A critical forebrain-brainstem circuit contributes to the adaptive and maladaptive cardiorespiratory responses to hypoxia - Chronic intermittent Hx (CIH), a hallmark of obstructive sleep apnea and many other diseases, leads to a long- term increase in the strength of the peripheral chemoreflex (PCR). An enhanced PCR subsequently increases sympathetic nerve activity (SNA), leading to hypertension even in wakefulness, a major contributing factor to downstream cardiovascular diseases such as heart failure and heart failure, leading killers of Americans. Orexin neurons in the hypothalamus have high activity in wakefulness and project to corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVN), a nucleus known to facilitate the PCR via its projections to the nucleus of the solitary tract (nTS). The overarching hypothesis driving this research is that neuronal circuit comprised of orexin neurons, CRH neurons in the PVN, and nTS neurons (orexin-CRH- nTS) facilitates the PCR and contributes to the hypertension that follows CIH. We will use an integrative approach utilizing an array of chemogenetic and in vitro techniques to resolve how the orexin-CRH-nTS enhances the PCR and contributes to the hypertension that follows CIH. Specific Aim 1: Does an orexin-CRH-nTS neural circuit facilitate the adaptive peripheral chemoreflex responses to Hx in the active phase, even in the absence of carotid body inputs? Our novel hypothesis is that the circuit increases the strength of the reflex, especially in the active phase and independently of chemoafferent inputs. Specific Aim 2: Does the orexin-CRH-nTS circuit contribute to sympathoexcitation and hypertension related to CIH, and is this effect dampened by estrogen? Our novel hypothesis is that CIH activates the orexin-CRH-nTS in a maladaptive fashion that leads to sympathoexcitation and hypertension. Through an inhibitory effect on orexin neurons, estrogen mitigates the excitatory influence of CIH on the activity of the circuit. CIH leads to increased peripheral chemoreflex sensitivity and hypertension, a major health problem as it leads to multiple cardiovascular diseases that are leading killers of Americans. These studies interrogate a hypothalamic-brainstem neural circuit (orexin-PVN-nTS) that facilitates the peripheral chemoreflex and thus the maladaptive cardiovascular responses to CIH. They provide the foundation for strategies targeting the hypothalamus to alleviate hypertension in patients experiencing CIH, as well as the initial insight into potential sex differences in maladaptive cardiovascular responses to CIH that have an origin in the hypothalamus.
