Francisco J. Alvarez (Committee Member), Jay B. Dean (Committee Member), David L. Goldstein (Committee Member), James E. Olson (Committee Member), Robert W. Putnam (Advisor)
Doctor of Philosophy (PhD)
The chemosensitive responses of individual nucleus tractus solitarius (NTS) neurons from neonatal rats have been extensively studied, but few studies have examined the chemosensitive responses of NTS neurons from adult rats. In addition, environmental conditions have been used to mimic respiratory diseases/disorders in rats to study how the cellular responses of individual neurons change to regulate breathing during pathological conditions. Lastly, it has been shown that substance P release increases in response to hypoxia from peripheral afferents that primarily terminate in the caudal NTS. We studied the effect of chronic hypoxia (CHx) and substance P on the response to hypercapnia of individual NTS neurons in control and CHx-adapted adult rats by simultaneously measuring the intracellular pH (pHi) and firing rate responses to hypercapnia using fluorescence imaging microscopy and the blind whole cell patch clamp technique. We found that NTS neurons from control adult rats have a lower steady state pHi, similar intrinsic responses to hypercapnic acidosis, and a similar response to isohydric hypercapnia (decreased ΔpHi and induced pHi recovery) compared to neonates. In CHx rats, we found that the percentage of NTS neurons activated by hypercapnia decreased and the percentage that were inhibited by hypercapnia increased with no change in their magnitude of response as compared to NTS neurons from control rats. Additionally, these changes appear to be intrinsic. Substance P significantly increased the basal firing rate and caused a significant decrease in steady state pHi in NTS neurons in control and CHx-adapted animals, although the increase in firing rate caused by substance P was significantly smaller in CHx-adapted animals. In contrast, substance P had no effect on the percentage of neurons that respond or the magnitude of the response of NTS neurons to hypercapnic acidosis. In conclusion, intrinsic chemosensitivity established early in life for NTS neurons is maintained throughout adulthood, and is not dependent on substance P. Also, CHx causes a suppression of the adult chemosensitive response of NTS neurons that is not dependent on substance P. Finally, we have identified a model system to study the mechanism of how chemosensitive neurons are inhibited by hypercapnia.
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