Synaptic Adaptations Induced by Prenatal Alcohol Exposure

产前酒精暴露诱导的突触适应

• 批准号: 9900696
• 负责人: Yao-Ying Ma
• 金额: $ 35.08万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-20 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9900696
• 关键词: AMPA Receptors; Address; Affect; Alcohols; Animals; Behavior; Behavioral; Biological; Brain; Cells; Cocaine; Control Animal; Data; Dendritic Spines; Development; Developmental Course; Disease; Drug Addiction; Elderly; Electrophysiology (science); Evaluation; Excitatory Synapse; Fetal Alcohol Exposure; Glutamates; In Vitro; Individual; Injections; Intravenous; Label; Life; Medial; Mediating; Mental disorders; Metabolic; Modeling; Morbidity - disease rate; Morphology; N-Methyl-D-Aspartate Receptors; Neurons; Nucleus Accumbens; Optics; Organism; Outcome; Pathologic; Pathway interactions; Permeability; Pharmaceutical Preparations; Pharmacology; Population; Predisposing Factor; Prefrontal Cortex; Process; Protocols documentation; Rattus; Research; Risk; Risk Factors; Risk-Taking; Rodent; Role; Self Administration; Shapes; Stains; Substance abuse problem; Synapses; Techniques; Testing; Time; Vertebral column; Work; addiction; alcohol exposure; base; density; drug abuse vulnerability; high risk; improved; nerve supply; neuroadaptation; neuromechanism; novel; optogenetics; patch clamp; postsynaptic; prenatal; prenatal experience; prevent; recruit; voltage

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.

项目概要/摘要 产前酒精暴露（PAE）是一种常见的危险因素，使受试者容易出现一系列精神问题。 疾病，特别是毒瘾。由于对 PAE 引起的神经适应的理解难以捉摸，可用 预防和治疗 PAE 引起的疾病的选择有限。在这项拟议的研究中，由三部分组成 关于 PAE 影响晚年成瘾风险的突触机制的假设将是 评价。该假说的第一部分规定，一条主要的谷氨酸能途径，起源于内侧 前额皮质 (mPFC) 并直接影响伏隔核中的主要神经元群 PAE 的目标是中型多棘神经元 (NAc)，以促进成瘾的发展。 此外，mPFC 的子区域针对 NAc 的不同区室，其中边缘下 mPFC (IL) 优先投射到 NAc 壳，前边缘 mPFC (PrL) 优先投射到 NAc 核心；我们的第二个特点 假设是 PAE 诱导的突触改变是路径/投射特异性的。第三个 我们的假设的一部分假设 PAE 通过以下方式导致 NAc 中突触的异常发育： 加速沉默突触（SS）的修剪/成熟，被认为是不成熟的谷氨酸能突触 含有稳定的 NMDA 受体（NMDAR）但缺乏稳定的 AMPA 受体（AMPAR），并且这 异常的成熟过程是由非典型 Ca2+ 通透性 (CP)-AMPAR 的募集引起的 MSN。根据我们的初步数据，我们预测 (1) SS 的成熟/修剪在 IL- 与对照动物（产前对照）相比，接受 PAE 的大鼠的壳投射而非 PrL 核心 (2) PAE 通过招募非典型 CP-AMPAR 影响 SS 的成熟/修剪， 而不是典型的 Ca2+ 不可渗透 (CI)-AMPAR 进入 NAc 中 MSN 上的兴奋性突触，并且 (3) PAE 使动物更容易寻求药物，这种效应可以通过操纵 PAE 来逆转 在 NAc 的特定兴奋性神经支配中诱导基于 SS 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、静脉自我给药、 光遗传学、单细胞染色和脊柱标记。这项工作的成果将提供一种新颖而精确的方法 了解 PAE 引起的精神障碍（例如物质）背后的神经机制的方法 滥用，并发现新的生物治疗靶点。