Role of the Hippocampal-mPFC Pathway in Social Memory Deficits in Autism

联系PD/PI：Pozzo-Miller，Lucas D. 项目摘要/摘要 海马体对空间记忆的形成和巩固至关重要，并对其他 通过其传出的投射完成认知任务。该项目的目标是确定是否更改了 自闭症小鼠模型海马区神经元网络活动传播至远端并发生改变 涉及社会行为的皮质区域。 自闭症谱系障碍的核心症状之一，如雷特综合征(RTT)，是一种社交缺陷 互动。在小鼠身上，类似的社会行为障碍可以通过改变兴奋和 内侧前额叶皮质(MPFC)的抑制(E/I)平衡。对于RTT，敲除突变的基因 在人类中，MeCP2导致腹侧海马区(VHip)由于E/I失衡而导致的过度活动 抑制减弱和兴奋增强，导致兴奋性突触的饱和突触可塑性。 有趣的是，VHIP的CA1锥体神经元将它们的轴突投射到mPFC，使直接的单突触 与兴奋性锥体神经元和抑制性中间神经元的联系。我们建议将这一特征描述为 VHIP通过这种长距离的单突触谷氨酸能投射影响mPFC的活性。重要的是，我们 将测试VHIP网络活动改变是否会导致mPFC功能障碍和社交功能障碍。 我们假设非典型的强VHIP传入改变了MeCP2 KO的mPFC中的网络活动 通过影响E/I平衡和突触可塑性，进而促进社会互动 赤字。为了验证这一假设，我们将在RTT的mPFC中确定VHIP直接传入的细胞靶点 利用光遗传学、化学遗传学、 体外和体内电生理学和钙离子成像，顺行和逆行追踪，无偏 机器学习行为评估。 我们提出了以下具体目标：1)识别和表征细胞靶标 MeCP2KO小鼠VHIP向mPFC的单突触投射；2)长时程增强的特征 MeCP2KO小鼠VHip-mPFC投射的突触可塑性；以及3)确定 调节投射mPFC的VHIP神经元的活动可以改变mPFC的功能和社会行为。 这些研究将提供有关长纤维的功能和结构特性的基本信息。 在发育中的大脑中VHIP和mPFC之间的距离连接。这项工作的影响延伸到 从RTT到其他神经精神障碍，在这些疾病中，网络功能障碍从 MPFC的海马体被认为是认知缺陷的原因之一。 第6页 项目摘要/摘要

Contact PD/PI: Pozzo-Miller, Lucas D. PROJECT SUMMARY / ABSTRACT The hippocampus is critical for the formation and consolidation of spatial memories and contributes to other cognitive tasks through its efferent projections. The goal of this project is to determine whether altered neuronal network activity in the hippocampus of an autism mouse model propagates to, and alters distal cortical regions involved in social behaviors. One of the core symptoms of autism spectrum disorders, such as Rett syndrome (RTT), is a deficit in social interaction. In mice, similar social behavior impairments can be modeled by altering the excitation and inhibition (E/I) balance in the medial prefrontal cortex (mPFC). For RTT, knocking out the gene that is mutated in humans, Mecp2, causes hyperactivity in the ventral hippocampus (vHIP) due to an E/I imbalance driven by impaired inhibition and enhanced excitation, resulting in saturated synaptic plasticity at excitatory synapses. Intriguingly, CA1 pyramidal neurons of the vHIP project their axons to the mPFC, making direct monosynaptic connections with excitatory pyramidal neurons and inhibitory interneurons. We propose to characterize how the vHIP influences mPFC activity through this long-range monosynaptic glutamatergic projection. Importantly, we will test whether altered vHIP network activity is causal to mPFC dysfunction and deficits in social interaction. We hypothesize that atypically strong vHIP afferents alter network activity in the mPFC of Mecp2 KO mice by affecting the E/I balance and synaptic plasticity, which in turn contributes to social interaction deficits. To test this hypothesis, we will identify the cellular targets of direct vHIP afferents in the mPFC of RTT mice and characterize their function in social behaviors using a combination of optogenetics, chemogenetics, ex vivo and in vivo electrophysiology and Ca2+ imaging, anterograde and retrograde tract tracing, and unbiased machine-learning behavioral assessments. We propose the following Specific Aims: 1) identify and characterize the cellular targets of the monosynaptic projection from the vHIP to the mPFC in Mecp2 KO mice; 2) characterize long-term synaptic plasticity of the vHIP-mPFC projection in Mecp2 KO mice; and 3) determine if chemogenetic modulation of the activity of mPFC-projecting vHIP neurons alters mPFC function and social behaviors. These studies will provide fundamental information on the functional and structural properties of the long- range connection between the vHIP and mPFC in the developing brain. The impact of this work extends beyond RTT to other neuropsychiatric disorders in which propagation of network dysfunction from the hippocampus to the mPFC is believed to contribute to cognitive deficits. Page 6 Project Summary/Abstract