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: 8346815
• 负责人: Steve M Potter
• 金额: $ 31.82万
• 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/8346815
• 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. PUBLIC HEALTH RELEVANCE: The way the brain regulates its sensitivity to input can cause devastating symptoms when input gets cut off, due to stroke, epilepsy, deafness in the inner ear, loss of a limb, or brain damage from physical trauma. Brain tissue can become too sensitive to its own spontaneous activity, causing seizures, ringing in the ears, chronic pain, or other serious neurological problems. This proposal is to create a new and powerful tool to actively correct this type of over-sensitivity and restore more normal neural activity patterns.

描述（由申请人提供）： 这是响应 PA-10-009 的多学科_生物工程研究补助金_ (BRG) 提案，具有设计驱动和发现驱动的元素。 它基于一个越来越流行的假设，即许多神经系统疾病的进展根源于已经变得适应不良的稳态可塑性。 这些可被归类为传入障碍，即中枢神经系统组织中数天或数周内出现破坏性同步群体爆发活动，其输入已因白质损伤、中风或感觉受体或周围神经损伤而大大减少或消除。 群体爆发产生的低频、高振幅放电可表现为癫痫、慢性疼痛、肌张力障碍、耳鸣或其他致残症状，具体取决于神经系统的哪一部分在传入神经阻滞后变得过度兴奋。 药物治疗常常完全无效。 这导致许多人提出涉及通过植入电极或经颅磁刺激进行直接局部脑刺激的疗法。 光遗传学提供了一种更加局部和特定的方式来刺激脑组织，因为它可以使特定的神经细胞类型对特定颜色的光敏感。 也就是说，光可以激活或沉默目标神经元，从而使异常的神经元正常化。 活动。 基于成功的闭环方法，通过多电极阵列刺激来平息培养皮质网络中癫痫样群体爆发，该项目旨在开发和优化闭环光遗传学工具，以控制稳态可塑性机制，并逆转传入神经缺失的组织表现出同步爆发的倾向。 该“群体钳”将采用多电极阵列基板的细胞外记录作为反馈信号，快速连续地调节彩色光脉冲，选择性地激活和抑制不同的神经元类型，以维持所需的活动水平。 表达由于体外制剂典型的传入阻滞而导致的群体放电的皮质网络将被固定在不同的活动设定点几天。 稳态反应，例如突触强度的变化，将通过细胞内记录和细胞外群体活动测量来监测。 使用腺相关病毒载体针对兴奋性锥体神经元或抑制性中间神经元的光遗传学构建体的组合，将比较它们作为可以操纵稳态可塑性的手柄的能力。 将开发反馈控制算法，以最有效和持久地缓解群体爆发，同时增强网络功能的测量，例如复杂光输入和尖峰输出之间的互信息。 通过提供一个可访问且可操作的测试台来研究不同的结构和参数，光遗传学群体夹具将为通过植入光纤采用闭环光刺激的各种神经系统疾病的基因治疗铺平道路。 公共健康相关性：当输入被切断时，大脑调节其对输入的敏感性的方式可能会导致毁灭性的症状，例如中风、癫痫、内耳聋、肢体丧失或身体创伤造成的脑损伤。 脑组织对其自身的自发活动变得过于敏感，导致癫痫发作、耳鸣、慢性疼痛或其他严重的神经系统问题。 该提案旨在创建一种新的强大工具来主动纠正这种类型的过度敏感并恢复更正常的神经活动模式。