A novel paradigm to dissect the function connectivity in Shank3 autism model

剖析 Shank3 自闭症模型中功能连接的新范式

基本信息

批准号：
9244943
负责人：
YONG-HUI JIANG
金额：
$ 19.58万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-01-13 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9244943
关键词：
Amygdaloid structure Animal Model Animals Autistic Disorder Behavior Behavioral Biological Neural Networks Birds Brain Brain region Cells Complex Cues Development Disease model Dissection Electrophysiology (science)Engineering Etiology Exons FOS gene Face Genes Goals Hippocampus (Brain)Human Hypothalamic structure Impairment Injection of therapeutic agent Intervention Knock-in Mouse Knowledge Link Manuscripts Maps Mediating Methods Modeling Molecular Motor Mus Mutant Strains Mice Mutate Mutation Neurons Nucleus Accumbens Pattern Process Property Proteins Research Personnel Sensory Site Slice Social Behavior Social Interaction Structure Subfamily lentivirinae System Techniques Testing Thalamic structure Time Ventral Tegmental Area Virus Wild Type Mouse autism spectrum disorder base behavior test behavioral response follow-up in vivo innovation mouse model neural circuit neuroimaging novel optogenetics programs receptor relating to nervous system social social communication success tool

项目摘要

Despite significant advances in identifying genes implicated in ASD, the neural circuit mechanisms that contribute to impaired social behaviors and communication in ASD remain elusive. This lack of knowledge represents a critical gap in the development of circuity-based treatment. Social interactions demand complex neural computations, including sensory processing of social cues, decisions to determine appropriate behavioral responses, and planning and execution of the motor programs necessary to enact these behaviors. Using neuroimaging studies, the general structure of neural networks involving amygdala, hypothalamus, thalamus, ventral tegmental area, nucleus accumbens, and ventral hippocampus have been associated with “social circuitry”. However, their exact neuron ensembles and how they mediate social behaviors remains poorly defined. Our overarching hypothesis is that the functional connectivity of these circuits is altered in ASD. The neural process responsible for social behaviors most likely results from the emergent properties of transiently active neural ensembles in social behavior circuits. In this application, we propose, for the first time, to use novel and innovative tools that enable neurons in these ensembles to be permanently tagged and subsequently manipulated in the living animal. Combining recent advances of Dr. Yong-hui Jiang (PI) and Dr. Fan Wang’s (Co-investigator) groups creates a unique opportunity to explore this direction. Jiang’s group recently produced an autism model with Shank3 complete deficiency by deleting exon 4-22 (∆e4-22) that has strong “construct” and “face” validity for SHANK3-related ASD. Shank3∆e4-22-/- mice recapitulate the ASD-like behaviors with impairments in social interaction and communication, as well as aberrant functional connectivity. Wang’s group developed a highly innovative technique: Capturing Activated Neuronal Ensembles (CANE). This novel technique “captures” and “manipulates” neuronal ensembles in mouse brains during behavior interaction. Combining the best autism model and innovative techniques provides an unprecedented opportunity to explore the most important question in modeling autism. We hypothesize that the complete deficiency of Shank3 leads to altered neural ensembles in social circuitry that underlie the observed impaired social behaviors. Our objective is to use the CANE method to identify the neural ensembles that underlie autism behavior in Shank3 mouse model. The causality between impaired circuit and behaviors will be investigated by in vivo recording and optogenetic manipulation. Our study is first application of the CANE method to dissect the social circuity in a genetically modified ASD mouse model and represents the first step toward the development of circuit specific treatment for ASD. More importantly, the success of this project will support a paradigm shift in how we model autism, as well as delineate the circuitry for other behaviors.

尽管在识别ASD中实现的基因方面取得了重大进展，但神经回路机制的发展在ASD中有助于社会行为和沟通的损害仍然难以捉摸。缺乏知识代表了基于电路的处理的开发中的一个关键差距。社会互动需要复杂神经计算，包括社会提示的感官处理，决定适当的决定行为响应以及制定这些行为所必需的电机程序的计划和执行。使用神经影像学研究，涉及杏仁核，下丘脑的神经元网络的一般结构，丘脑，腹侧对盖区，伏隔核和腹侧海马与 “社会巡回赛”。但是，他们确切的神经元合奏以及它们如何介导社会行为仍然存在定义不佳。我们的总体假设是这些电路的功能连接性发生了变化 ASD。负责社会行为的神经过程很可能是由社会行为电路中的瞬时主动神经合奏。在此应用程序中，我们提出了第一个时间，使用新颖和创新的工具，使这些合奏中的神经元能够永久标记随后在活动物中操纵。结合了Yong-Hui Jiang博士（PI）和范·王（Fan Wang）博士（共同投资者）团体创造了一个独特的机会来探索这一方向。江的小组最近，通过删除具有Shank3完全缺陷的自闭症模型，通过删除具有具有的外显子4-22（∆E4-22）与Shank3相关的ASD的强大“结构”和“面部”有效性。 shank3ΔE4-22 - / - 小鼠概括了ASD样社交互动和沟通障碍的行为以及功能异常连接性。王的小组开发了一种高度创新的技术：捕获激活的神经元合奏（甘蔗）。这种新颖的技术“捕获”和“操纵”在老鼠大脑中的神经元合奏行为互动。结合最佳的自闭症模型和创新技术提供了前所未有的探索自闭症建模最重要的问题的机会。我们假设完整 Shank3的不足导致社会电路中的神经合奏发生了改变，这是观察到的受损社会行为。我们的目标是使用拐杖方法来识别基于 Shank3鼠标模型中的自闭症行为。电路和行为受损之间的因果关系将是通过体内记录和光遗传操作进行了研究。我们的研究是甘蔗的第一个应用在一般修改的ASD鼠标模型中剖析社交电路的方法，并表示第一步为了开发ASD电路特定处理。更重要的是，该项目的成功将支持我们对自闭症建模的方式的范式转变，并为其他行为描述电路。