Synaptic Adaptations Induced by Prenatal Alcohol Exposure

项目总结/摘要 产前酒精暴露（PAE）是一种常见的危险因素，使受试者易患一系列精神疾病。 疾病，特别是药物成瘾。由于对PAE引起的神经适应的理解模糊， 预防和治疗PAE诱导的疾病的选择有限。在这项研究中，一个三部分 关于PAE影响晚年成瘾风险的突触机制的假设将是 评估。这一假说的第一部分规定，一个主要的多巴胺能通路，起源于内侧 前额叶皮层（mPFC）和直接影响的主要神经元的人口在脑桥核 (NAc)PAE靶向于中等大小的多刺神经元（MSNs），以促进成瘾发展。 此外，mPFC的子区域针对NAc的不同隔室，边缘下mPFC（IL） 优先投射到NAc外壳和前边缘mPFC（PrL）到NAc核心;我们的第二个特征是 这一假说的观点是PAE诱导的突触改变是通路/投射特异性的。第三 我们假设的一个组成部分假设PAE导致NAc中异常的突触发育， 加速沉默突触（SS）的修剪/成熟，被认为是不成熟的突触能突触 含有稳定的NMDA受体（NMDARs），但缺乏稳定的AMPA受体（AMPAs）， 异常的成熟过程是由非典型的Ca 2+渗透性（CP）-AMPAR的募集引起的。 MSN。基于我们的初步数据，我们预测：（1）在IL-1中，SS的成熟/修剪加速， 与对照动物（产前对照）相比，PAE大鼠的壳突起，而不是PrL-核心 （2）PAE通过募集非典型CP-AMPAR影响SS的成熟/修剪， 而不是典型的Ca 2+不渗透性（CI）-AMPAR进入NAc中MSN上的兴奋性突触，以及（3） PAE使动物更容易寻求药物，这种作用可以通过操纵PAE来逆转。 诱导的特定兴奋性神经支配NAc的SS为基础的突触改变。这些假设将 采用最先进的技术进行测试，包括全细胞膜片钳，静脉内自我给药， 光遗传学、单细胞染色和棘标记。这项工作的结果将提供一个新颖和精确的 了解潜在的PAE引起的精神障碍，如物质， 滥用，并发现新的生物治疗目标。

PROJECT SUMMARY / ABSTRACT Prenatal alcohol exposure (PAE) is a common risk factor that predisposes subjects to an array of mental disorders, particularly drug addiction. Due to elusive understanding of PAE-elicited neuroadaptations, available options to prevent and treat PAE-induced disorders are limited. In this proposed research, a three-part hypothesis regarding the synaptic mechanisms by which PAE affects risk for addictions in later life will be evaluated. The first part of this hypothesis stipulates that a major glutamatergic pathway, originating in the medial prefrontal cortex (mPFC) and directly influencing the principal neuronal population in the nucleus accumbens (NAc), the medium-sized spiny neurons (MSNs), is targeted by PAE to promote addiction development. Additionally, sub-regions of the mPFC target distinct compartments of the NAc, with the infralimbic mPFC (IL) preferentially projecting to the NAc shell and the prelimbic mPFC (PrL) to the NAc core; a second feature of our hypothesis is the idea that PAE-induced synaptic alterations are pathway/projection-specific. The third component of our hypothesis postulates that PAE leads to aberrant synaptic development in the NAc by accelerating the pruning/maturation of silent synapses (SSs), thought to be immature glutamatergic synapses containing stable NMDA receptors (NMDARs) but lacking stable AMPA receptors (AMPARs), and that this abnormal maturational process results from the recruitment of atypical Ca2+-permeable (CP)-AMPARs in the MSNs. Based upon our preliminary data, we predict that (1) Maturation/pruning of SSs is accelerated in the IL- shell projections but not PrL-core from rats subjected to PAE, compared to control animals (prenatal control exposure, PCE), (2) PAE affects the maturation/pruning of SSs via the recruitment of atypical CP-AMPARs, rather than the typical Ca2+-impermeable (CI)-AMPARs into excitatory synapses on MSNs in the NAc, and (3) PAE predisposes animals to heightened drug-seeking, an effect that can be reversed by manipulating PAE- induced SS-based synaptic alterations in the specific excitatory innervation to the NAc. These hypotheses will be tested employing state-of-the-art techniques including whole-cell patch clamp, intravenous self-administration, optogenetics, single-cell staining and spine labeling. The outcome of this work will provide a novel and precise approach to understanding the neural mechanisms underlying PAE-induced mental disorders such as substance abuse, and to discovering novel biological targets for treatment.