Mechanisms of Somatosensory Circuit Remapping After Cortical Injury in Mice

小鼠皮质损伤后体感回路重新映射的机制

• 批准号: 10445074
• 负责人: William Abel Zeiger
• 金额: $ 20.35万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-15 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10445074
• 关键词: Animal Model; Animals; Area; Atlases; Behavioral; Biological Models; Brain; Brain Mapping; Brain region; Calcium; California; Cell Shape; Cells; Clinical Sciences; Communities; Complex; Control Animal; Dendritic Spines; Development; Development Plans; Equilibrium; Etiology; Exhibits; Functional Magnetic Resonance Imaging; Functional disorder; Future; Gene Expression; Global Change; Goals; Human; Image; Imaging Techniques; Impairment; Individual; Injury; Institutes; Institution; Interneurons; Knowledge; Label; Learning; Lesion; Light; Los Angeles; Measures; Mediating; Mentors; Methods; Movement Disorders; Mus; Nervous System Trauma; Neuraxis; Neurology; Neurons; Neurosciences; Parvalbumins; Pathologic; Pathologic Processes; Physicians; Play; Positron-Emission Tomography; Pyramidal Cells; Recovery; Recovery of Function; Research; Research Personnel; Resolution; Resources; Role; Scientist; Sensory; Shapes; Site; Somatosensory Cortex; Stroke; Technical Expertise; Testing; Therapeutic; Time; Tissues; Translational Research; Universities; Vibrissae; Work; axonal sprouting; base; career; career development; designer receptors exclusively activated by designer drugs; disability; experience; human model; in vivo; in vivo calcium imaging; insight; mouse model; nervous system disorder; neural circuit; neuronal circuitry; neuroregulation; novel; post stroke; professor; response; sensory discrimination; somatosensory; stroke model; translational study; two-photon; whisker discrimination

PROJECT SUMMARY / ABSTRACT Circuits in the healthy central nervous system (CNS) have the capacity for reorganization and remapping of functionality. Growing evidence suggests that circuit remapping may contribute to a number of neurologic diseases as well. For example, it has been widely hypothesized that remapping of circuits underlies recovery after a focal lesion of the CNS, such as stroke. However, how specific changes in neuronal circuits mediate improvement in function and recovery after cortical injury remains a major gap in our understanding. Here, Dr. Zeiger will utilize advanced techniques for imaging and manipulating circuits in vivo to define the local and global changes in neural circuits that occur following a lesion of the somatosensory cortex in mice. In Aim 1, Dr. Zeiger will investigate the role of GABAergic parvalbumin (PV) cells in peri-lesional remapping of somatosensory function after small lesions to the cortex. PV cells shape cortical sensory representations and regulate experience-dependent plasticity. Dr. Zeiger hypothesizes that PV cells in peri-lesional cortex play a critical role in functional remapping. He will test this hypothesis by 1) recording sensory-evoked responses from PV and pyramidal cells throughout recovery using in vivo two-photon (2P) calcium imaging and 2) modulating PV cell activity using DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) and measuring the effects on circuit remapping. In Aim 2, Dr. Zeiger will identify novel candidate brain regions for remapping of lost functionalities that mediate behavioral recovery after large cortical lesions. He hypothesizes that remapping after large lesions involves distributed networks of neurons across multiple brain regions. He will test this by generating a quantitative atlas of all remapped whisker-responsive neurons following recovery, allowing identification of novel candidate regions important for remapping. He will then measure changes in circuit function in these sites over time during recovery and confirm the roles of these regions by manipulating neuronal activity with DREADDs and testing the effect on recovery of somatosensory function. Dr. Zeiger is currently an Assistant Professor in Neurology at the University of California – Los Angeles (UCLA). His long-term career goal is to work as a physician-scientist investigating mechanisms of circuit dysfunction contributing to neurologic disease. As part of this proposal he will carry out a detailed career development plan focusing on gaining technical skills in advanced neuroscience methods for investigating neuronal circuits, expanding his knowledge of how circuit dysfunction contributes to movement disorders, and transitioning to an independent career. This work will be carried out at UCLA, a renowned research institution with an extensive community of investigators in neuroscience and neurology and supported by numerous institutional resources such as the UCLA Clinical and Translational Science Institute. Dr. Zeiger’s career development will be guided by a team of mentors including his primary mentor Dr. Carlos Portera-Cailliau and co-mentors Dr. Jeff Bronstein and Dr. S. Thomas Carmichael.

项目摘要/摘要 健康的中枢神经系统(CNS)中的回路具有重组和重新映射的能力 功能性。越来越多的证据表明，回路重新映射可能有助于许多神经学 疾病也是如此。例如，人们普遍假设，电路的重新映射是恢复的基础 中枢神经系统局灶性病变后，如中风。然而，神经元回路的具体变化是如何调节的 皮质损伤后功能和恢复的改善仍然是我们认识上的一个主要差距。在这里，博士。 Zeiger将利用体内成像和操作电路的先进技术来定义局部和全局 小鼠躯体感觉皮质受损后发生的神经回路变化。在《目标1》中，齐格博士 将研究GABA能小白蛋白(PV)细胞在躯体感觉周围性重新定位中的作用 小损伤后大脑皮层功能受损。光伏细胞塑造大脑皮层感觉表征和调节 依赖经验的可塑性。齐格博士假设皮损周围皮质中的光伏细胞起着关键作用 在功能重新映射中。他将通过1)记录来自PV的感官诱发反应和 利用体内双光子钙成像和2)调节PV细胞，实现锥体细胞的全程恢复 使用DREADDS(由设计师药物独占激活的设计师受体)的活性和测量 对电路重新映射的影响。在目标2中，齐格博士将确定重新定位Lost的新的候选脑区 调节大脑皮层损伤后行为恢复的功能。他假设重新映射后 大型损伤涉及分布在多个大脑区域的神经元网络。他将通过以下方式测试这一点 在恢复后生成所有重新映射的胡须反应神经元的定量图谱，允许 识别对重新定位重要的新候选区域。然后，他将测量电路功能的变化 在恢复过程中随着时间的推移，并通过操纵神经元活动确认这些区域的作用 并检测其对躯体感觉功能恢复的影响。 齐格博士目前是加州大学洛杉矶分校的神经学助理教授 (加州大学洛杉矶分校)。他的长期职业目标是成为一名研究电路机制的内科科学家。 导致神经系统疾病的功能障碍。作为这项提议的一部分，他将进行详细的职业生涯 发展计划，重点是获得高级神经科学研究方法方面的技术技能 神经回路，扩大了他关于回路障碍如何导致运动障碍的知识，以及 过渡到独立的事业。这项工作将在加州大学洛杉矶分校进行，这是一家著名的研究机构 拥有广泛的神经科学和神经学研究人员社区，并得到了众多 机构资源，如加州大学洛杉矶分校临床和转化科学研究所。齐格博士的职业生涯 开发将由一个导师团队指导，其中包括他的主要导师Carlos Portera-Cailliau博士和 共同导师杰夫·布朗斯坦博士和S·托马斯·卡迈克尔博士。