UC San Diego

Following hours to days in hypoxia, a time dependent increase in ventilation occurs, termed ventilatory acclimatization to hypoxia (VAH). Hallmarks of VAH include an increased slope of the isocapnic hypoxic ventilatory response (HVR) and hyperventilation that persists upon return to normoxia (Powell et al., 1998). VAH involves changes in the sensitivity of the carotid body to hypoxia (Nielsen et al., 1988) and the central nervous system to carotid body afferent input (Dwinell & Powell, 1999). My dissertation tests the hypothesis that plasticity occurs in the Nucleus Tractus Solitarius (NTS), which receives the first synapse from the carotid body afferents (Housley et al., 1987) and also contains CO₂-sensitive cells (Dean et al., 1989). To determine if plasticity in the NTS contributes to VAH, we used two approaches: stimulating CO₂-sensitive cells in the NTS and lesioning a specific type of neuron in the NTS and measuring ventilatory responses to CO₂ and O₂ before and after acclimatization to chronic hypoxia. Stimulation of the NTS central chemoreceptor cells by focal acidosis increased phrenic nerve activity in anesthetized rats, as reported by other investigators (Coates et al., 1993). The response in chronically hypoxic animals was significantly less than in the normoxic controls in contrast to the increase we predicted to explain the persistent hyperventilation in normoxia with VAH. However, this decreased responsiveness of NTS CO₂-sensitive cells in chronic hypoxia is consistent with cellular data suggesting an increase in the number of cells inhibited by hypercapnia after chronic hypoxia (Nichols et al., 2009). Our lesion studies targeted neurokinin 1 receptor positive cells (NK1R) in the NTS because similar lesions in other central chemosensitive sites have been shown to reduce the hypercapnic ventilatory response (Nattie & Li, 2002b; Nattie et al., 2004). We measured the ventilatory responses to hypercapnia and hypoxia in normoxic and chronically hypoxic rats following the lesion of NK1R cells in the NTS. No effects of the lesion were seen in normoxic rats. However, ventilation in room air and hypoxia was significantly greater in lesioned animals after chronic hypoxia. This suggests that NK1R cells in the NTS attenuate the arterial chemoreflex after chronic hypoxia. There was also a non-significant trend for ventilation to increase during hypercapnia in lesioned animals after chronic hypoxia. These studies have established plasticity in the NTS during chronic hypoxia but the exact mechanisms and their contribution to VAH remain to be determined.