GABA MECHANISMS IN BARORECEPTOR INTEGRATION IN NTS

这项提议的总体目标是更好地了解大脑如何整合从动脉压力感受器接收到的信息。这样的理解有助于深入了解中枢神经系统在正常和病理情况下如何调节血压和心率。在该奖项的任期内，我们已经表明，在慢性高血压动物中，负责整合压力感受器传入输入的生理和药理学机制发生了改变。这次竞争性更新的具体目标是进一步确定这些变化的性质、时间进程和功能意义。为此，我们设计了实验来检验一般的假设，即慢性肾包膜高血压时观察到的动脉压力感受性反射的中枢重置至少部分是通过抑制NTS内的传递来调节的。在该奖项的任期内，以前的工作已经为高血压中发生的特定变化提供了洞察力；因此，提出了4个具体目标来检验这些研究产生的假说。具体目的1：慢性高血压与孤束核内GABAA介导的抑制作用增加有关。这种抑制是由于NTS内GABA能神经元放电增加所致。这些GABA能神经元抑制其他整合压力感受器传入输入的NTS神经元；因此，这些变化有助于削弱NTS神经元的反应和反射重置。特定目的2：慢性高血压诱导接受单突触主动脉神经传入的NTS神经元突触后GABAB受体表达增加。这种GABAB受体功能的增强有助于慢性高血压患者NTS神经元反应的钝化和反射的重置。具体目标3：慢性高血压大鼠NTS内GABAA和GABAB机制的改变是由于动脉压力感受器和心肺机械感受器的外周传入输入水平升高所致。具体目的4：与正常血压大鼠相比，慢性高血压大鼠在静息血压水平活跃的NTS神经元数量和对压力阶段性增加而激活的神经元数量增加。高血压病患者NTS压力感受性传入传入水平升高。假设在慢性高血压期间，NTS神经元的生理和药理学发生改变，导致抑制作用增强，并抵消传入输入的增加。这使NTS神经元放电正常化，从而获得反射增益。这些适应赋予了压力反射缓冲能力，否则在高血压时这种能力可能会大大降低。因此，了解诱导和支持这些适应的机制对于我们理解高血压的心血管调节是非常重要的。

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.