This proposal represents a continuing effort to identify the cellular mechanisms which underlie the integration of peripheral, cardio- respiratory afferent inputs within the central nervous system. I will continue to investigate the integration of arterial chemoreceptor (CR) afferent inputs within the nucleus tractus solitarius (NTS), the initial site of termination of CR afferent fibers within the central nervous system. During the previous funding period the synaptic basis of CR afferent integration within NTS was examined. This proposal will extend these observations and begin an examination of the pharmacological mechanisms which underlie CR afferent integration within the NTS. Specifically, the role of two neurotransmitter receptors which have been implicated as possible mediators of CR evoked excitation of NTS neurons will be examined. A large body of evidence suggests that both excitatory amino acid and tachykinin receptors within NTS play a role in chemoreflex regulation of the cardiovascular and respiratory systems. This proposal will use two complimentary approaches to investigate the possible role of excitatory amino acid and tachykinin receptors in the integration of CR inputs within NTS in anesthetized rats. Extracellular recording and iontophoretic techniques will be used to examine NTS neurons receiving mono- and/or poly-synaptic CR inputs and determine the effects of excitatory amino acid and tachykinin receptor agonists and antagonists on (1) spontaneous discharge, (2) carotid sinus nerve evoked discharge and (3) CR evoked discharge. Intracellular recording techniques will be used to further study the integration of CR afferent inputs within NTS by examining (1) membrane potential responses to a graded series of CR stimuli and (2) if the response to activation of CR inputs is altered (enhanced) during and following high frequency stimulation of the carotid sinus nerve. Intracellular recording techniques will be used in combination with immunohistochemical techniques to determine morphology, axonal projection, and the anatomical relationships between tachykinin (Substance P) immunoreactive elements and NTS neurons receiving CR inputs at both the light and electron microscopic level. The immunohistochemical studies will provide insights into the anatomical substrates of afferent integration within NTS, while the iontophoretic studies will provide insights into the functional significance of neuroactive substances previously implicated in cardio-respiratory regulation. These studies will extend our understanding of physiological and pharmacological mechanisms mediating the central integration of CR afferent inputs. Such information is critical if we are to fully understand mechanisms by which the central nervous system regulates blood pressure and respiration in normal (e.g., exercise, sleep) and pathophysiological conditions (e.g., hypertension, hypoxia and hemorrhage).
|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|