Central nervous system plasticity in sympathoinhibition in pregnancy

描述（由申请人提供）：在正常妊娠中，容量控制系统的重置维持升高的血容量，交感神经流出的动脉压力感受器反射控制适于防止高血压，以牺牲对膨胀刺激的代偿性反应为代价（尽管心脏和脉管系统的基线交感神经张力轻度升高）。妊娠期严重高血压疾病的一个标志是缺乏这些适应性和过度的交感神经兴奋。P.I.研究的长期目标。的实验室是为了了解卵巢激素对中枢神经系统控制交感神经活动的影响机制。本项目的目的是确定：1。如果怀孕与含有交感投射神经元的大脑区域的抑制性输入的差异变化有关; 2.）一氧化氮（NO）对交感神经投射神经元上的抑制性神经递质GABA的调节是否在妊娠和非妊娠大鼠之间不同;和3.）如果孕酮的神经活性类固醇代谢物31-OH，DHP有助于在含有前交感神经元的不同脑区域中GABA能抑制的明显差异。拟议实验的优势在于参与研究者的各种专业知识，这允许在整个动物，细胞群，单细胞和分子水平上进行多层次的方法。妊娠和分娩期间的出血和高血压疾病是孕产妇死亡率（约占死亡人数的30%）和发病率的重要原因。因此，这些实验的结果具有重要的国家健康意义。公共卫生相关性：在发达国家，出血和高血压疾病占孕产妇死亡的30%左右，在欠发达国家，这一比例甚至更高。在正常妊娠中发生控制血管收缩神经活动的主要适应性变化，尽管通常对胎儿和母体健康有益，但会导致对直立性和出血性低血压的易感性增加。严重的妊娠期高血压疾病的特征是血管收缩活性增强。在本申请中提出的实验被设计为确定在血管收缩神经的中枢神经系统控制中妊娠诱导的适应的机制，并且与妊娠和分娩期间的产妇健康高度相关。

DESCRIPTION (provided by applicant): In normal pregnancy resetting of volume control systems maintains elevated blood volume, and arterial baroreflex control of sympathetic outflow is adapted to protect against hypertension, at the expense of compensatory responses to hypotensive stimuli (although baseline sympathetic tone to the heart and vasculature is mildly elevated). A hallmark of serious hypertensive disorders in pregnancy is the lack of these adaptations and exaggerated sympathoexcitation. The long term goal of research in the P.I.'s laboratory is to understand mechanisms for effects of ovarian hormones on central nervous system control of sympathetic nerve activity. Aims of the current project are to determine: 1.) If pregnancy is associated with differential changes in inhibitory inputs to regions of the brain containing sympathetic projection neurons; 2.) if nitric oxide (NO) modulation of the inhibitory neurotransmitter GABA on sympathetic projection neurons differs between pregnant and nonpregnant rats; and 3.) if the neuroactive steroid metabolite of progesterone, 31-OH, DHP, contributes to apparent differences in GABAergic inhibition in different brain regions containing presympathetic neurons. A strength of the proposed experiments is the varied expertise of participating investigators which allows for a multilevel approach at the whole animal, cell population, single cell, and molecular level. Hemorrhage and hypertensive disorders during pregnancy and delivery contribute significantly to maternal mortality (~30% of deaths) and morbidity. Thus, results from these experiments have important national health implications. PUBLIC HEALTH RELEVANCE: Hemorrhage and hypertensive disorders account for ~ 30% of maternal deaths in developed countries and this percentage is even greater in less developed countries. Major adaptations in control of vasoconstrictor nerve activity occur in normal pregnancy and, although generally beneficial for fetal and maternal health, result in increased susceptibility to orthostatic and hemorrhagic hypotension. Serious hypertensive disorders of pregnancy are characterized by exaggerated vasoconstrictor activity. Experiments proposed in this application are designed to determine mechanisms for pregnancy-induced adaptations in central nervous system control of vasoconstrictor nerves and are highly relevant to maternal health during pregnancy and delivery.