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

定义 16p11.2 缺失对纹状体多巴胺受体 D1 表达神经元奖赏反应的分子影响

基本信息

批准号：
10750328
负责人：
Benjamin Kelvington
金额：
$ 3.49万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10750328
关键词：
16p11.2 Address Affect Affinity Chromatography Animals Attention deficit hyperactivity disorder Behavior Brain region Calcium Calcium Signaling Cell Nucleus Cell physiology Chronic Consumption Copy Number Polymorphism Corpus striatum structure Data Disease Disease model Dopamine Dopamine D1 Receptor Etiology Exhibits Fiber Fluorescence Functional disorder Gene Expression Gene Expression Regulation Genes Genetic Transcription Genomic Segment Goals Histones Human Impairment Individual Intellectual functioning disability Intervention Knowledge Learning Mass Spectrum Analysis Mediating Mediator Modeling Molecular Mus Neurobiology Neurodevelopmental Disorder Neurons Penetrance Phase Phenotype Photometry Play Population Post Translational Modification Analysis Post-Translational Protein Processing Process Recurrence Regulator Genes Research Rewards Ribosomes Role Signal Induction Signal Transduction Sorting Stimulus Study models Sucrose Support System Synapses System Techniques Tissue-Specific Gene Expression Transcript Transgenic Animals Translating Work autism spectrum disorder behavioral phenotyping effective intervention experience experimental study extracellular histone modification in vivo insight male mouse model neurotransmission novel response reward processing sex touchscreen transcriptome transcriptome sequencing translatome

项目摘要

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.

项目摘要/摘要神经发育障碍（NDDS），例如自闭症谱系障碍，注意力缺陷多动症疾病和智力残疾是一组具有挑战性的疾病，具有较大的表型重叠和主要未知病因。缺乏针对最大受损的有效介入策略 NDD的各个方面，主要是由于缺乏有关其潜在的细胞和分子机制的知识。删除16p11.2区域的一份副本会导致NDD在人类中的高渗透率，因为它可以忠实地在小鼠中建模，这种缺失是NDD神经生物学研究的最喜欢的模型。小鼠缺乏与人类16p11.2区域（16p del）的基因组区域直系同源的副本表现出行为与人类NDD相关的表型，包括奖励学习中的男性特异性赤字。这种赤字是当在多巴胺受体D1表达培养基神经元中特别诱导16p del时概括纹状体的（D1+ MSN），这意味着这种神经元人群对于奖励系统功能障碍至关重要 NDD。众所周知，D1+ MSN在信号奖励和学习动作奖励关联中起关键作用，但是，对于这些细胞的功能如何改变了NDD，知之甚少。在这里，我们建议使用16p del 描绘D1+ MSN在NDD背景下对奖励的响应的模型。神经元反应的能力已知经验和存储信息需要仔细调节的基因表达。在此过程中神经元信号被转导到核，其中分子机制促进了特定的表达产物又改变神经元功能的基因。这些分子机制的破坏是强烈的与NDD的发生有关，以及多个证据表明基因的调节 16p del小鼠中的表达被破坏。该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 D1+ MSN在16p del小鼠的纹状体中的响应。在特定目标1中，我们将表征基因表达在这种神经元人群中奖励引起的变化。在特定的目标2中，奖励依赖性组蛋白后将表征16p del D1+ MSN中的翻译修改。最后，在特定的目标3中，我们将概述在触摸屏操作任务中，这些神经元中钙信号传导的改变。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，该模型将提供关键洞悉整个NDD范围内观察到的与奖励相关的行为表型。