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: 10301676
• 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/10301676
• 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.

项目总结/摘要 健康中枢神经系统（CNS）中的回路具有重组和重新映射神经元的能力。 功能.越来越多的证据表明，电路重新映射可能有助于一些神经系统疾病， 疾病也一样。例如，人们普遍假设，电路的重新映射是恢复的基础 在中枢神经系统的局灶性病变（例如中风）之后。然而，神经回路中的特定变化如何介导 在我们的理解中，皮质损伤后功能和恢复的改善仍然是一个主要的空白。在这里，博士。 Zeiger将利用先进的技术在体内成像和操纵电路，以确定局部和全局 小鼠躯体感觉皮层损伤后神经回路的变化。在目标1中， 将研究GABA能小清蛋白（PV）细胞在躯体感觉神经元损伤周围重映射中的作用。 功能后，小病变的皮质。PV细胞塑造皮层感觉表征并调节 依赖经验的可塑性Zeiger博士假设病变周围皮层的PV细胞在 在功能重映射中。他将通过1）记录PV的感觉诱发反应， 使用体内双光子（2 P）钙成像和2）调节PV细胞 使用DREADDs（设计师药物独家激活的设计师受体）和测量 对电路重新映射的影响。在目标2中，Zeiger博士将确定新的候选大脑区域，用于重新映射丢失的大脑区域。 在大的皮质损伤后介导行为恢复的功能。他假设， 大的病变涉及跨多个脑区的神经元分布网络。他将通过 生成恢复后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的候选区域。然后他将测量电路功能的变化 并通过操纵神经元活动来确认这些区域的作用 与DREADDs和测试对恢复躯体感觉功能的影响。 博士Zeiger目前是加州-洛杉矶大学神经病学助理教授 （UCLA）。他的长期职业目标是作为一名物理学家兼科学家， 导致神经系统疾病的功能障碍。作为这项建议的一部分，他将进行详细的职业生涯， 发展计划，重点是获得先进的神经科学方法的技术技能， 神经元回路，扩大了他对回路功能障碍如何导致运动障碍的认识， 向独立职业过渡。这项工作将在著名的研究机构加州大学洛杉矶分校进行 拥有广泛的神经科学和神经病学研究人员社区，并得到众多 机构资源，如加州大学洛杉矶分校临床和转化科学研究所。Zeiger博士的职业生涯 开发将由一个导师团队指导，包括他的主要导师卡洛斯波特拉-卡里奥博士， 共同导师Jeff Bronstein博士和S.托马斯卡迈克尔。