Imprinting a Connectome: Developmental Circuit Approach to Mental Illness

描述（由申请人提供）：在神经回路发育的关键时期，大脑功能由基因和环境塑造。当这些因素的复杂融合导致异常的线路连接时，可能会出现精神疾病。在这里，我们建议通过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。我们结合了PI最近关于基因组印记的真实大小的见解，这可能是各种疾病中的起源效应的基础;识别触发电路重新布线以响应早期生活经验的特定细胞类型;以及可视化和重建哺乳动物皮层中单个神经元的所有突触输入和输出的创新技术。利用大大提高的计算能力和方法，我们在这个项目中的目标是使用一套新的神经元回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：涉及多种认知发育障碍的关键细胞类型的完整连接图和印记基因表达谱。开始，我们战略性地集中在内侧前额叶皮层（mPFC）的小白蛋白（PV）阳性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，并且特别容易受到广泛的遗传和环境压力的影响，就像印记基因一样。动物模型中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。然后，获得这些数据的管道对于其他情况将非常相似，因此一旦为一种细胞类型，年龄，性别或突变体建立了数据库，就可以直接重复其他数据库。我们的共同目标是建立一个发展性“连接病”的系统解剖范式，这将激发新的基于回路的精神疾病治疗。

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.