Circuit Analysis and Modulation

电路分析与调制

基本信息

批准号：
10221028
负责人：
Benjamin R Arenkiel
金额：
$ 20.55万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-22 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10221028
关键词：
Acoustics Affect Animal Model Animals Attention Behavior Behavioral Biological Assay Brain Brain Stem Cell Communication Cell Culture Techniques Chronic Clinical Cognition Communities Custom Deep Brain Stimulation Dependovirus Disease Disease model Electrophysiology (science)Engineering Experimental Designs Functional Imaging Functional disorder Gene Expression Generations Genetic Goals Human Image In Vitro Individual Intellectual and Developmental Disabilities Research Centers Intellectual functioning disability Investigation Laboratories Lentivirus Light Maps Measurement Medicine Methods Molecular Mus Nerve Tissue Nervous System Physiology Neurons Neurosciences Optics Pathway interactions Pattern Physiological Preparation Production Property Proteins Pupil Readiness Reagent Reporter Reproducibility Research Research Personnel Rodent Rodent Model Sensory Services Slice Startle Reaction Sum Synapses System Techniques Technology Testing Time Tissues Tracer Transgenic Mice Transgenic Organisms Translating Viral Viral Vector Virus Work adeno-associated viral vector base cell type clinical biomarkers college cost effective cost efficient design developmental disease experimental study flexibility gain of function genetic approach genetic manipulation in vivo knock-down member motor deficit mouse model nervous system disorder neural circuit neurophysiology neuroregulation neurotropic neurotropic virus novel optogenetics pre-clinical preclinical study prepulse inhibition programs relating to nervous system response sensory gating small hairpin RNA sound tool two-photon virus genetics

项目摘要

Intellectual and developmental disabilities (IDDs) manifest as dysfunction in neural circuits. Thus, understanding and ultimately treating IDDs requires directly and precisely interfacing with neural circuits in animal models and the human brain. The goal of the Circuit Analysis & Modulation (CAM) Core is to provide a set of techniques and approaches for BCM IDDRC investigators, and the broader scientific community, which provide a path from hypothesis to pre-clinical readiness regarding neural circuit dysfunction in IDDs. The CAM Core is comprised of three sub-cores. The Tool Generation & Characterization sub-core will develop neurotropic viruses tailored to the particular needs of IDDRC neural circuit studies, and provide assistance applying the tools to their experiments. We will focus on lenti- and adeno-associated viral vectors that are engineered to drive gene expression in desired cell types. In particular, constructed viruses will allow investigators to target mainstay and emerging powerful optogenetic proteins to individual neurons, neuronal subsets, or desired lineages to suit their experimental design. These viral vectors afford the spatial and temporal flexibility of stereotaxic targeting, and provide a time- and cost-efficient alternative to transgenic mouse design. These tools provide valuable information about neuronal firing properties or patterns of connectivity, or provide a means to synthetically perturb function, facilitating study of normal circuit function or disease. The Circuit Assessment sub-core will provide assessment of sensory and neuromodulatory systems in mice and humans, both of which feature prominently in many IDDs. Prepulse inhibition (PPI) of acoustics startle is at the intersection of sensory and neuromodulatory functions, and PPI deficits are observed in many IDDs. We offer use of our novel human ‘brain state and cognition’ testing suite, which uses pupillometry to extract multiple indicators of neuromodulatory function in sensory recognition and sensorimotor gating, as well as an analogous high-throughput mouse system to IDDRC members. We also offer sophisticated attention tasks that tap into broader circuits, and two-photon imaging of circuit function in the PPI and attention tasks. The Circuit Modulation sub-core will perform in vivo neural recordings and targeted brain stimulation for IDDRC investigators. Combining optogenetic and chemogenetic methods with neurophysiological recordings allows testing circuit mechanisms with ground truth electrical readouts. In addition, targeted chronic deep brain stimulation has been increasingly applied to function- specific neuronal assemblies or pathways in preclinical studies of various neurological diseases, including IDDs. Thus we will provide assistance, design, and service towards testing targeted electrophysiological recordings or stimulation of nervous tissue in rodent models of IDD. In sum, the CAM core as a whole will provide powerful viral tools, electrical and optical recording and stimulation approaches, and cross-species non-invasive circuit assessment, in order to translate hypotheses about neural circuit dysfunction into pre-clinical readiness for IDD treatments.

智力和发育障碍（IDD）表现为神经回路功能障碍，因此，理解能力障碍。最终治疗 IDD 需要直接、精确地连接动物模型中的神经回路电路分析和调制 (CAM) 核心的目标是提供一套技术。为 BCM IDDRC 研究人员和更广泛的科学界提供了一条途径关于 IDD 神经回路功能障碍的临床前准备假设 CAM 核心由以下部分组成。工具生成和表征子核心将开发针对神经网络的病毒。 IDDRC 神经回路研究的特殊需求，并提供将这些工具应用于其研究的帮助我们将重点关注经过改造以驱动基因的慢病毒和腺相关病毒载体。特别是，构建的病毒将允许研究人员瞄准主流和目标细胞。针对单个神经元、神经元亚群或所需谱系的新兴强大光遗传学蛋白，以适应其需求这些病毒载体提供了立体定位的空间和时间灵活性，以及这些工具为转基因小鼠设计提供了一种节省时间和成本的替代方案。有关神经放电特性或连接模式的信息，或提供一种综合方法扰乱功能，促进正常回路功能或疾病的研究。提供对小鼠和人类的感觉和神经调节系统的评估，这两种系统都具有在许多 IDD 中，声学惊吓的前脉冲抑制 (PPI) 处于感觉和惊吓的交叉点。在许多 IDD 中观察到神经调节功能和 PPI 缺陷，我们提供新型人类“大脑”的使用。状态和认知测试套件，使用瞳孔测量来提取神经调节的多个指标在感觉识别和感觉运动门控以及类似的高通量小鼠系统中发挥作用我们还向 IDDRC 成员提供复杂的注意力任务，这些任务涉及更广泛的电路和双光子。 PPI 中的电路功能成像和注意力任务将在体内执行。为 IDDRC 研究人员提供神经记录和定向脑刺激。具有神经生理学记录的化学遗传学方法可以用真实情况测试电路机制此外，有针对性的慢性深部脑刺激已越来越多地应用于功能- 各种神经系统疾病（包括 IDD）的临床前研究中的特定神经元组件或通路。因此，我们将提供帮助、设计和服务来测试有针对性的电生理记录或总之，CAM 核心作为一个整体将提供强大的 IDD 啮齿动物模型神经组织刺激。病毒工具、电学和光学记录和刺激方法以及跨物种非侵入性电路评估，以便将有关神经回路功能障碍的假设转化为 IDD 的临床前准备治疗。