Optogenetic Tools to Measure Information Processing in Prefrontal Microcircuits

描述（由申请人提供）：我感兴趣的是神经元的细胞和突触特性如何影响网络振荡等活动的涌现模式，以及这些模式如何反过来影响神经回路的功能。虽然已知神经精神病学疾病（如精神分裂症）中细胞和突触的无数特性会发生改变，但很难确切理解这些改变如何导致被认为产生临床症状的回路功能障碍。我的目标是成为一个实验室的首席研究员，该实验室（1）使用体外电生理学在精神疾病的动物模型中识别细胞和突触损伤，（2）使用体外和计算机实验来测量由于这些损伤而导致的电路功能缺陷，（3）测试恢复这些电路功能是否可以挽救体内的病理行为。为了补充我的电生理学和计算神经科学的知识，我建议学习在体外和体内使用个体发育刺激，并研究啮齿动物的行为表型相关的神经精神疾病。我将接受卡尔·戴瑟罗斯的指导，他的实验室是个体发育技术的先驱。利用个体发育工具精确控制前额叶微回路中的刺激模式，利用信息论定量测量信息处理，我们已经阐明了脑节律增强前额叶微回路中信息处理的机制。现在，我建议研究多巴胺的作用和模拟精神分裂症方面的操纵，以回答以下问题：（1）D1和D2受体刺激是否对前额叶微电路的信噪比有相反的影响？(2)阻断NMDA受体和/或干扰DISCI抑制γ频率同步或改变前额叶微电路的信息处理？(3)有节奏的个体发育刺激前额叶神经元能改善PCP和DISCI干扰对工作记忆的影响吗？我们相信，这些实验不仅将揭示前额叶微电路的运作和精神分裂症功能障碍的可能模式，而且还建立了强大的新方法来研究神经精神病学疾病中的电路功能障碍。

DESCRIPTION (provided by applicant): I am interested in how cellular and synaptic properties of neurons affect emergent patterns of activity such as network oscillations, and how these patterns in turn affect the function of neural circuits. Although myriad properties of cells and synapses are known to be altered in neuropsychiatry diseases such as schizophrenia, it has been difficult to understand exactly how these alterations cause the circuit dysfunction thought to produce clinical symptoms. My goal is to be the principal investigator of a laboratory which (1) identifies cellular and synaptic lesions in animal models of psychiatric disease using in vitro electrophysiology, (2) uses in vitro and in silico experiments to measure circuit functions that are deficient as a result of these lesions, and (3) tests whether restoring these circuit functions can rescue pathological behaviors in vivo. To complement my knowledge of electrophysiology and computational neuroscience, I propose learning to use ontogenetic stimulation in vitro and in vivo, and to study rodent behavioral phenotypes relevant to neuropsychiatry disease. I will be mentored by Karl Deisseroth, whose laboratory has pioneered ontogenetic technology. Using ontogenetic tools to precisely control patterns of stimulation in prefrontal microcircuits, and information theory to quantitatively measure information processing, we have already elucidated mechanisms by which brain rhythms enhance information processing in prefrontal microcircuits. Now, I propose to study the effects of dopamine and manipulations that model aspects of schizophrenia to answer the following questions: (1) Do Dl and D2 receptor stimulation have opposing effects on the signal-to-noise ratio in prefrontal microcircuits? (2) Does blocking NMDA receptors and/or disrupting DISCI suppress gamma-frequency synchronization or alter information processing in prefrontal microcircuits? (3) Can rhythmic ontogenetic stimulation of prefrontal neurons ameliorate effects of PCP and DISCI disruption on working memory? We believe that these experiments will not only shed light on the workings of prefrontal microcircuits and possible modes of dysfunction in schizophrenia, but also establish powerful new ways to study circuit dysfunction in neuropsychiatry disease.