Statement of Problem: The arterial chemoreflex is an essential protective mechanism for adaptive responses to hypoxia (Hx). However, chemoreflex dysfunction, including over-excitation of chemoreflex pathways leads to respiratory instability, increased sympathetic nerve activity (SNA) and hypertension in disease states, including heart failure and hypertension. Information regarding mechanisms of action in the chemoreflex neurocircuitry is lacking. The neuropeptide neurons CRH and OT neurons in the paraventricular nucleus of the hypothalamus (PVN) may influence sympathoexcitatory and respiratory control via projections to brainstem cardiorespiratory nuclei. Previous studies indicate that CRH increases cardiorespiratory function in both healthy subjects and elderly patients dependent on artificial respiration, suggesting that CRH may offer therapeutic potential in various disease states that display chemoreflex dysfunction. However, the central mechanisms by which PVN neuropeptide neurons contribute to these responses are unclear.
Specific Aims :
Aim 1 : To determine the contribution of PVN CRH neurons to cardiorespiratory control at baseline and in response to peripheral chemoreflex stimulation Aim 2: To determine the contribution of PVN OT neurons to cardiorespiratory control, and examine central interactions between CRH and OT in the nTS Experimental Approach: The overall Hypothesis of this project is that PVN CRH neurons that project to the nTS enhance cardiorespiratory responses to chemoreflex stimulation via activation of nTS CRH receptors and OTergic mechanisms.
Aim 1 will determine the extent to which PVN CRH neurons contribute to cardiorespiratory output at baseline and during peripheral chemoreflex stimulation via projections to the nTS.
Aim 2 will determine the extent to which PVN CRH and OT neurons modulate cardiorespiratory responses to chemoreflex via interactions within the nTS. Significance of Results: The long-term objectives of this study are to further characterize interactions between the PVN and the nTS, and the mechanisms by which this reciprocal pathway shapes cardiorespiratory responses to peripheral chemoreflex stimulation. Determining the pathways, circuits and mechanism(s) mediating chemoreflex function and how these may be changed in disease would be of great benefit in designing rational and targeted therapeutic approaches in these debilitating diseases.
Chemoreflex dysfunction, including over-excitation of chemoreflex pathways leads to respiratory instability and increased sympathetic nerve activity (SNA) in disease states, including heart failure and hypertension. Recent evidence suggests that neuropeptides produced in the brain regulate cardiorespiratory function. Using a variety of experimental techniques, our experiments will examine central nervous system mechanisms by which these neuropeptides contribute to shaping cardiorespiratory responses to peripheral chemoreflex stimulation. Our results will provide insight into mechanisms of chemoreflex function and potential therapeutic benefits in cardiorespiratory function for patients with cardiorespiratory disease.