Reorganization of the Central Visual System by Inhibitory Neuron Transplantation

通过抑制性神经元移植重组中枢视觉系统

• 批准号: 9919570
• 负责人: Sunil Gandhi
• 金额: $ 49.75万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9919570
• 关键词: Adolescent; Adult; Anatomy; Base of the Brain; Brain; Calcium; Cell Transplantation; Cells; Childhood; Contralateral; Corpus Callosum; Data; Development; Dissection; Embryo; Equilibrium; Glutamates; Goals; Housing; Image; Impairment; Intuition; Light; Maps; Measures; Mediating; Microscopy; Modeling; Mus; Neurons; Parvalbumins; Pattern; Pharmacology; Rabies; Regulation; Resolution; Role; Sensory; Slice; Structure; Supporting Cell; Testing; Thalamic structure; Time; Tissues; Transplantation; Viral; Visual; Visual Acuity; Visual Cortex; Visual impairment; Visual system structure; Whole-Cell Recordings; area striata; awake; base; brain repair; calcium indicator; cell type; chemical genetics; critical period; designer receptors exclusively activated by designer drugs; experience; in vivo; inhibitory neuron; insight; monocular deprivation; multiphoton imaging; novel; optogenetics; relating to nervous system; response; tool; two-photon; visual deprivation; visual plasticity

The transplantation of embryonic inhibitory neurons has recently emerged as a promising avenue for cell-based brain repair. Previously, we and others have shown that transplanted inhibitory neurons restore juvenile plasticity to the circuits of adult visual cortex. In this study, we set out to elucidate the mechanisms for transplant-induced cortical plasticity. We hypothesize that transplanted inhibitory neurons reactivate plasticity by creating a new, disinhibitory microcircuit in recipient adult visual cortex. First, we will map out the effects of transplantation on the inter- and intralaminar balance of excitation and inhibition. Next, we will compare the cell-type specific effects of brief monocular deprivation on visual activity in host cortex. Lastly, we will test whether transplanted neurons make long-range connections with appropriate circuits. To evaluate these hypotheses, this proposal will take advantage of recent advances in optogenetic dissection of inhibitory circuits in brain slice, multiphoton imaging of defined cortical cell types using genetically encoded calcium indicators, chemical-genetic tools for testing the mechanisms of transplant- induced plasticity and viral tracing and whole brain clearing to identify the brain-wide connections onto transplanted cells. If successful, the proposed studies shed light on the mechanisms of transplant-induced cortical reorganization. These studies are also likely to give insight into the normal developmental regulation of cortical plasticity by inhibitory cells.

胚胎抑制性神经元的移植最近成为一个有前途的途径 用于细胞脑修复以前，我们和其他人已经证明，移植的抑制性神经元 恢复青少年视觉皮层回路的可塑性。在这项研究中，我们着手阐明 移植诱导皮质可塑性的机制。我们假设移植的抑制性神经元 通过在受体成人视觉皮层中创建一个新的去抑制微回路来重新激活可塑性。一是 绘制出移植对兴奋和抑制的板间和板内平衡的影响。 接下来，我们将比较短暂单眼剥夺对宿主视觉活动的细胞类型特异性影响 皮层最后，我们将测试移植的神经元是否与合适的神经元建立长距离连接。 电路.为了评估这些假设，该提案将利用光遗传学的最新进展， 脑切片中抑制回路的解剖，使用 基因编码的钙指标，用于测试移植机制的化学遗传工具， 诱导可塑性和病毒追踪和全脑清除，以确定大脑范围内的连接， 移植细胞如果成功，拟议的研究将阐明移植诱导的机制。 皮层重组这些研究也有可能让我们了解正常的发展， 抑制性细胞对皮层可塑性的调节。