A projection from the hypothalamic paraventricular nucleus to the nucleus tractus solitarii is critical for cardiorespiratory responses to hypoxia

Abstract

The arterial chemoreflex is an essential protective mechanism for adaptive responses to hypoxia. Stimulation of peripheral chemoreceptors initiates a reflex response that generates compensatory physiological responses, including increased ventilation, arterial pressure and sympathetic nerve activity. However, chemoreflex dysfunction, including over-excitation of chemoreflex pathways, leads to respiratory instability and increased sympathetic nerve activity (SNA) in disease states including heart failure, hypertension and obstructive sleep apnea (170, 199, 232). Determining the mechanisms involved in the central chemoreflex neurocircuitry and its plasticity in health and disease may lead to the development of targeted therapies in cardiorespiratory disease. This dissertation seeks to provide new insight into the neural circuits that drive chemoreflex function. Compensatory responses to chemoreflex stimulation are generated through coordinated interactions between nuclei in the brainstem, forebrain and spinal cord. However, the underlying neurocircuitry, including relevant connections between these nuclei, and the signaling mechanisms that take place within each region are not completely understood. The nucleus tractus solitarii (nTS) and the paraventricular nucleus (PVN) are two central nuclei known to drive chemoreflex function and are implicated in altered cardiorespiratory responses resulting from chemoreflex dysfunction. These two regions form reciprocal connections but the extent to which these connections influence cardiorespiratory regulation and specifically chemoreflex function is unclear. The overarching goal of this dissertation is to examine whether a population of PVN neurons that project to the nTS is involved in shaping cardiorespiratory responses to chemorefle activation by hypoxia. The experiments performed in the three studies (Chapters 2-4) test the overall hypothesis that a descending PVN-nTS projection is an essential component of chemoreflex neurocircuitry; chemoreflex-evoked activation of this pathway is critical for compensatory cardiorespiratory responses to hypoxia.