Prenatal Ethanol Exposure and Nitric Oxide Signaling in Serotonin Neurons

项目摘要 产前酒精暴露(PE)可引起胎儿酒精谱障碍(FASD)，其特征为 严重的认知、运动障碍和情绪障碍，包括严重的焦虑症。FASD影响高达5% 并对家庭、个人和社会造成毁灭性的负担，使其成为 美国和世界范围内最严重的健康问题。目前，FASD的有效治疗方法是 有限，这强调了需要更好地了解支撑 与FASD相关的行为缺陷。过去几十年进行的研究已经证实， 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-羟色胺)系统功能障碍在抑郁症和严重焦虑症中起主要作用 PE改变中缝背核(DRN)5-羟色胺神经元功能的机制与FASD相关 而受影响的确切5-羟色胺网络仍不清楚。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-羟色胺(5-HT)神经元功能的影响。这些研究的结果 研究证实，引发焦虑表型的体育可以显著增加DRN的活性 5-羟色胺能神经元，通过持续增强DRN中的谷氨酸能传递。重要的是，一部小说 我们的初步机制研究发现，这些效应是由增强的一氧化氮(NO)介导的。 发信号。在这个应用程序中，我们将在这一进展的基础上，测试增强的新假设 PE大鼠的硝能功能介导谷氨酸能传递到DRN 5-羟色胺神经元的增强， 确定受影响的5-羟色胺投射神经元的亚群(S)，并解剖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信号介导 DRN内谷氨酸突触的增强和DRN 5-羟色胺投射神经元的亚群(S)的鉴定 受影响。在目的2中，我们将解剖谷氨酸能传入(S)对PE大鼠DRN5-羟色胺神经元的改变。在《目标3》中， 我们将测试减少对DRN 5-HT神经元的特定谷氨酸能输入是否可以缓解PE大鼠的焦虑。 这一多学科的方法将确定5-羟色胺系统功能障碍的细胞机制 明确PE大鼠焦虑表型的神经回路。这些实验的结果 也将为未来旨在开发有效治疗情绪障碍的方法的研究奠定基础 与FASD相关。

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.