Imprinting a Connectome: Developmental Circuit Approach to Mental Illness

描述（申请人提供）：在神经回路发育的关键时期，大脑功能受基因和环境的影响。当这些因素的复杂融合导致神经网络异常时，就可能出现精神疾病。在这里，我们建议在开发系统中以单细胞分辨率进行复杂的全基因组和神经回路分析来应对这一挑战。我们将pi最近关于基因组印记的真实规模的见解结合起来，这可能是各种疾病中父母起源效应的基础；识别触发电路重新布线的特定细胞类型，以响应早期生活经历；以及创新的技术来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。利用大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，但迄今为止无法实现的目标：完整的连接图和涉及多种认知发育障碍的关键细胞类型的印迹基因表达谱。首先，我们策略性地关注内侧前额皮质（mPFC）中的小白蛋白（PV）阳性GABA神经元。这种抑制性细胞类型在大脑正常发育和加工过程中起着至关重要的作用，并且特别容易受到广泛的遗传和环境压力因素的影响，就像印记基因一样。跨动物模型的神经回路失调的共同特征可能会告知正在建模的人类疾病。获取此类数据的途径在其他情况下将非常相似，因此，一旦确定了一种细胞类型、年龄、性别或突变，就可以直接对其他情况进行重复。我们的共同目标是建立一个系统解剖发育性“连接病”的范例，这应该会激发新的基于神经回路的精神疾病治疗方法。

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.