Imprinting a Connectome: Developmental Circuit Approach to Mental Illness

描述(申请人提供)：在神经元回路发育的关键时期，大脑功能由基因和环境决定。当这些因素的复杂汇聚导致异常连接时，可能会出现精神疾病。在这里，我们建议在开发系统中通过在单细胞分辨率下进行复杂的全基因组和神经电路分析来应对这一挑战。我们结合了PI关于基因组印记的真实大小的最新见解，这可能是各种疾病中起源父母效应的基础；识别触发响应早期生活经验的电路重新布线的特定细胞类型；以及可视化和重建哺乳动物皮质中单个神经元的所有突触输入和输出的创新技术。利用极大改进的计算能力和方法，我们在这个项目中的目标是使用一套新的神经元电路分析工具来实现一个相当简单但迄今无法实现的目标：一个与多种认知发育障碍有关的关键细胞类型的完整连接图和印记基因表达谱。首先，我们战略性地关注内侧前额叶皮质(MPFC)中小白蛋白(PV)阳性的GABA神经元。这种抑制性细胞类型在正常大脑发育和处理的时间安排中起着关键作用，特别容易受到广泛的遗传和环境应激源的影响，印记基因也是如此。动物模型中神经回路失调的共同特征可能会为正在建模的人类疾病提供信息。然后，获取此类数据的渠道将非常类似于其他情况，因此一旦为一种细胞类型、年龄、性别或突变建立了数据，就可以直接对其他情况重复。我们的共同目标是建立一个系统地剖析发育性“连接疾病”的范例，这应该会启发精神疾病的新的基于电路的治疗方法。

DESCRIPTION (provided by applicant): Brain function is shaped by genes and environment during critical periods of neuronal circuit development. Mental illness may arise when the complex convergence of these factors results in aberrant wiring. Here, we propose to meet this challenge by sophisticated, whole genome and neural circuit analyses at single-cell resolution in developing systems. We unite recent insights by the PIs regarding the true magnitude of genomic imprinting, which may underlie parent-of-origin effects in a variety of disorders; the identification of specific cell-types that trigger the re-wiring of circuits in response to early life experience; and innovative technologies to visualize and reconstruct all synaptic inputs and outputs of an individual neuron in the mammalian cortex. Taking advantage of vastly improved computational power and methods, our goal in this project is to use a suite of new neuronal circuit analysis tools to attain a rather simple, but heretofore unattainable goal: the complete connectional diagram and imprinted gene expression profile of a pivotal cell type implicated in multiple cognitive developmental disorders. To begin, we focus strategically on the parvalbumin (PV)-positive GABA neuron in medial prefrontal cortex (mPFC). This inhibitory cell type plays a critical role in timing normal brain development and processing, and is particularly vulnerable to a broad spectrum of genetic and environmental stressors, as are imprinted genes. Shared features of neural circuit dysregulation across animal models are likely to inform the human disorder being modeled. The pipeline to obtain such data will then be very similar for other cases, so that once it is established for one cell-type, age, sex, or mutant, it will be straight forward to repeat for others. Our collective goal is to establish a paradigm for the systematic dissection of developmental 'connectopathies,' which should inspire novel circuit-based therapies for mental illness.