Abnormal Prefrontal Network Structure Underlying Anxiety in Autism

项目摘要 孤独症是一种广泛性的发育障碍，由细胞或分子水平的异质性损伤引起 影响大脑分布区域的功能。共病焦虑和其他精神疾病是常见的， 这可能是由于与自闭症核心特征共享的潜在机制。突触后密度蛋白丢失 Shank 3与分子水平上的突触缺陷以及自闭症和智力残疾有关。 孤独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化，降低了前额叶皮层对 输入.我建议检验这一假设，即前额叶活动的异常募集是对vHPC输入的反应， 在焦虑期间，在Shank 3敲除（KO）小鼠中， 我将首先定义集合激活响应于前额叶内vHPC输入而发生的特异性。 微电路，并确定在缺乏Shank 3的小鼠中整体募集改变的程度。这些 小鼠异常焦虑并且具有异常的社会互动。我已经证明了这个网络 KO小鼠前额叶切片的组织是异常的;单个神经元更加活跃， 集体活动的组织也不正常。具体来说，成对相关性异常高， KO产生异常的活动模式。我量化了网络采样的活动模式， 计数由2、3、4或5个神经元的组合组成的特定n-神经元基序的数目。这揭示 KO采样更多的模式，但是采样的模式不太可能更频繁地出现 than in shuffled改组data数据.这表明，虽然KO样本的活动模式更多样化，但它是以一种 无组织的方式。这可能会增加噪声或降低集成招聘期间的精度 行为我建议测试这些网络活动的变化如何影响PFC对焦虑的反应。 使用来自腹侧海马的限定输入的光遗传学刺激来检查神经元输入 响应指定输入而招募的合奏（目标1）。然后我会用植入的显微内窥镜 在焦虑相关行为（目标2）期间招募不同神经元集合的精确度 完整的动物，以及腹侧海马体的焦虑输入导致激活的精确性 PFC投射到杏仁核（目标3）。 这些研究与自闭症直接相关，尽管我们对遗传学的了解有了显着增加， 以及自闭症的细胞病理学基础，仍然缺乏治疗选择。这个指导奖 将提供机会，发展分析大型， 神经元的动态群体。我将由Vikaas Sohal博士指导，他是一位临床科学家和医学专家。 光遗传学、神经精神和发育障碍。我打算提交R 01并过渡到该角色 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.