Central nervous system plasticity in sympathoinhibition in pregnancy

描述(申请人提供)：在正常妊娠中，重置容量控制系统会保持较高的血容量，而动脉压力感受性反射控制交感神经流出是为了预防高血压，但会牺牲对低血压刺激的代偿反应(尽管心脏和血管系统的基线交感神经张力略有升高)。妊娠期严重高血压疾病的一个特点是缺乏这些适应和夸大的交感神经兴奋。P.I.S实验室的长期研究目标是了解卵巢激素对中枢神经系统交感神经活动控制的作用机制。当前项目的目标是确定：1.)如果怀孕与大脑中含有交感投射神经元的区域的抑制性输入的不同变化有关；如果一氧化氮(NO)对抑制性神经递质GABA对交感投射神经元的调制在怀孕和未怀孕大鼠之间有所不同；如果孕酮的神经活性类固醇代谢物，31-OH，DHP，有助于在含有交感前神经元的不同脑区对GABA能抑制的明显差异。提议的实验的一个优点是参与研究人员的不同专业知识，允许在整个动物、细胞种群、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对产妇死亡率(约占死亡人数的30%)和发病率有很大影响。因此，这些实验的结果对国家健康具有重要影响。公共卫生相关性：在发达国家，出血和高血压疾病约占孕产妇死亡的30%，而在欠发达国家，这一比例更高。控制血管收缩神经活动的主要适应发生在正常妊娠，尽管通常有益于胎儿和母亲的健康，但导致对直立性低血压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点是血管收缩活动过度。本申请中提出的实验旨在确定中枢神经系统对血管收缩神经的控制中妊娠诱导的适应机制，并与怀孕和分娩期间的母亲健康高度相关。

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.