflex function
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Previous studies have shown that orexin neurons in the hypothalamus facilitate the hypercapnic ventilatory response, particularly during wakefulness when orexin neurons are most active. However, the acute effects of orexin on breathing and its role in cardiorespiratory responses to acute hypoxia have been inadequately explored. This study aimed to clarify orexin's involvement in peripheral chemoreflex (PCR)-mediated cardiorespiratory responses to hypoxia across active (i.e., wakefulness) and inactive (i.e., sleep) phases of the circadian cycle. We explored how orexin neurons regulate baseline cardiorespiratory function and modulate reflexive respiratory adjustment during acute hypoxia. Additionally, we investigated whether orexin neurons have the same influence on the peripheral chemoreflex in females across stages of the estrous cycle and identified the central neural pathways through which orexin neurons act to facilitate the peripheral chemoreflex. My findings revealed that orexin facilitates the peripheral chemoreflex, especially during the active phase. In females, orexin neurons have a greater influence on the peripheral chemoreflex during diestrus, when estrogens are low. Hypoxia increases the proportion of activated PVN-projecting orexin neurons, and orexin facilitates the hypoxiainduced activation of nTS-projecting CRH neurons, likely via Ox1R. I also provided evidence that the CRH-nTS pathway is necessary for the full expression of the peripheral chemoreflex, but that orexin also contributes to the peripheral chemoreflex through additional pathway(s). In conclusion, orexin neurons contribute to the peripheral chemoreflex, likely via nTS-projecting CRH neurons but also at other, yet-to-be-identified sites. Orexin neurons are important for the adaptive cardiorespiratory responses to hypoxia and could be involved in the development of cardiovascular dysfunction associated with an augmented peripheral chemoreflex, including hypertension and downstream comorbidities.
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Ph. D.