Optogenetic Population Clamp to Study Long-term Plasticity in Vitro

光遗传学群体钳研究体外长期可塑性

• 批准号: 8681565
• 负责人: ROBERT J BUTERA
• 金额: $ 29.38万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8681565
• 关键词: Address; Algorithms; Animal Model; Animals; Applications Grants; Auditory; Basic Science; Beds; Biomedical Engineering; Brain; Brain Injuries; Brain region; Cells; Cessation of life; Chemicals; Color; Complex; Computer software; Controlled Study; Data; Databases; Deafferentation procedure; Disease; Disease remission; Dystonia; Ear; Electrodes; Electroencephalography; Electrophysiology (science); Elements; Engineering; Environment; Epilepsy; Etiology; Feedback; Fiber Optics; Frequencies; Future; Goals; Hearing; Homeostasis; Human; Image; Implant; Implanted Electrodes; In Vitro; Internet; Interneurons; Labyrinth; Lead; Light; Limb structure; Longitudinal Studies; Measures; Methods; Modeling; Monitor; Nervous System Part; Nervous system structure; Neural Inhibition; Neurologic; Neurons; Neurosciences; Optics; Output; Parkinson Disease; Pattern; Peripheral Nerves; Pharmacological Treatment; Physiologic pulse; Plant Roots; Population; Preparation; Primates; Research Personnel; Research Project Grants; Resolution; Rodent; Role; Seizures; Sensory Receptors; Signal Transduction; Stroke; Symptoms; Synapses; System; Techniques; Technology; Testing; Therapeutic; Time; Tinnitus; Tissue Donors; Tissues; Transcranial magnetic stimulation; Transgenic Animals; Transgenic Organisms; Trauma; Viral Vector; Wit; adeno-associated viral vector; base; brain tissue; cell type; chronic pain; data mining; data sharing; deafness; density; design; extracellular; gene therapy; hippocampal pyramidal neuron; improved; in vitro Model; in vitro testing; information processing; insight; nervous system disorder; neural circuit; neuroregulation; novel; novel strategies; optogenetics; photonics; relating to nervous system; response; somatosensory; therapeutic gene; tool; white matter damage

DESCRIPTION (provided by applicant): This is a multi-disciplinary _Bioengineering Research Grants_ (BRG) proposal in response to PA-10-009, with design-driven and discovery-driven elements. It is based on a hypothesis that is gaining in popularity, that the progression of a number of neurological disorders is rooted in homeostatic plasticity that has become maladaptive. These can be classified as de-afferentation disorders, where disruptive synchronized population bursting activity develops across days or weeks, in CNS tissue whose inputs have been greatly reduced or eliminated by white matter damage, stroke, or damage to sensory receptors or peripheral nerves. Low-frequency, high-amplitude electrical discharges from population bursting can manifest as seizures, chronic pain, dystonia, tinnitus, or other disabling symptoms, depending on which part of the nervous system has become hyper-excitable after deafferentation. Pharmacological treatments are often completely ineffective. This has lead many to propose therapies that involve direct, localized brain stimulation with implanted electrodes or transcranial magnetic stimulation. Optogenetics provides a much more localized and specific way to stimulate brain tissue, because it can render defined neural cell types sensitive to light of specific colors. Wit it, light can either activate or silence targeted neurons in an effort to normalize aberrant neural activity. Based on a successful closed-loop approach to quieting seizure-like population bursting in cultured cortical networks with multi-electrode array stimulation, this project is to develop and optimize a closed-loop optogenetic tool to gain control over homeostatic plasticity mechanisms, and to reverse the tendency of deafferented tissue to express synchronized bursting. This _Population Clamp_ will employ extracellular recording from multi-electrode array substrates as the feedback signal, to rapidly and continuously adjust pulses of colored light, selectively activating and inhibiting different neuron types, to maintain a desired activity level. Cortical networks expressing population discharges due to the deafferentation typical of in vitro preparations will be clamped to different activity set----points for days. Homeostatic responses, such as changes in synaptic strength, will be monitored with intracellular recording and extracellular measures of population activity. Combinations of optogenetic constructs, directed at excitatory pyramidal neurons or inhibitory interneurons using adeno-associated viral vectors, will be compared in terms of their ability to serve as handles by which homeostatic plasticity can be manipulated. Feedback control algorithms will be developed that enable the most effective and enduring remission of population bursting, while enhancing measures of network function, such as the mutual information between complex light input and spiking output. By providing an accessible and manipulable test bed for studying different constructs and parameters, the Optogenetic Population Clamp will pave the way for gene-therapeutic treatments of a variety of neurological disorders that employ closed-loop light stimulation via implanted fiber optics.

描述（由申请人提供）： 这是一个多学科的_bio Giankinering Research Grants_（BRG）提案，响应PA-10-009，并带有设计驱动和发现驱动的元素。 它是基于一个普及的假设，即许多神经系统疾病的进展源于已成为适应不良的稳态可塑性。 这些可以归类为消除反应障碍​​，在几天或几周内发生破坏性同步的人口爆发活动，在中枢神经系统组织中，其输入大大降低或通过白质损害，中风或对感觉受体或外围神经的损害大大降低或消除。 从人口爆发中的低频，高振幅电气排放可以表现为癫痫发作，慢性疼痛，肌张力障碍，耳鸣或其他残疾症状，具体取决于神经系统的哪一部分在脱发后变得多余。 药理治疗通常完全无效。 这使许多人提出了涉及植入电极或经颅磁刺激的直接局部脑刺激的疗法。 光遗传学提供了一种更具局部和特定的刺激脑组织的方法，因为它可以使定义的神经细胞类型对特定颜色的光敏感。 机智，光可以激活或沉默的靶向神经元，以使异常神经归一化 活动。 基于一种成功的闭环方法，可以使具有多电极阵列刺激的培养皮层网络中的癫痫发作样种群爆发，该项目是为了开发和优化一种闭环光遗传学工具，以控制对稳态可塑性机制的控制，并逆转脱离组织的趋势，以表达脱附的组织表达同步同步爆发。 该_人群夹将采用从多电极阵列底物作为反馈信号的细胞外记录，以快速，连续调整有色光的脉冲，有选择地激活和抑制不同的神经元类型，以维持所需的活性水平。 由于典型的体外制剂典型的剥离而表达人口排放的皮质网络将被夹在几天的不同活动设置中。 稳态反应，例如突触强度的变化，将通过细胞内记录和人群活性的细胞外测量来监测。 使用腺体相关病毒载体的兴奋性金字塔神经元或抑制性神经元的光遗传构建体的组合将根据其作为手柄的能力进行比较，可以通过操纵稳态可塑性。 将开发反馈控制算法，使人口爆发的最有效，最持久的缓解，同时增强网络功能的度量，例如复杂的光输入和尖峰输出之间的相互信息。 通过为研究不同的构建体和参数提供可访问且可操纵的测试床，光遗传种群夹将为通过植入植入光纤采用闭环光刺激的多种神经系统疾病的基因治疗铺平道路。