Optical Dissection of the Neural Circuitry Controlling Sensorimotor Gating

项目摘要/摘要 候选人/环境：琼斯·帕克博士是斯坦福大学生物系助理研究员 大学。最近，帕克博士与辉瑞的迈克尔·埃勒斯博士完成了博士后研究，帕克博士试图 扩展他的专业知识，使用自由行为小鼠的钙成像来研究Mark博士的神经精神障碍 施尼泽的实验室，也就是这项技术的先驱。职业发展：该奖项将确保博士。 帕克完成了他在获取和分析大规模钙成像数据集方面的培训，并将促进他的 过渡到一个新的研究领域。更具体地说，它为帕克博士提供了时间来完善他的编程和 分析技能，并使他接触到精神疾病的基础研究。最终，这一奖项将使博尔顿博士。 帕克将利用尖端技术在未来的独立研究中执行更先进的程序 一群人。研究策略：个体精神疾病可以由许多不同的基因和 环境风险因素使得针对其根本原因的治疗变得极其困难。一 对这种“一种疾病的多条途径”关系的解释是，负责一组给定疾病的大脑区域 症状可能会被来自多个其他大脑区域的不同连接所干扰。从而更好地了解 与疾病相关的神经回路可能解释了该回路被破坏的许多方式，以产生相同的一组 症状。为了解决这个问题，我们将使用病毒遗传方法对钙离子进行光遗传操作或成像 投射到控制感觉运动门控的大脑核的不同神经元群体中的活动。中国的赤字 感觉运动门控发生在一系列不同的神经精神疾病中，表明有多种方式 使控制行为的电路中断。在啮齿动物中，感觉运动门控很容易被评估 测量脉冲前抑制(PPI)，它测试微弱的听觉前刺激对动物的 声学惊吓反应(ASR)。控制ASR的基本神经回路有很好的特征：脑桥尾侧 核团(PNC)根据来自耳蜗核的听觉信息调节惊吓反应的幅度。 为了确定大脑哪些区域如何以及哪些区域调节ASR和PPI，我们将使用逆行运输的CRE- 重组酶表达病毒(CAV2-CRE)选择性表达基因编码的钙传感器(GCaMP6)或 兴奋性/抑制性视蛋白(ChR2/NpHR)在神经元中直接投射到PNC。然后我们将使用微缩模型 荧光显微镜成像声学惊厥和PPI过程中PNC投射神经元的钙活动。至 为我们在PPI过程中观察到的PNC投射神经元的动力学建立一个因果作用，我们也将从光遗传学角度 在声学惊吓和PPI期间操纵这些神经元。我们的初步数据揭示了两个新发现的直达 对PNC的预测，一个可能是兴奋的，一个可能是抑制的。基于这一差异，我们 假设这些上游核对PNC活性和PPI做出相反的贡献。因为这些原子核可能 PPI以外的神经精神症状，我们的发现可能为以下疾病提供新的治疗目标 治疗各种神经精神疾病。

Project Summary/Abstract CANDIDATE/ENVIRONMENT: Dr. Jones Parker is a research associate in the Department of Biology at Stanford University. Having recently completed a postdoctoral fellowship with Dr. Michael Ehlers at Pfizer, Dr. Parker seeks to expand upon his expertise using calcium imaging in freely behaving mice to study neuropsychiatric disorders in Dr. Mark Schnitzer's laboratory, where the technique was pioneered. CAREER DEVELOPMENT: This award will ensure that Dr. Parker finalizes his training in the acquisition and analysis of large-scale calcium imaging datasets and will facilitate his transition into a new field of research. More specifically, it affords Dr. Parker the time to refine his programming and analysis skills and provides him exposure to basic research in psychiatric diseases. Ultimately, this award will position Dr. Parker to draw upon cutting-edge techniques to execute more developed programs in his future independent research group. RESEARCH STRATEGY: The fact that individual mental illnesses can result from a host of diverse genetic and environmental risk factors has made it exceedingly difficult to therapeutically target their underlying causes. One explanation for this `many pathways to one disease' relationship is that the brain region responsible for a given set of symptoms can become disrupted by distinct connections from multiple other brain regions. Thus a better understanding disease-related neural circuitry might explain the many ways the circuitry can be disrupted to yield the same set of symptoms. To address this idea, we will use a viral-genetic approach to optogenetically manipulate or image calcium activity in distinct neuronal populations that project to the brain nucleus that controls sensorimotor gating. Deficits in sensorimotor gating occur in a wide range of diverse neuropsychiatric disorders, suggesting that there are multiple ways for the circuitry controlling the behavior to become disrupted. Sensorimotor gating is readily assessed in rodents by measuring pre-pulse inhibiton (PPI), which tests the ability of a weak, auditory pre-stimulus to attenuate an animal's acoustic startle response (ASR). The basic neural circuit controlling the ASR is well characterized: the caudal pontine nucleus (PnC) modulates the amplitude of the startle response based on auditory information from the cochlear nucleus. To determine how and which brain regions modulate the ASR and PPI, we will use a retrogradely transported Cre- recombinase expressing virus (CAV2-Cre) to selectively express the genetically encoded calcium sensor (GCaMP6) or excitatory/inhibitory opsins (ChR2/NpHR) in neurons that directly project to the PnC. We will then use miniature fluorescence microscopes to image calcium activity in PnC-projecting neurons during acoustic startle and PPI. To establish a causal role for the dynamics we observe in PnC-projecting neurons during PPI, we will also optogenetically manipulate these neurons during acoustic startle and PPI. Our preliminary data reveal two newly discovered direct projections to the PnC, one that is likely excitatory and one that is likely inhibitory. Based on this difference, we hypothesize that these upstream nuclei make opposing contributions to PnC activity and PPI. As these nuclei may contribute to neuropsychiatric symptoms other than PPI, our findings potentially provide novel therapeutic targets for treating diverse neuropsychiatric disorders.