GABA MECHANISMS IN BARORECEPTOR INTEGRATION IN NTS

这项建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的信息。 这种理解提供了对中枢神经系统如何在正常和病理情况下调节血压和心率的见解。 在这个奖项的任期内，我们已经表明，负责整合压力感受器传入输入的生理和药理学机制在慢性高血压动物中被改变。这一竞争性更新的具体目标是进一步确定这些改造的性质、时间进程和功能意义。 为此，设计了实验来测试以下一般假设：在慢性肾包裹高血压中观察到的动脉压力反射的中枢重置至少部分是通过抑制NTS内的传输来介导的。 在该奖项的任期内，以前的工作提供了对高血压发生的具体变化的见解;因此，提出了4个具体目标来测试这些研究中产生的假设。 具体目的1：慢性高血压与NTS内GABAA介导的抑制增加相关。 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。 具体目标二：慢性高血压诱导接受单突触主动脉神经输入的NTS神经元中GABAB受体突触后表达增加。 这种GABAB受体功能的增加有助于慢性高血压中NTS神经元反应的钝化和反射重置。 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。 具体目标4：在慢性高血压大鼠中，与血压正常大鼠中活跃和激活的神经元数量相比，在动脉压的静息水平下活跃的NTS神经元数量和响应于压力分级增加而激活的神经元数量增加。高血压时，压力感受器传入神经传入到孤束核的水平增加。 据推测，在慢性高血压期间，NTS神经元的生理学和药理学发生改变，导致增强的抑制和抵消升高的传入输入。 这使NTS神经元放电正常化，从而使反射增益正常化。 这些适应赋予压力反射缓冲能力，否则可能会大大降低高血压。 因此，了解这些适应的诱导和基础的机制将是非常重要的，在我们的心血管调节高血压的理解。

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.