Optical dissection of the neural circuitry controlling sensorimotor gating

项目总结/摘要 候选人/环境：琼斯帕克博士是斯坦福大学生物系的研究助理 大学帕克博士最近完成了与辉瑞公司的迈克尔·埃勒斯博士的博士后研究， 扩展他的专业知识，使用钙成像在自由行为的小鼠研究神经精神疾病在马克博士 Schnitzer的实验室，该技术的先驱。职业发展：这个奖项将确保博士。 帕克完成了他在大规模钙成像数据集的采集和分析方面的培训， 进入一个新的研究领域。更具体地说，它为帕克博士提供了时间来完善他的程序， 分析技能，并使他接触到精神疾病的基础研究。最终，这个奖项将定位博士。 帕克在未来的独立研究中利用尖端技术执行更先进的程序 组研究策略：事实上，个体精神疾病可能是由多种遗传和 环境风险因素使得治疗性地针对其根本原因变得极其困难。一 对这种“多种途径导致一种疾病”的关系的解释是，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破坏。更好地理解 疾病相关的神经回路可能解释了许多方式的电路可以被破坏，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学方法来光遗传学操纵或成像钙 投射到控制感觉运动门控的脑核团的不同神经元群体的活动。赤字 感觉运动门控发生在各种各样的神经精神疾病中，这表明有多种方式 控制行为的电路会被破坏感觉运动门控在啮齿类动物中很容易评估， 测量前脉冲振幅（PPI），它测试弱的听觉前刺激减弱动物的听觉的能力。 声惊吓反应（ASR）。控制ASR的基本神经回路被很好地表征：脑桥尾侧 核（PnC）基于来自耳蜗核的听觉信息调节惊吓反应的幅度。 为了确定如何以及哪些大脑区域调节ASR和PPI，我们将使用逆行转运的Cre- 重组酶表达病毒（CAV 2-Cre）以选择性表达遗传编码的钙传感器（GCaMP 6），或 刺激性/抑制性视蛋白（ChR 2/NpHR）在神经元中直接投射到PnC。然后我们将使用微型 荧光显微镜成像钙活动的PnC投射神经元在声惊吓和PPI。到 建立一个因果关系的作用，我们观察到的动力学在PnC投射神经元在PPI期间，我们也将光遗传学 操纵这些神经元在声惊吓和PPI。我们的初步数据揭示了两个新发现的直接 PnC的投射，一个可能是兴奋性的，一个可能是抑制性的。基于这种差异，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 有助于PPI以外的神经精神症状，我们的研究结果可能提供新的治疗靶点， 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.