Cellular and Epigenetic Mechanisms for Social Critical Windows in Mice

! 项目摘要 神经发育障碍，如精神分裂症和自闭症谱系障碍，代表了一种神经发育障碍。 这给我们的公共卫生系统带来了沉重的负担，影响了美国约15%的儿童。尝试 治疗这些疾病已被证明在很大程度上是不成功的，部分原因是缺乏对发育的理解。 将各种遗传和环境风险因素与临床表型联系起来的途径。社会 行为通常在神经发育障碍中失调，但对神经发育障碍的神经机制知之甚少。 控制社会行为发展的机制。适当的成人社会行为可能依赖于 特定神经元回路的经验依赖性成熟和染色质组织的潜在变化 在关键的发展窗口。这对神经表观遗传学的传统方法提出了挑战， 考虑到几乎所有的表观基因组方法都是横截面的， 单一时间点。在这个提议中，我们利用小鼠模型来桥接特定的特定的细胞的新颖的体内真实的时间成像。 细胞群体的发展与表观基因组方法，以允许，在细胞类型特异性的方式， 回顾性评估社会经验依赖的染色质重组发生在社会 前额叶皮层（PFC）的关键窗口。我们的试点数据表明， PFC中的小清蛋白阳性中间神经元（PVIs）在调节成人社会行为中的作用，以及 青少年社会经验对他们成年后的正常活动的影响。然而，我们不知道社交 发育过程中的经历改变了PFC-PVIs的成年功能。我们的方法将使用光纤测光， 在青少年社会经验存在和不存在的情况下，监测PVI在整个发展过程中的活动。 我们还将使用载体构建体用于细菌DNA的瞬时表达，特别是在PFC-PVIs内 腺嘌呤甲基转移酶（Dam）与核纤层的核心组分laminb 1融合，形成蛋白质网络 在核外围，提供结构支持并调节基因表达。这种方法将 使我们能够探索在一个关键时期，核板层基因组的变化如何与社会经验相关， 窗口与细胞类型特异性转录和成年小鼠体内活性变化相关。我们将 采用回顾性和传统横断面方法，研究PVIs的发展是如何 受社会经验的影响。 !

! Project Summary Neurodevelopmental disorders, such as schizophrenia and autism spectrum disorders represent a substantial burden to our public health system, affecting around 15% of children in the United States. Attempts to treat these disorders have proven largely unsuccessful, in part due to a lack of understanding of developmental pathways linking a diverse range of genetic and environmental risk factors with clinical phenotypes. Social behavior is commonly dysregulated in neurodevelopmental disorders, yet little is known about the neural mechanisms governing social behavior development. Appropriate adult social behavior likely relies on experience-dependent maturation of specific neuronal circuits and underlying changes in chromatin organization during key developmental windows. This represents a challenge to traditional approaches in neuroepigenetics, given that virtually all epigenomic approaches are cross-sectional, providing snapshots of genome function for a single time point. In this proposal, we leverage mouse models to bridge novel in vivo real time imaging of specific cell populations across development with epigenomic approaches, to allow, in a cell-type specific manner, retrospective assessment of social experience-dependent chromatin reorganization occurring during a social critical window in the developing prefrontal cortex (PFC). Our pilot data demonstrate an essential role for parvalbumin positive interneurons (PVIs) in PFC in regulating adult social behavior, as well as a necessity of juvenile social experience in shaping their proper activation in adult. However, it is unknown how social experience during development alters adult functioning of PFC-PVIs. Our approach will use fiber photometry to monitor activity of PVIs across development, both in the presence and absence of juvenile social experience. We will also employ vector constructs for transient expression, specifically within PFC-PVIs, of bacterial DNA adenine methyltransferase (Dam) fused with laminb1, a core component of the nuclear lamina, a protein network at the nuclear periphery that provides both structural support and regulates gene expression. This approach will allow us to explore how nuclear laminar-genomic changes associated with social experience during a critical window correlate with both cell type specific transcriptional, and in vivo activity changes in adult mice. We will take both a retrospective as well as traditional cross-sectional approach, to study how development of PVIs is affected by social experience. !