Project 1 - Developmental Exposure Alcohol Research Center

中枢神经系统的发育是一个长期的过程；然而，有两个值得注意的时期 对酒精毒性的脆弱性--在胎儿和青少年发育期间。这些时间也是 这对临床非常重要，因为许多人在胎儿和青春期接触过酒精。这个 胎儿和青少年正在进行的发育事件是完全不同的，因此乙醇诱导的潜在 变化也各不相同。胎儿发育和青春期的精液事件是定义 细胞的命运和树突的生长和细化。本研究将探索以下影响 通过检验假设：(1)乙醇通过改变中枢神经系统的组成来影响中枢神经系统的组成 未确定的神经元前体细胞的命运，(2)乙醇影响重塑的突触连接 在青春期以一种时间依赖的方式，以及(3)青春期的可塑性是由变化启动的 在胎儿发育过程中，青春期的这种变化建立了大脑结构的长期变化 在成人身上。重点将放在大脑皮层，因为它对学习等活动至关重要， 记忆和执行功能被认为是酒精的行为目标。这些研究将利用 转基因小鼠具有选定的神经元群体，即第V层的锥体神经元，内源性 荧光。研究将确定(1)胎儿酒精暴露对神经元命运的影响以及 转录因子Foxg1在这一过程中的作用，(2)青少年酒精暴露的影响 树突状细胞、脊髓和突触的可塑性以及兴奋性和抑制性神经递质系统的作用 在可塑性方面，以及(3)胎儿和额外的青春期接触是否结合在一起 大脑皮质结构可能发生永久性变化。因此，该项目的目标是测试“酒精中毒 “生成器”假说是引弧的核心--胎儿编程建立成人大脑结构 青少年接触乙醇会加剧这一过程。

The central nervous system develops over a protracted period; yet, there are two times of notable vulnerability to ethanol toxicity- during fetal and adolescent development. These are also times that are of critical clinical importance because many are exposed to alcohol during fetal and adolescent life. The ongoing developmental events in the fetus and adolescent are quite different, thus the potential for ethanolinduced changes also differ. Seminal events in fetal development and during adolescence are the definition of cell fate and dendritic growth and refinement, respectively. The present study will explore the effects of ethanol on these processes by testing the hypotheses that (1) ethanol affects CNS composition by altering the fates of undetermined neuronal progenitors, (2) ethanol affects synaptic connections that are remodeled during adolescence in a time-dependent manner, and (3) plasticity in the adolescent is primed by alterations in fetal development and that such changes in the adolescent establish long-term changes in brain structure in the adult. The focus will be the cerebral cortex because it is critical for activities such as learning, memory, and executive function, acknowledged behavioral targets of ethanol. These studies will exploit transgenic mice that have a select population of neurons, pyramidal neurons in layer V, that endogenously fluoresce. Studies will determine (1) the effects of fetal ethanol exposure on neuronal fate and the contribution of the transcription factor Foxgl in that process, (2) the effects of adolescent ethanol exposure on dendritic, spine, and synaptic plasticity and the role of excitatory and inhibitory neurotransmitter systems in that plasticity, and (3) whether fetal and additional adolescent exposure combine for greater and potentially permanent changes in cortical structure. Thus, the goal of this project is to test the "alcoholism generator" hypothesis central to the DEARC- that fetal programming sets up the structure of the adult brain and that this process is exacerbated by adolescent exposure to ethanol.