Abnormal Prefrontal Network Structure Underlying Anxiety in Autism

自闭症焦虑背后的异常前额叶网络结构

• 批准号: 10495033
• 负责人: Nicholas Alonzo Frost
• 金额: $ 20.02万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-26 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10495033
• 关键词: Abnormal; Prefrontal; Network; Structure; Underlying

Project Summary Autism is a pervasive developmental disorder caused by heterogeneous insults at the cellular or molecular level affecting the function of distributed brain regions. Co-morbid anxiety and other psychiatric disorders are common, likely due to underlying mechanisms shared with core features of autism. Loss of the postsynaptic density protein Shank3 is associated with deficits in synapses at the molecular level, as well as autism and intellectual disability. Autism is associated with changes in prefrontal circuit function which likely impede the spatial and temporal patterning of neuronal ensemble activity, degrading the precision with which the prefrontal cortex responds to input. I propose to test the hypothesis that abnormal recruitment of prefrontal activity in response to vHPC input during anxiety contributes to abnormal anxiety in the Shank3 knockout (KO) mouse. I will first define the specificity with which ensemble activation occurs in response to vHPC input within prefrontal microcircuits, and determine the degree to which ensemble recruitment is altered in mice lacking Shank3. These mice are abnormally anxious and have abnormal social interaction. I have demonstrated that network organization in prefrontal slices from KO mice is abnormal; individual neurons are more active, and the organization of ensemble activity also abnormal. Specifically, pairwise correlations are abnormally high and the KO generates abnormal patterns of activity. I quantified the patterns of activity sampled by the network by counting the number of specific n-neuron motifs consisting of combinations of 2,3,4, or 5 neurons. This revealed that the KO samples a greater number of patterns, but patterns sampled are less likely to occur more frequently than in shuffled data. This suggests that while the KO samples more diverse modes of activity, it does so in a disorganized manner. This may increase noise or decrease the precision of ensemble recruitment during behavior. I propose to test how these changes in network activity affect how the PFC responds to anxiogenic input using optogenetic stimulation of defined inputs from the ventral hippocampus to examine neuronal ensembles recruited in response to specified input (Aim 1). I will then use implanted microendoscopes to explore the precision with which distinct ensembles of neurons are recruited during anxiety-related behavior (Aim 2) in the intact animal, and the precision with which anxiogenic input from the ventral hippocampus results in activation of PFC projections to the amygdala (Aim 3). These studies are of immediate relevance to autism, as despite a dramatic increase in our knowledge of genetic and cellular pathology underlying autism there remains a paucity of therapeutic options. This mentored award will provide the opportunity to develop technical skills and quantitative methods needed for the analysis of large, dynamic populations of neurons. I will be mentored by Dr. Vikaas Sohal, a clinician-scientist and an expert in optogenetics, neuropsychiatric and developmental disorders. I intend to submit an R01 and transition to the role of independent investigator by the end of this award.

项目概要 自闭症是一种由细胞或分子水平上的异质性损伤引起的普遍性发育障碍 影响分布脑区的功能。共病焦虑和其他精神疾病很常见， 可能是由于与自闭症核心特征共有的潜在机制。突触后密度蛋白的丢失 Shank3 与分子水平上的突触缺陷以及自闭症和智力障碍有关。 自闭症与前额叶回路功能的变化有关，这可能会阻碍空间和时间 神经元整体活动的模式，降低前额叶皮层响应的精度 输入。我建议检验以下假设：响应 vHPC 输入的前额叶活动异常募集 焦虑期间导致 Shank3 敲除 (KO) 小鼠异常焦虑。 我将首先定义响应前额叶内的 vHPC 输入而发生整体激活的特异性 微电路，并确定缺乏 Shank3 的小鼠中集合招募改变的程度。这些 小鼠异常焦虑并且有异常的社交互动。我已经证明了网络 KO小鼠前额叶切片组织异常；单个神经元更加活跃，并且 乐团活动的组织也异常。具体来说，成对相关性异常高，并且 KO 会产生异常的活动模式。我通过以下方式量化了网络采样的活动模式 计算由 2、3、4 或 5 个神经元组合组成的特定 n 神经元基序的数量。这透露了 KO 采样了更多数量的模式，但采样的模式不太可能更频繁地出现 比打乱后的数据。这表明，虽然 KO 采样了更多样化的活动模式，但它是在 无组织的方式。这可能会增加噪音或降低集合招募的精度 行为。我建议测试网络活动的这些变化如何影响 PFC 对致焦虑的反应 使用来自腹侧海马的确定输入的光遗传学刺激来检查神经元的输入 根据指定的输入而招募的集成体（目标 1）。然后我将使用植入式显微内窥镜来探索 在焦虑相关行为（目标 2）中招募不同神经元群的精确度 完整的动物，以及来自腹侧海马的致焦虑输入导致激活的精确度 PFC 对杏仁核的预测（目标 3）。 这些研究与自闭症直接相关，尽管我们的遗传知识急剧增加 和自闭症背后的细胞病理学相比，治疗选择仍然很少。本次辅导奖 将提供发展大型分析所需的技术技能和定量方法的机会， 动态的神经元群体。我将得到维卡斯·索哈尔 (Vikaas Sohal) 博士的指导，他是一位临床医生兼科学家，也是以下领域的专家 光遗传学、神经精神学和发育障碍。我打算提交 R01 并过渡到该职位 独立调查员在本奖项结束时。