GABA MECHANISMS IN BARORECEPTOR INTEGRATION IN NTS

这项提议的总体目标是更好地理解大脑是如何整合从动脉压力感受器接收到的信息的。这种理解提供了对正常和病理情况下中枢神经系统如何调节血压和心率的见解。在这个奖项的任期内，我们已经证明了负责压力感受器传入输入整合的生理和药理学机制在慢性高血压动物中发生了改变。这种竞争性更新的具体目标是进一步定义这些变化的性质、时间进程和功能意义。为此，研究人员设计了一些实验来验证一个普遍假设，即在慢性肾包裹性高血压中观察到的动脉压力反射的中心重置是通过抑制NTS内的传播来介导的，至少部分是这样。在此奖项任期内，以前的工作提供了对高血压发生的特定改变的见解；因此，提出了4个具体目标来检验这些研究产生的假设。特异性目的1：慢性高血压与NTS中GABAA介导的抑制增加有关。这种抑制是NTS中gaba能神经元放电增加的结果。这些gaba能神经元抑制整合压力感受器传入输入的其他NTS神经元；因此，这些变化有助于NTS神经元反应的钝化和反射重置。特异性目的2：慢性高血压诱导接受单突触主动脉神经输入的NTS神经元突触后GABAB受体表达增加。这种GABAB受体功能的增加有助于慢性高血压患者NTS神经元反应和反射重置的减弱。特异性目的3：慢性高血压大鼠NTS中GABAA和GABAB机制的改变是由动脉压力感受器和心肺机械感受器的外周传入输入的强直性升高引起的。特异性目的4：与正常高血压大鼠相比，慢性高血压大鼠在静息动脉压水平下活跃的NTS神经元数量和响应逐渐升高的压力而激活的神经元数量增加。高血压患者NTS的压力感受器传入输入水平升高。据推测，在慢性高血压期间，NTS神经元的生理和药理学发生改变，导致抑制增强并抵消传入输入的升高。这使NTS神经元放电正常化，从而使反射增益正常化。这些适应赋予高压反射缓冲能力，否则在高血压中可能会大大降低。因此，了解诱导和支持这些适应的机制将对我们理解高血压的心血管调节具有重要意义。

The overall goal of this proposal is to gain a better understanding of how the brain integrates the information it receives from the arterial baroreceptors. Such understanding provides insights into how the central nervous system regulates blood pressure and heart rate under normal and pathological situations. During the tenure of this award we have shown that the physiological and pharmacological mechanisms responsible for the integration of baroreceptor afferent inputs are altered in chronically hypertensive animals. The specific goal of this competitive renewal is to further define the nature, the time course and the functional significance of these alterations. To this end, experiments have been designed to test the general hypothesis that the central resetting of the arterial baroreflex observed in chronic renal wrap hypertension is mediated, at least in part, by inhibition of transmission within the NTS. Previous work during the tenure of this award has provided insights into specific alterations that occur in hypertension; therefore 4 specific aims are proposed to test hypotheses that arise from these studies. Specific Aim 1: Chronic hypertension is associated with increased GABAA mediated inhibition within the NTS. This inhibition is the result of an increase in the discharge of GABAergic neurons in the NTS. These GABAergic neurons inhibit other NTS neurons that integrate baroreceptor afferent inputs; therefore these changes contribute to a blunting of NTS neuronal responses and reflex resetting. Specific Aim 2: Chronic hypertension induces increased post-synaptic expression of GABAB receptors in NTS neurons receiving monosynaptic aortic nerve inputs. This increase in GABAB receptor function contributes to a blunting of NTS neuronal responses and reflex resetting in chronic hypertension. Specific Aim 3: Alterations in GABAA and GABAB mechanisms within the NTS of chronically hypertensive rats result from a tonically elevated level of peripheral afferent input from the arterial baroreceptors and cardiopulmonary mechanoreceptors. Specific Aim 4: In chronically hypertensive rats the number of NTS neurons active at the resting level of arterial pressure and the number of neurons activated in response to graded increases in pressure is increased compared to the number of neurons active and activated in normotensive rats. The level of baroreceptor afferent input to the NTS is increased in hypertension. It is hypothesized that during chronic hypertension alterations occur in the physiology and pharmacology of NTS neurons that result in enhanced inhibition and counteract the elevated afferent input. This normalizes NTS neuronal discharge and thereby reflex gain. These adaptations confer a baroreflex buffering capability that might otherwise be greatly reduced in hypertension. Therefore, understanding the mechanisms that induce and underlie these adaptations will be of great importance in our understanding of cardiovascular regulation in hypertension.