Abnormal Prefrontal Network Structure Underlying Anxiety in Autism

项目摘要 自闭症是一种普遍存在的发育障碍，由细胞或分子水平的异质性侮辱引起。 影响大脑分布区域的功能。共病焦虑和其他精神障碍很常见， 可能是由于自闭症的核心特征所共有的潜在机制。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改变有关，这可能阻碍空间和时间上的 神经元整体活动模式，降低前额叶皮质反应的精确度 输入。我建议检验一种假设，即前额叶活动的异常招募对vHPC输入的反应 在焦虑过程中，导致Shank3基因敲除(KO)小鼠的异常焦虑。 我将首先定义响应前额叶内vHPC输入而发生集合激活的特异性 微电路，并确定在缺乏Shank3的小鼠中集合募集改变的程度。这些 老鼠异常焦虑，有不正常的社交互动。我已经证明了这个网络 KO小鼠前额叶脑片的组织结构异常；单个神经元更加活跃， 合奏活动的组织也不正常。具体地说，成对相关性异常高，而且 KO会产生反常的活动模式。我量化了网络抽样的活动模式 计算由2、3、4或5个神经元的组合组成的特定n神经元模体的数目。这揭示了 KO对更多的模式进行采样，但采样的模式不太可能出现得更频繁 而不是洗牌后的数据。这表明，虽然KO的活动模式更加多样化，但它是在一个 杂乱无章的态度。这可能会增加噪声或降低集合招募的精度 行为。我建议测试这些网络活动的变化如何影响PFC对焦虑症的反应 通过对来自腹侧海马区的特定输入进行光遗传刺激来检查神经元 为回应具体投入而招募的合奏(目标1)。然后我会用植入的显微内窥镜来探索 焦虑相关行为(目标2)中不同神经元集合被招募的精确度 完整的动物，以及腹侧海马区引起焦虑的输入导致激活的精确度 PFC投射至杏仁核(目标3)。 这些研究与自闭症直接相关，因为尽管我们对基因的了解急剧增加 而自闭症背后的细胞病理学仍然缺乏治疗选择。这是一个导师奖 将提供机会发展所需的技术技能和定量方法来分析大型、 动态的神经元群体。我将得到维卡斯·索哈尔医生的指导，他是一位临床科学家和 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 在这个奖项结束前独立调查员的名单。

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.