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

海马-mPFC 通路在自闭症社交记忆缺陷中的作用

• 批准号: 10533173
• 负责人: Lucas D Pozzo-Miller
• 金额: $ 6.44万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10533173
• 关键词: Affect; Axon; Behavior assessment; Brain; Cognitive deficits; Distal; Electrophysiology (science); Equilibrium; Excitatory Synapse; Functional disorder; Genes; Glutamates; Goals; Hippocampus (Brain); Human; Hyperactivity; Image; Impairment; Interneurons; Knock-out; Knockout Mice; Machine Learning; Medial; Memory impairment; Methyl-CpG-Binding Protein 2; Modeling; Mus; Mutate; Neurons; Pathway interactions; Prefrontal Cortex; Property; Rett Syndrome; Role; Social Behavior; Social Interaction; Symptoms; Synaptic plasticity; Syndrome; Testing; Work; autism spectrum disorder; behavioral impairment; cellular targeting; cognitive ability; cognitive task; hippocampal pyramidal neuron; in vivo; mouse model; network dysfunction; neuropsychiatric disorder; optogenetics; social; social deficits; spatial memory

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

联系PD/PI：Pozzo-Miller，Lucas D. 项目总结/摘要 海马体对于空间记忆的形成和巩固至关重要，并有助于其他记忆的形成。 通过传出投射完成认知任务。该项目的目标是确定是否改变 自闭症小鼠模型海马中的神经元网络活动传播到远端， 参与社会行为的皮层区域 自闭症谱系障碍的核心症状之一，如Rett综合征（RTT），是社交能力的缺陷。 互动在小鼠中，类似的社会行为障碍可以通过改变兴奋和 内侧前额叶皮层（mPFC）的抑制（E/I）平衡。对于RTT，敲除突变的基因 在人类中，Mecp 2由于E/I不平衡而导致腹侧海马体（vHIP）活动过度， 抑制减弱和兴奋增强，导致兴奋性突触处的饱和突触可塑性。 有趣的是，vHIP的CA 1锥体神经元将它们的轴突投射到mPFC，使直接单突触 与兴奋性锥体神经元和抑制性中间神经元的连接。我们建议描述 vHIP通过这种长距离单突触突触神经元投射影响mPFC活性。重要的是我们 将测试vHIP网络活动的改变是否是mPFC功能障碍和社会交往缺陷的原因。 我们假设，脑内强烈的vHIP传入改变了Mecp 2 KO mPFC的网络活动 通过影响E/I平衡和突触可塑性，这反过来又有助于社会互动 赤字为了验证这一假设，我们将确定RTT mPFC中直接vHIP传入的细胞靶点 并使用光遗传学，化学遗传学， 离体和体内电生理学和Ca 2+成像，顺行和逆行追踪，以及无偏倚 机器学习行为评估。 我们提出了以下具体目标：1）识别和表征的细胞靶点， Mecp 2 KO小鼠中从vHIP到mPFC的单突触投射; 2）表征长期 Mecp 2 KO小鼠中vHIP-mPFC投射的突触可塑性;和3）确定是否化学遗传 调节mPFC投射vHIP神经元的活性改变mPFC功能和社会行为。 这些研究将提供关于长链的功能和结构特性的基本信息， vHIP和mPFC在发育中的大脑之间的范围连接。这项工作的影响范围 除了RTT之外，还有其他神经精神疾病，其中网络功能障碍的传播来自 海马体到mPFC被认为有助于认知缺陷。 第6页 项目总结/摘要