Circuit Analysis and Modulation

电路分析与调制

• 批准号: 10427284
• 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
• 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/10427284
• 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

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(IDDS)表现为神经回路功能障碍。因此，理解 最终治疗IDDS需要直接和精确地与动物模型和 人类的大脑。电路分析与调制(CAM)核心的目标是提供一套技术 和方法，为BCM IDDRC调查人员和更广泛的科学界提供了一条途径 IDDS患者神经回路功能障碍的临床前准备情况的假说。CAM核心由以下部分组成 三个子核。工具生成和特征化子核心将开发神经嗜性病毒 IDDRC神经回路研究的特殊需求，并提供将这些工具应用于其 实验。我们将专注于Lenti和腺相关病毒载体，它们被设计成驱动基因 以所需的单元格类型表示。特别是，构建的病毒将使调查人员能够针对主体和 向单个神经元、神经元亚群或所需谱系提供强大的光遗传蛋白，以适应其 实验设计。这些病毒载体提供了立体定向的空间和时间灵活性，并且 为转基因小鼠的设计提供了一种既省时又经济的替代方案。这些工具提供了宝贵的 有关神经元放电特性或连接模式的信息，或提供一种综合 扰乱功能，便于研究正常的电路功能或疾病。巡回评估子核心将 提供对小鼠和人类感觉和神经调节系统的评估，这两个系统都具有 在许多IDDS中表现突出。声学惊厥的脉冲前抑制(PPI)位于感觉和听觉的交叉点 在许多IDDS中观察到神经调节功能和PPI缺陷。我们提供我们的新奇人脑的用途 状态和认知测试套件，使用瞳孔测量法提取神经调制的多个指标 在感觉识别和感觉运动门控中的功能，以及类似的高通量鼠标系统 给国际民主与发展中心成员。我们还提供复杂的注意力任务，利用更广泛的电路和双光子 PPI和注意任务中的电路功能成像。电路调制子核将在体内运行 为IDDRC调查人员提供神经记录和定向脑刺激。结合光生和 具有神经生理记录的化学发生方法允许用基本事实测试电路机制 电子读数。此外，有针对性的慢性脑深部刺激越来越多地应用于功能- 在包括IDDS在内的各种神经系统疾病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，以测试目标电生理记录或 IDD啮齿动物模型对神经组织的刺激作用。总而言之，CAM核心作为一个整体将提供强大的 病毒工具、电和光记录和刺激方法以及跨物种非侵入性电路 评估，以便将神经回路功能障碍的假说转化为IDD的临床前准备 治疗。