Imprinting a Connectome: Developmental Circuit Approach to Mental Illness

印记连接组：治疗精神疾病的发育回路方法

• 批准号: 8328632
• 负责人: Takao K Hensch
• 金额: $ 170.44万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-05 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8328632
• 关键词: Age; Animal Model; Brain; Cells; Cognitive; Complex; Data; Development; Disease; Dissection; Environment; Epigenetic Process; Gene Expression Profile; Genes; Genetic; Genome; Genomic Imprinting; Goals; Human; Image; Individual; Informatics; Life Experience; Medial; Mental disorders; Methods; Modeling; Neurons; Neurosciences; Output; Parents; Parvalbumins; Play; Prefrontal Cortex; Process; Resolution; Role; Shapes; Synapses; System; Time; Training; Universities; base; cell type; critical period; developmental disease; environmental stressor; gamma-Aminobutyric Acid; imprint; improved; innovative technologies; insight; meetings; mutant; neural circuit; novel; response; sex; tool

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.

描述（由申请人提供）：在神经元电路发育的关键时期，大脑功能由基因和环境塑造。当这些因素的复杂收敛导致布线异常时，可能会出现精神疾病。在这里，我们建议通过在开发系统中单细胞分辨率进行复杂的，整个基因组和神经电路分析来应对这一挑战。我们团结了PI的最新见解，内容涉及基因组印迹的真正幅度，这可能是各种疾病中的父母产生影响的基础。鉴定特定的细胞类型，这些细胞类型会引发回应早期生活经验的电路；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。利用大大改善的计算能力和方法，我们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：完整的连接图和含义的枢轴细胞类型的印迹元素表达谱，该类型与多种认知性发育障碍有关。首先，我们从策略性地关注白细胞蛋白（PV） - 阳性GABA神经元（MPFC）。这种抑制性细胞类型在正常的大脑发育和加工中起着至关重要的作用，并且尤其容易受到广泛的遗传和环境压力源的影响，以及印迹基因也是如此。跨动物模型的神经回路失调的共同特征可能会为正在建模的人类障碍提供信息。然后，在其他情况下，获得此类数据的管道将非常相似，因此，一旦为一个细胞类型，年龄，性别或突变体建立了该数据，则将直接重复他人。我们的集体目标是为发展性“连接疗法”的系统解剖建立一个范式，这应该激发基于新型的精神疾病疗法。