社交行为关键脑区海马CA2环路的解析及调控机制研究

Social recognition requires functionally highly integrated neural circuits mediating emotion and memory. Defects in social recognition are a key behavioral phenotype in devastating mental disabilities including autism and schizophrenia. Studies on the neurobiological mechanisms of social deficits could not be carried out until recent report revealing the critical role of hippocampal CA2 region in social memory. We have been working on the molecular mechanisms of autism related genes, e.g. Neuroligin/Neurexin and PAK1/3, in the development of functional and behavioral abnormalities. We found that these genes can affect social memory at behavioral level by modulating hippocampal synaptic plasticity and microcircuits. In this project, we propose to identify neural circuits containing hippocampal CA2 region. Second, to investigate the regulatory effects and mechanisms of CA2 pyramidal neurons by synaptic plasticity and microcircuits, and the effects on the neural circuits containing CA2 pyramidal neurons. Next, we will utilize mouse models exhibiting social memory deficits to examine the effects of autism-related genes and acute stress on the formation, maintenance and functions of CA2 neural circuits. We will also test potential rescue approaches by manipulating molecular and cellular defects in these mice. Taken together, this study may provide novel knowledge of neural circuits containing hippocampal CA2 region and its modulatory mechanisms. Using CA2 as an example, this study may extend our understanding on the general neurobiological basis for social recognition, and rationalize diagnosis and treatment paradigm of social disabilities in the future.

社交认知是大脑情感和记忆神经环路高度整合的功能性产物。社交障碍是儿童孤独症、精神分裂症等多种重大神经精神疾病的核心行为学症状，但机制不明。近期报道和我们的研究表明，海马体CA2区对于动物的社交记忆和突触可塑性调节至关重要。我们前期的研究显示，自闭症关联基因NLG/NRX和PAK1/3等可通过多种途径，如突触可塑性、微环路等显著影响动物的社交记忆行为表型。本课题将基于此，深入解析包含海马CA2区的神经环路的结构基础；在微环路、突触可塑性层面探讨CA2区锥体神经元的活性调节机制及该调节作用对其参与构建的长距离神经环路功能的影响；探究这些疾病关联基因和环境应激对CA2区神经环路形成、维持及功能行使的影响，并测试可能的挽救方法。本项目将系统解析海马CA2区所参与构建的社交认知关键神经环路的构造及调节模式，阐明大脑社交认知功能的神经生物学机制，为相关神经精神疾病的诊治和预防提供科学依据和思路。

社交记忆是大脑情感和记忆神经环路高度整合的功能性产物，社交障碍是儿童自闭症、精神分裂症等多种重大神经精神疾病的核心行为学症状，海马体CA2脑区被证实对动物的社交记忆形成至关重要，但社交记忆形成的分子及环路机制目前尚不清楚。我们前期的研究显示，自闭症关联基因nlg1、nlg3等可通过多种途径，如突触可塑性、微环路等显著影响动物的社交记忆行为表型。本课题综合运用多种技术手段，深入解析了海马CA2区的社交记忆神经环路的结构基础，鉴定出了从MS经CA2到CA1神经元这一关键社交记忆神经环路；揭示CA2神经元能够通过影响星形胶质细胞活性，调控腺苷（ATP）释放，进而影响CA1区的LTP，以及动物的社交记忆。本课题的研究结果还显示，NLG1分子可能通过调节CA2神经元的兴奋性，调控社交记忆；而NLG3分子则可以通过调控HPC区星形胶质细胞的活性，影响CA1的突触可塑性以及社交记忆。此外，我们通过组学分析鉴定了CA2特异表达的基因谱、研发了CA2特异的Cre腺相关病毒、建立了适合分析自由活动小鼠深部脑区钙活动的新型双光子显微镜系统（FHIRM-TPM）的技术等。综上所述，我们的工作阐明了社交记忆形成的部分关键分子及环路机制，为揭示学习记忆以及自闭症等神经精神疾病的内在机制提供了重要基础。

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