Optogenetic Tools to Measure Information Processing in Prefrontal Microcircuits

我感兴趣的是神经元的细胞和突触属性如何影响网络振荡等新出现的活动模式，以及这些模式如何反过来影响神经电路的功能。尽管已知在精神分裂症等神经精神疾病中，细胞和突触的各种属性会发生变化，但人们很难确切地理解这些变化是如何导致电路功能障碍的，这些功能障碍被认为会产生临床症状。我的目标是成为一个实验室的首席研究员，该实验室(1)使用体外电生理学识别精神疾病动物模型中的细胞和突触损伤，(2)使用体外和电子实验来测量由于这些损伤而导致的电路功能缺陷，以及(3)测试恢复这些电路功能是否可以挽救体内的病理行为。为了补充我在电生理学和计算神经科学方面的知识，我建议学习在体外和体内使用光遗传刺激，并研究与神经精神疾病相关的啮齿动物行为表型。我将得到卡尔·戴瑟罗斯的指导，他的实验室是光基因技术的先驱。利用光遗传学工具精确控制前额叶微电路中的刺激模式，以及信息论定量测量信息处理，我们已经阐明了大脑节律增强前额叶微电路中信息处理的机制。现在，我提议研究多巴胺和模拟精神分裂症各个方面的手法的作用，以回答以下问题：(1)刺激D1和D2受体是否对前额微电路的信噪比有相反的影响？(2)阻断NMDA受体和/或干扰DISCI是否抑制伽马频率同步或改变前额微电路的信息处理？(3)前额神经元的节律性光遗传刺激能否改善PCP和DISCI干扰对工作记忆的影响？我们相信，这些实验不仅将阐明精神分裂症前额叶微电路的工作原理和可能的功能障碍模式，而且还将建立强有力的新方法来研究神经精神疾病中的电路功能障碍。

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 neuropsychiatric 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 optogenetic stimulation in vitro and in vivo, and to study rodent behavioral phenotypes relevant to neuropsychiatric disease. I will be mentored by Karl Deisseroth, whose laboratory has pioneered optogenetic technology. Using optogenetic 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 optogenetic 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 neuropsychiatric disease.