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

尽管在识别与ASD有关的基因方面取得了重大进展，但神经回路机制 导致社交行为受损，自闭症患者的沟通仍然难以捉摸。这种对知识的缺乏 代表了以迂回为基础的治疗发展中的一个严重差距。社交互动需要复杂性 神经计算，包括对社会线索的感觉处理，决定适当的 行为反应，以及制定这些行为所必需的运动程序的计划和执行。 利用神经成像研究，涉及杏仁核、下丘脑、 丘脑、腹侧被盖区、伏隔核和腹侧海马区与 “社交网络”。然而，它们确切的神经元集合以及它们如何调节社会行为仍然存在 定义不明确。我们最重要的假设是，这些电路的功能连接性在 ASD.负责社会行为的神经过程很可能是由于 社会行为环路中短暂活跃的神经集合。在本申请中，我们首先提出 时间，使用新颖和创新的工具，使这些集合中的神经元能够被永久标记 然后在活着的动物身上进行操作。结合江永辉博士的最新进展和 王凡博士的团队为探索这一方向创造了一个独特的机会。江氏群 最近通过删除外显子4-22(∆e4-22)产生了一个具有Shank3完全缺陷的自闭症模型，该模型具有 与SHANK3相关的ASD具有较强的“构念”和“面子”效度。SHANK3∆e4-22-/-小鼠概括了ASD样 在社交和沟通方面有障碍的行为，以及功能异常 连通性。王的团队开发了一种高度创新的技术：捕捉激活的神经元集合 (甘蔗)。这项新技术“捕捉”并“操纵”了小鼠大脑中的神经元群。 行为互动。将最好的自闭症模型和创新技术相结合，提供了前所未有的 探索自闭症模型中最重要的问题的机会。我们假设完整的 Shank3的缺失导致观察到的受损患者背后的社会回路中的神经集合发生改变 社会行为。我们的目标是使用CANES方法来识别作为基础的神经集合 Shank3小鼠模型中的自闭症行为。受损的电路和行为之间的因果关系将是 通过活体记录和光遗传操作进行研究。我们的研究是甘蔗的首次应用。 在转基因ASD小鼠模型中解剖社会回路的方法，并代表了第一步 走向ASD的电路特异性治疗的发展。更重要的是，这个项目的成功将 支持我们对自闭症建模方式的范式转变，以及描绘其他行为的回路。

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.