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.

项目摘要 自闭症是由细胞或分子水平的异质损伤引起的普遍性发育障碍 影响分布式大脑区域的功能。合并焦虑和其他精神疾病很常见， 可能是由于具有自闭症核心特征的基本机制。突触后密度蛋白的丧失 shank3与分子水平的突触以及自闭症和智力障碍的缺陷有关。 自闭症与前额叶电路功能的变化有关，这可能会阻碍空间和时间 神经元合奏活动的模式，降低前额叶皮层反应的精度 输入。我建议检验以下假设：响应VHPC输入的异常募集前额叶活性 在焦虑症中，会导致Shank3敲除（KO）小鼠的异常焦虑。 我将首先定义集合激活的特异性，以响应前额叶内的VHPC输入 微电路，并确定缺乏shank3的小鼠改变整体募集的程度。这些 小鼠异常焦虑，社会互动异常。我已经证明了网络 来自KO小鼠的前额叶切片中的组织是异常的；个体神经元更活跃， 整体活动的组织也异常。具体而言，成对相关性异常高，并且 KO会产生异常活动模式。我量化了网络采样的活动模式 计算由2,3,4或5个神经元组合的特定N-神经元基序的数量。这揭示了 KO样品样本数量更多，但采样的模式较少发生的可能性较小 而不是在洗牌数据中。这表明虽然KO样本采样了更多不同的活动模式，但它在 混乱的方式。这可能会增加噪音或降低合奏招募的精度 行为。我建议测试网络活动中的这些变化如何影响PFC对焦虑的反应方式 使用来自腹侧海马的定义输入的光遗传学刺激检查神经元 响应指定输入（AIM 1）而招募的合奏。然后，我将使用植入的微型镜检查探索 在焦虑相关行为中募集不同神经元的不同集合的精度（AIM 2） 完整的动物，以及腹侧海马的焦虑输入的精度导致激活 PFC对杏仁核的预测（AIM 3）。 这些研究与自闭症直接相关，因为尽管我们对遗传的了解急剧增加 和基础自闭症的细胞病理学仍然很少治疗选择。这个指导的奖项 将提供机会开发大型分析所需的技术技能和定量方法 神经元的动态种群。我将受到临床医生和专家Vikaas Sohal博士的指导 光遗传学，神经精神病学和发育障碍。我打算提交R01并过渡到该角色 本奖项结束时独立调查员的工作。