Developmental origins of mental illness: evolution and reversibility

摘要： 改变的网络动力学（脑节律）是大多数（如果不是所有）大脑疾病的基础，但我们知道， 几乎没有关于这种动力学如何在正常行为的功能关系中进化的信息。 利用来自母公司Conte赠款的现有生理数据， 详细的计算模型，拟议的项目构建了一个基于电路的战略， 跟踪中间神经元功能和涉及网络动态的针对性干预。我们将 构建关键期动态模型，以了解其基本机制 从主要的抑制性动态到网络出现的转变， 锥体细胞和中间神经元，是成年大脑皮层网络处理的特征。 以前的数据表明，这种转变是从伽马振荡开始的， 只有抑制性细胞（ING）的网络。我们假设，ING是在初始阶段， 未成熟皮层网络的转变，其中感觉输入无处不在 处理，到一个更像成人的网络状态，其中复杂的，皮层处理， 感觉输入发生，包括门控和工作记忆。我们假设 涉及丘脑和皮层之间网络相互作用的变化。我们将执行数据 分析现有数据，以调查这一过程通常如何随着时间的推移而演变， 在Rett综合征的MeCP2小鼠模型中出轨，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地 适用于许多神经发育障碍以外的母康特中心。

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.