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Circuit Analysis and Modulation

电路分析与调制

基本信息

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
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/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

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（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中的神经回路连接，人类的大脑。电路分析和调制（CAM）核心的目标是提供一套技术和方法，为CNOIDDRC调查人员和更广泛的科学界，这提供了一条道路，关于IDDs神经回路功能障碍的临床前准备假设。CAM核心包括三个子核心。工具生成和表征子核心将开发专为以下目的定制的嗜神经病毒： IDDRC神经回路研究的特殊需求，并提供应用工具的帮助，实验我们将重点关注慢病毒和腺相关病毒载体，这些载体被设计用于驱动基因表达。在所需细胞类型中表达。特别是，构建的病毒将使研究人员能够针对主干和新兴的强大的光遗传学蛋白质，以个别神经元，神经元子集或所需的谱系，以适应他们的需求。实验设计这些病毒载体提供了立体定位靶向的空间和时间灵活性，为转基因小鼠的设计提供了一种时间和成本效益高的替代方案。这些工具提供了宝贵的关于神经元放电特性或连接模式的信息，或者提供合成地干扰功能，促进正常电路功能或疾病的研究。巡回评估子核心将提供小鼠和人类的感觉和神经调节系统的评估，两者都具有在许多IDDs中，声惊吓的前脉冲抑制（PPI）处于感觉和在许多IDD中观察到神经调节功能和PPI缺陷。我们提供使用我们新的人类大脑状态和认知的测试套件，它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中的功能，以及类似的高通量鼠标系统 IDDRC成员。我们还提供复杂的注意力任务，利用更广泛的电路，双光子在PPI和注意力任务中的电路功能成像。电路调制子核心将在体内执行神经记录和有针对性的大脑刺激IDDRC调查。结合光遗传学和具有神经生理学记录的化学遗传学方法允许用地面实况测试电路机制电子读数此外，有针对性的慢性脑深部电刺激已越来越多地应用于功能- 在各种神经系统疾病（包括IDDs）的临床前研究中使用特定的神经元组装或通路。因此，我们将提供援助，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。总之，CAM核心作为一个整体将提供强大的病毒工具、电和光学记录和刺激方法以及跨物种非侵入性电路评估，以便将关于神经回路功能障碍的假设转化为IDD的临床前准备治疗。