Defining the molecular impact of 16p11.2 deletion on reward response in striatal dopamine receptor D1-expressing neurons

项目总结/摘要 神经发育障碍（NDD），如自闭症谱系障碍，注意力缺陷多动障碍 障碍和智力残疾是一组具有挑战性的条件，具有很大的表型重叠， 主要是未知的病因。缺乏有效的干预策略，以针对最有损害的 NDD的各个方面，很大程度上是由于缺乏对其基本细胞和分子机制的了解。 16p11.2区域的一个拷贝的缺失导致人类中NDD的高表达率，并且因为它可以 在小鼠中被忠实地建模，这种缺失是用于NDD的神经生物学研究的有利模型。缺乏小鼠 与人16p11.2区域（16 pDEL）直向同源的基因组区域的一个拷贝表现出行为 与人类NDD相关的表型，包括奖励学习中的男性特异性缺陷。这一赤字是 当在表达多巴胺受体D1的中型多棘神经元中特异性诱导16 p DEL时， (D1+ MSNs）的纹状体，暗示这一神经元群体作为关键的奖励系统功能障碍， NDD。已知D1+ MSN在发出奖励信号和学习动作-奖励关联方面发挥关键作用， 但是对于这些细胞的功能在NDD中是如何改变的知之甚少。在这里，我们建议使用16 p DEL 模型来描述D1+ MSN如何在NDD的背景下对奖励做出反应。神经元的反应能力 已知体验和储存信息需要仔细调节基因表达。在此过程中 神经元信号被传递到细胞核，在细胞核中分子机制促进特异性 基因的产物反过来改变神经元的功能。这些分子机制的破坏是强烈的 与NDD的发生有关，多项证据表明，基因调控 在16 pDEL小鼠中表达被破坏。本提案中概述的实验将使用最先进的 转基因动物和分析技术，以研究控制奖励的分子机制 16 p DEL小鼠纹状体中D1+ MSN的反应。在具体目标1中，我们将描述基因表达 在这个神经元群体中由奖励引起的变化。在特定目标2中，奖励依赖性组蛋白后 将表征16 p DEL D1+ MSN中的翻译修饰。最后，在具体目标3中，我们将概述 在触摸屏操作任务期间这些神经元中钙信号的改变。这项工作有望揭示 NDD模型中奖励系统功能障碍的分子机制，这将提供关键的 深入了解在整个NDD谱中观察到的奖励相关行为表型。

PROJECT SUMMARY/ABSTRACT Neurodevelopmental disorders (NDDs) such as Autism Spectrum Disorder, Attention Deficit Hyperactivity Disorder, and Intellectual Disability are a challenging set of conditions with large phenotypic overlap and predominantly unknown etiology. There is a lack of effective interventional strategies to target the most impairing aspects of NDDs, owing largely to a lack of knowledge about their underlying cellular and molecular mechanisms. Deletion of one copy of the 16p11.2 region results in a high penetrance of NDDs in humans, and because it can be faithfully modeled in mice, this deletion is a favored model for the neurobiological study of NDDs. Mice lacking one copy of the genomic region orthologous to the human 16p11.2 region (16p DEL) exhibit behavioral phenotypes with relevance to human NDDs including a male-specific deficit in reward learning. This deficit is recapitulated when 16p DEL is induced specifically in dopamine receptor D1-expressing medium spiny neurons (D1+ MSNs) of the striatum, implicating this neuronal population as critical to reward system dysfunction in NDDs. D1+ MSNs are known to play a critical role in signaling reward and learning action-reward associations, but little is known about how the function of these cells is altered in NDDs. Here, we propose to use the 16p DEL model to delineate how D1+ MSNs respond to reward in the context of NDDs. The ability of neurons to respond to experience and store information is known to require carefully regulated gene expression. During this process neuronal signals are transduced to the nucleus where molecular mechanisms facilitate the expression of specific genes whose products in turn alter neuronal function. Disruptions of these molecular mechanisms are strongly associated with the occurrence of NDDs, and multiple pieces of evidence suggest that the regulation of gene expression is disrupted in 16p DEL mice. The experiments outlined in this proposal will use state-of-the-art transgenic animals and analytical techniques to investigate the molecular mechanisms controlling the reward response of D1+ MSNs in the striatum of 16p DEL mice. In Specific Aim 1, we will characterize gene expression changes induced by reward in this neuronal population. In Specific Aim 2, reward-dependent histone post- translational modifications in 16p DEL D1+ MSNs will be characterized. Finally, in Specific Aim 3, we will outline alterations of calcium signaling in these neurons during a touchscreen operant task. This work promises to reveal the molecular mechanisms underlying reward system dysfunction in an NDD model, which will provide critical insight into the reward-related behavioral phenotypes observed throughout the spectrum of NDDs.