In Vivo Analysis of Cortical Projection Neurons

皮质投射神经元的体内分析

基本信息

批准号：
8816156
负责人：
Gordon M Shepherd
金额：
$ 19.31万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8816156
关键词：
Address Amyotrophic Lateral Sclerosis Animal Model Animals Area Autistic Disorder Axon Behavior Behavior Control Behavioral Paradigm Brain Calcium Cells Cognitive Complex Corpus striatum structure Data Dendrites Disease Fiber Optics Future Goals Health Human Huntington Disease Image Investigation Knowledge Learning Link Measures Methods Mission Monitor Motor Motor Cortex Movement Multiple Sclerosis Mus National Institute of Neurological Disorders and Stroke Neocortex Neuraxis Neurologic Neurons Output Paralysed Parkinson Disease Pathology Pattern Pharmacogenetics Photometry Population Process Property Public Health Rabies virus Recombinants Reporter Research Resolution Role Signal Transduction Slice Spinal Cord Spinal cord injury Stroke Synapses Time United States National Institutes of Health Viral Viral Vector Whole-Cell Recordings awake base calcium indicator cell type clinically relevant disability hippocampal pyramidal neuron improved in vivo innovation insight interest mental function mouse model neocortical nervous system disorder neuropsychiatry novel strategies optical fiber optogenetics programs relating to nervous system research study temporal measurement tool two-photon

项目摘要

DESCRIPTION (provided by applicant): An essential aspect of human behavior is the ability to perform skilled and purposive movements. This ability relies on an intact neocortex, and in particular on different classes of projection neurons that convey neural information from the neocortex to downstream circuits involved in behavior. Two classes of cortical projection neurons are of particular interest - corticospinal neurons, projecting to the spinal cord, and corticostriatal neurons, projecting to the striatum bilaterally. While much has been learned from brain slice experiments about the cellular and synaptic properties of corticospinal and corticostriatal neurons, knowledge about their activity patterns in vivo in relation to volitional movements has been impeded due to a lack of easy to use methods for selectively recording from and manipulating the activity of these projection neurons. Here, building on prior ex vivo experiments, we propose a research program to develop new approaches to address this gap. In one aim, we will develop multiple complementary approaches to record the activities of corticospinal and corticostriatal neurons in the awake, moving mouse. In one set of studies we will use in vivo whole-cell recordings to record from motor cortex neurons at high sensitivity and temporal resolution, with post-hoc identification of cell types. In parallel studies we will infect corticospinal and corticostriatal neurons with recombinant rabies viruses carrying genetically encoded calcium indicators (GECIs), and detect activity either at high resolution using two- photon calcium imaging or at a population level using optical fibers. In our second aim, we will develop methods to manipulate the activities of corticospinal and corticostriatal neurons in the awake, moving mice. By either up- or down-regulate projection neuron activity using optogenetic or pharmacogenetic tools, we will be able to begin to address the question of how corticospinal and corticostriatal neurons' activities are causally related to movement parameters. The proposed research program is innovative and significant, we believe, because it will generate multiple new experimental paradigms for probing the in vivo functions of cortical projection neurons, not only in motor areas but across all of neocortex, and because these tools will be readily applicable to mouse models of neurological disease.

描述（由申请人提供）：人类行为的一个基本方面是能够执行熟练和有目的运动的能力。这种能力依赖于完整的新皮层，尤其是在不同类别的投影神经元中传达神经信息从新皮层传达到行为所涉及的下游回路。两类的皮质投射神经元特别感兴趣 - 皮质脊髓神经元，投射到脊髓和皮质纹状体神经元，双侧投射到纹状体上。尽管从大脑切片实验中学到了很多有关皮质脊髓和皮质纹状体神经元细胞和突触特性的知识，但由于缺乏易于从和选择性地记录的方法，因此影响了与自愿运动有关其体内活动模式的了解操纵这些投影神经元的活性。在这里，在先前的离体实验的基础上，我们提出了一项研究计划，以开发新的方法来解决这一差距。在一个目的中，我们将开发多种互补方法，以记录清醒的移动鼠标中皮质脊髓和皮质纹状体神经元的活动。在一组研究中，我们将使用体内全细胞记录以高灵敏度和时间分辨率记录运动皮质神经元，并在事后鉴定细胞类型。在平行研究中，我们将感染皮质脊髓和皮质纹状体神经元具有重组狂犬病病毒，携带遗传编码的钙指示剂（GECIS），并使用两光子钙成像或使用光纤在种群水平下在高分辨率下检测活性。在我们的第二个目标中，我们将开发方法来操纵清醒中的皮质脊髓和皮质纹状体神经元的活性，移动小鼠。通过使用光遗传学或药物遗传学工具上调或下调投射神经元活性，我们将能够开始解决皮质脊髓和皮质层神经元如何与运动参数有因果关系的问题。我们认为，拟议的研究计划具有创新性和重要意义，因为它将产生多个新的实验范式，用于探测皮质投影神经元的体内功能，不仅在运动区域，而且在所有新皮层中，而且这些工具都会随时适用对神经疾病的小鼠模型。