Prenatal Ethanol Exposure and Nitric Oxide Signaling in Serotonin Neurons

项目摘要 产前乙醇暴露（PE）可导致胎儿酒精谱系障碍（FASD），其特征为： 严重的认知、运动缺陷和情绪障碍，包括严重的焦虑症。FASD影响高达5% 它对家庭、个人和社会造成了毁灭性的负担，使其成为世界上 这是美国和全世界最严重的健康问题。目前，FASD的有效治疗方法是 有限的，这强调了需要更好地了解神经机制的基础， 与FASD相关的行为缺陷。过去几十年的研究表明， 损害5-羟色胺（5-HT）系统的发育和功能。尽管人们普遍认为， 5-羟色胺（5-HT）系统的功能障碍在抑郁症和严重焦虑症中起主要作用 与FASD相关，PE改变中缝背核（DRn）5-HT神经元功能的机制 受影响的5-HT网络的确切位置仍然未知。为了解决这些重要的知识差距，我们 研究了PE对中缝背核（DRn）5-HT神经元功能的影响。的结果予以 研究已经确定，诱导焦虑表型的PE深刻地增加了DRn的活性 5-HT神经元，通过持续增强DRn中的多巴胺能传递。重要的是，一部小说 我们的初步机制研究发现，这些作用是由增强的一氧化氮（NO）介导的， 发信号。在这个应用程序中，我们将建立在这一进展和测试的新假设，增强 PE大鼠的氮能功能介导了多巴胺能传递到DRn 5-HT神经元的增强， 识别受影响的5-HT投射神经元的子集，并剖析介导焦虑的神经元网络 PE大鼠的表型。在目标1中，我们将检验增强的NO信号传导介导 增强DRn中的谷氨酸突触，并鉴定DRn 5-HT投射神经元的子集 影响。目的二：研究PE大鼠DRN 5-HT神经元的突触能输入。在目标3中， 我们将测试减少对DRn 5-HT神经元的特异性多巴胺能输入是否减轻PE大鼠的焦虑。 这种多学科的方法将确定介导5-HT系统功能障碍的细胞机制 并确定PE大鼠焦虑表型的神经回路。这些实验的结果 也将为未来的研究奠定基础，旨在开发有效的治疗情绪障碍 与FASD有关。

Project Summary Prenatal ethanol exposure (PE) causes fetal alcohol spectrum disorders (FASD), which is characterized by severe cognitive, motor deficits and mood disorders including, major anxiety disorder. FASD affects up to 5% of children and exerts a devastating burden on families, individuals and costs to the society making it one of the most significant health problems in the USA and worldwide. Currently, effective treatments of FASD are limited, which underscores the need for a better understanding of the neuronal mechanisms underpinning the behavioral deficits associated with FASD. Research conducted over the last decades has established that PE impairs the development and function of serotonin (5-HT) system. Although it is widely recognized that dysfunctions of the serotonin (5-HT) system play a major role in depression and major anxiety disorders associated with FASD, the mechanisms by which PE alters the function of dorsal raphe (DRn) 5-HT neurons and the precise 5-HT networks affected remain unknown. To address these important knowledge gaps, we have examined the impact of PE on the function of dorsal raphe (DRn) 5-HT neurons. The results of these studies have established that PE, which induces anxiety phenotype, profoundly, increases the activity of DRn 5-HT neurons, via a persistent potentiation of glutamatergic transmission in the DRn. Importantly, a novel finding of our preliminary mechanistic studies is that these effects are mediated by enhanced nitric oxide (NO) signaling. In this application, we will build on this progress and test the novel hypothesis that enhanced nitrergic function in PE rats mediates the potentiation of glutamatergic transmission onto DRn 5-HT neurons, identify the subset(s) of 5-HT projecting neurons affected, and dissect the neuronal networks mediating anxiety phenotype of PE rats. In Aim 1, we will test the hypothesis that enhanced NO signaling mediates the potentiation of glutamate synapses in the DRn, and identify the subset(s) of DRn 5-HT projecting neurons affected. In Aim 2, we will dissect the glutamatergic input(s) to DRn 5-HT neurons altered in PE rats. In Aim 3, we will test whether reducing specific glutamatergic inputs to DRn 5-HT neurons alleviates anxiety in PE rats. This multidisciplinary approach will identify the cellular mechanisms mediating the dysfunction of 5-HT system and define the neuronal circuitries underlying anxiety phenotype of PE rats. The outcome of these experiments will also lay the foundation for future studies aiming at developing effective therapy of mood disorders associated with FASD.