Circuit Analysis and Modulation

电路分析与调制

• 批准号: 10675502
• 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/10675502
• 关键词: Acoustics; Affect; Animal Model; Animals; Attention; Behavior; Behavioral; Biological Assay; Biological Markers; 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; Outsourcing; Pathway interactions; Pattern; Physiologic pulse; Physiological; Preparation; Production; Property; Proteins; Pupil; Readiness; Reagent; Reporter; Reproducibility; Research; Research Personnel; Rodent; Rodent Model; Sensory; Services; Slice; Startle Reaction; Synapses; System; Techniques; Technology; Testing; Time; Tissues; Tracer; Transgenic Mice; Transgenic Organisms; Translating; Viral; Viral Vector; Virus; Work; adeno-associated viral vector; cell type; 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; neural circuit; neurophysiology; neuroregulation; neurotropic; neurotropic virus; novel; optogenetics; pre-clinical; preclinical study; prepulse inhibition; programs; response; sensory gating; small hairpin RNA; sound; tool; two-photon

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）表现为神经回路中的功能障碍。那，理解 最终处理IDD需要直接，精确地与动物模型中的神经回路接口 人脑。电路分析与调制（CAM）核心的目标是提供一组技术 以及BCM IDDRC调查人员和更广泛的科学界的方法，这为 关于IDD中神经回路功能障碍的临床前准备的假设。凸轮芯已完成 三个子核。工具的产生和表征子核将开发出量身定制的神经性病毒 IDDRC神经循环研究的特殊需求，并提供了将工具应用于其的帮助 实验。我们将专注于扁豆和腺相关的病毒载体，这些病毒载体旨在驱动基因 所需的细胞类型中的表达。特别是，构造的病毒将允许研究人员针对中流tay和 向单个神经元，神经元子集或所需谱系形成强大的光遗传蛋白，以适应其 实验设计。这些病毒载体提供了立体定位靶向的空间和暂时灵活性，以及 提供转基因小鼠设计的时间和成本效益替代方案。这些工具提供了宝贵的 有关神经元触发属性或连接模式的信息，或提供合成的方法 扰动功能，支持正常电路功能或疾病的研究。电路评估子核将 提供小鼠和人类的感觉和神经调节系统的评估，这两个特征 在许多IDD中显着。声学的抑制（PPI）是在感觉和 在许多IDD中观察到神经调节功能，PPI定义。我们提供新颖的人类大脑 状态和认知测试套件，该套件使用化学计量法提取多个神经调节指标 感觉识别和感觉运动门控的功能以及类似的高通量鼠标系统 给IDDRC成员。我们还提供了复杂的注意任务，这些任务利用了更广泛的电路和两光孔 PPI和注意任务中电路功能的成像。电路调制子核将在体内执行 IDDRC研究人员的神经记录和针对性的大脑刺激。结合光遗传学和 具有神经生理记录的化学发生方法允许测试具有地面真相的电路机制 电气读数。此外，靶向慢性深脑刺激已越来越多地应用于功能 - 包括IDD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途径。 我们将提供帮助，设计和服务，以测试有针对性的电生理记录或 IDD啮齿动物模型中神经组织的刺激。总而言之，凸轮核心将提供强大的功能 病毒工具，电气记录和刺激方法以及跨物种非侵入性电路 评估，以将有关神经回路功能障碍的假设转化为IDD的临床前准备就绪 治疗。