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Tony
G. Waldrop, PhD
Physiological and molecular properties of hypoxia-sensitive neurons located in the ventrolateral medulla and caudal hypothalamus are being investigated.Electrophysiological and molecular studies are being performed on both posterior hypothalamic (PH) and ventrolateral medullary (VLM) neurons that are sensitive to changes in PCO2 or PO2. The purpose of these studies is to identify the "central hypoxic chemoreceptor" that has long been postulated but not isolated to a specific neuroanatomical site. Our previous in vitro studies with whole cell patch recordings demonstrated that these neurons are excited by hypoxia.
Excitation consists of a depolarization, a decrease in input resistance, and an increased frequency of discharge. This response changes as a function of age (i.e., neurons from neonatal animals are less likely than those from juvenile animals to be excited by hypoxia). Pharmalogical and northern blot analyses have indicated that this excitatory response is associated with changes in sodium current. Molecular techniques are being used to evaluate the mRNA of single, hypoxia-sensitive neurons.
A second area is concerned with a hypothalamic abnormality that likely contributes to the elevated blood pressure present in spontaneously hypertensive rats. Our studies have shown that spontaneously hypertensive rats (SHR) possess an alteration in the GABAergic input to posterior hypothalamic neurons. Since this area exerts an excitatory influence upon arterial pressure and heart rate, loss of this GABAergic mechanism may contribute to origination and/or maintenance of an elevated pressure in these rats. Our electrophysiological studies have found that posterior hypothalamic neurons studied both in vivo and in vitro (brain slice preparation) have an altered discharge pattern and elevated firing frequency in SHRs compared to normotensive rats. Immunocytochemical examination revealed that there were 50% fewer neurons containing glutamic acid decarboxylase, the GABA synthesizing enzyme, in the caudal hypothalamus of the SHR as compared to hypertensive rats. Northern blot analysis found a 33% reduction in GAD mRNA in the caudal hypothalamus of the SHR. Recent studies have shown that chronic exercise results in a lowering of arterial pressure which is accompanied by an upregulation of GAD gene expression in SHRs.
Fan, Y.-P., E.M. Horn and T.G. Waldrop (2000). Biophysical characterization of rat caudal hypothalamic neurons: Calcium channel contribution to excitability. J Neurophysiol 84:2896-2903. Horn, E.M. and T.G. Waldrop (2000). Hypoxic augmentation of fast-inactivating and persistent sodium currents in rat caudal hypothalamic neurons. J Neurophysiol 84:2572-2581. Kramer, J.M., J.A. Beatty, H.R. Little, E.D. Plowey and T.G. Waldrop (2001). Chronic exercise alters caudal hypothalamic regulation of the cardiovascular system in hypertensive rats. Am J Physiol 280:R389-R397. Little, H.R., J.M. Kramer, J.A. Beatty and T.G. Waldrop (2001) Chronic exercise increases GAD gene expression in the caudal hypothalamus of spontaneously hypertensive rats. Mol Brain Res 95:48-54. Kramer, J.M., T. Aragones and T.G. Waldrop (2001). Reflex cardiovascular responses originating in exercising muscles of mice. J Appl Physiol. 90(2):579-85. Kramer, J.M. and T.G. Waldrop (2001). Spontaneously hypertensive rats exhibit altered cardiovascular and neuronal responses to muscle contraction. Exp Physiol. 86(6):717-24. Kramer, J.M.,
J.A. Beatty, E.D. Plowey and T.G. Waldrop (2002). Exercise and hypertension:
a model for central neural plasticity.
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