Developmental origins of mental illness: evolution and reversibility

摘要： 改变的网络动态(大脑节律)是大多数(如果不是全部)大脑紊乱的基础，但我们知道 几乎没有关于这种动态如何在功能关系上演变为正常行为的内容。 利用来自父母CONTE赠款的现有生理数据来产生生物物理学 详细的计算模型，建议的项目构建了一种基于电路的策略 跟踪神经元间功能和涉及网络动态的定向干预。我们会 构建关键期动力学模型以了解其背后的基本机制 从以抑制为主的动力向涉及的网络的出现的转变 锥体细胞和中间神经元，是成人大脑皮质网络处理的特征。 之前的数据表明，这种转变始于由提供的伽马振荡 仅抑制性细胞网络(ING)。我们假设荷兰国际集团是 转换不成熟的皮质网络，其中感觉输入无处不在 到更像成人的网络状态，在这种状态下，复杂的皮质处理 感觉输入发生，包括门控和工作记忆。我们假设这一转变 涉及丘脑和皮质之间网络相互作用的变化。我们将执行数据 对现有数据进行分析，以调查这一过程通常如何随时间演变以及如何演变 在Rett综合征MeCP2小鼠模型中脱轨并被细胞特异性基因拯救 修复。我们预计这种开创性的计算精神病学方法将广泛应用于 适用于家长孔特中心以外的许多神经发育障碍。

Abstract: Altered network dynamics (brain rhythms) underlie most if not all brain disorders, yet we know almost nothing about how such dynamics evolve in functional relationship to normal behavior. Leveraging existing physiological data from the parent Conte grant to generate biophysically detailed computational models, the proposed project constructs a circuit-based strategy for tracking interneuron function and targeted intervention that involves network dynamics. We will construct models of critical period dynamics to understand the essential mechanisms underlying the transition from a predominantly inhibitory dynamic to the emergence of networks involving pyramidal cells and interneurons, characteristic of cortical network processing in the adult brain. Previous data suggests that the transformation is begun with a gamma oscillation provided by networks of only inhibitory cells (ING). We hypothesize that ING is the initial stage in the transformation of the immature cortical network, in which sensory input is ubiquitously processed, to a more adult-like network state in which sophisticated, cortical processing of sensory input occurs, including gating and working memory. We hypothesize the transformation involves changes in network interactions between thalamus and cortex. We will perform data analysis on existing data to investigate how this process normally evolves over time and how it is derailed in the MeCP2 mouse model of Rett Syndrome and rescued by cell-specific gene restoration. We anticipate this pioneering computational psychiatry approach to be broadly applicable to many neurodevelopmental disorders beyond the parent Conte center.