Reorganization of the Central Visual System by Inhibitory Neuron Transplantation

胚胎抑制性神经元移植是最近出现的一种很有前途的方法。 用于基于细胞的大脑修复。此前，我们和其他人已经证明了移植的抑制性神经元 将幼年的可塑性恢复到成年视皮层的回路。在这项研究中，我们试图阐明 移植诱导的皮质可塑性的机制。我们假设移植的抑制性神经元 通过在受体成人视皮层中创建一个新的、去抑制的微电路来重新激活可塑性。首先，我们将 绘制出移植对层间和层内兴奋和抑制平衡的影响。 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 大脑皮层。最后，我们将测试移植的神经元是否与适当的 电路。为了评估这些假说，这项建议将利用光遗传学的最新进展。 大脑切片中抑制电路的解剖，定义的皮质细胞类型的多光子成像使用 基因编码的钙指示剂，测试移植机制的化学遗传工具- 诱导可塑性和病毒追踪以及全脑清除以确定全脑连接到 移植的细胞。如果成功，拟议的研究将有助于阐明移植诱导的机制 皮质重组。这些研究也可能让我们深入了解正常的发育 抑制细胞对皮质可塑性的调节。

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.