We have reported several important adaptations in the response to acute hypoxia (AH) following exposure to chronic hypoxia (CH). Exposure to CH enhances the cardio-respiratory response to AH. CH abolishes post-hypoxia frequency decline (PHFD) following AH. We also found that following exposure to CH, NTS neurons are less sensitive to GABA inhibition. Abolition of PHFD, which depends upon neurons in the ventro-lateral pons overlapping the A5 noradrenergic cell group, and reduced GABA inhibition of NTS neurons, could contribute to the enhanced cardio-respiratory response to AH following CH. The amount and activity of tyrosine hydroxylase (TH, rate-limiting enzyme in the synthesis of catecholamines) are increased within the noradrenergic, A2 cell group of NTS following CH, suggesting that these neurons play a role in the response to CH. This competitive renewal proposes a model where, following CH, glutamatergic NTS neurons exhibit a potentiated response to afferent stimulation and noradrenergic neurons exhibit a reduced response to activation of GABA-A receptors. These adaptations contribute to the enhanced response to AH following CH by enhancing excitation of sympathetic and respiratory outputs and enhancing inhibition of A5 neurons that abolishes PHFD. To test these hypotheses, Specific Aim 1 will examine the integration of arterial chemoreceptor inputs within the NTS following exposure to CH. It is hypothesized that during CH, alterations occur in synaptic integration so that the cells exhibit an enhanced response to afferent stimulation.
Specific Aim 2 will examine the functional significance of the changes observed in Specific Aim 1 by examining responses of A5 neurons to AH following CH. The hypothesis is that following CH, AH inhibits A5 neurons presumed to mediate PHFD via an alpha2-receptor mechanism and AH excites A5 neurons presumed to mediate sympatho-excitation. In both Aims experiments are described to selectively deplete catecholaminergic neurons in TNS and A5 and examine the consequences on the response to AH before and after exposure to CH. The proposed studies will determine the changes CH evokes in specific populations of NTS neurons defined by afferent input (carotid body), output projection (RVLM, PVN, A5) and phenotype (glutamatergic, catecholaminergic, GABAergic). The proposed studies will provide new insights into the central neuronal network response to AH and possible alterations in the network as a consequence of CH.
| Zhang, Weirong; Mifflin, Steve (2010) Plasticity of GABAergic mechanisms within the nucleus of the solitary tract in hypertension. Hypertension 55:201-6 |
| Zhang, Weirong; Carreño, Flávia R; Cunningham, J Thomas et al. (2009) Chronic sustained hypoxia enhances both evoked EPSCs and norepinephrine inhibition of glutamatergic afferent inputs in the nucleus of the solitary tract. J Neurosci 29:3093-102 |
