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

尽管在确定与ASD有关的基因方面取得了重大进展，但神经回路机制， 导致ASD中受损的社会行为和沟通仍然难以捉摸。人们缺乏了解 代表了基于回路的治疗发展中的关键差距。社会互动需要复杂的 神经计算，包括社会线索的感官处理，决定，以确定适当的 行为反应，以及制定这些行为所需的运动程序的计划和执行。 利用神经影像学研究，涉及杏仁核，下丘脑， 丘脑、腹侧被盖区、中脑核和腹侧海马与 “社交电路”然而，它们确切的神经元集合以及它们如何介导社会行为仍然存在 定义不好。我们的首要假设是，这些回路的功能连接在 自闭症负责社会行为的神经过程最有可能是由 社会行为回路中短暂活跃的神经系统。在本申请中，我们提出，首先 时间，使用新颖和创新的工具，使神经元在这些合奏，以永久标记 随后在活体动物中进行操作。结合Jiang Yong-hui博士（PI）的最新进展， 博士Fan Wang（合作研究者）的团队为探索这一方向创造了一个独特的机会。姜氏集团 最近通过删除外显子4-22（外显子4 -22）产生了Shank 3完全缺陷的自闭症模型， 对SHANK 3相关ASD具有较强的“结构”和“表面”效度。Shank 3嵌合体4 -22-/-小鼠再现了ASD样 行为与社会交往和沟通障碍，以及异常的功能 连通性。Wang的团队开发了一种高度创新的技术：捕获激活的神经元集合 （CANE）.这项新技术“捕获”和“操纵”小鼠大脑中的神经元集合， 行为互动结合最好的自闭症模型和创新技术， 有机会探索自闭症建模中最重要的问题。我们假设完整的 Shank 3的缺乏会导致社会回路中的神经集合改变，这些神经集合是观察到的受损的 社会行为我们的目标是使用CANE方法来识别神经系综， Shank 3小鼠模型中的自闭症行为。受损回路与行为之间的因果关系将是 通过体内记录和光遗传学操作研究。本研究是CANE的首次应用 一种方法来剖析社会电路在遗传修饰的ASD小鼠模型，并代表了第一步 发展针对ASD的回路特异性治疗。更重要的是，该项目的成功将 支持我们如何模拟自闭症的范式转变，以及描绘其他行为的电路。

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.