Reconstruction and Regulation of Neural Circuitry by Human Neurons

摘要 细胞疗法有望治疗CNS疾病。这是由一些帕金森氏症的临床益处所暗示的。 接受人胎儿中脑组织移植以替代 中脑多巴胺（mDA）神经元变性。能够有效地产生功能性神经元， 人类多能干细胞（PSCs）拓展了细胞治疗的前景。然而，对于许多人来说， 神经系统疾病面临重大障碍。特别是，移植的神经元往往不能重建一个 特定于失去功能的功能电路。在PD中，DA神经元通常直接移植到 纹状体，而不是其家的位置实质黑质。因此，移植的细胞及其 修复后的电路失去了用于功能调制的适当输入。 为了解决这些关键问题，我们将通过细胞移植到黑质纹状体， 在PD模型小鼠中的黑质，并确定移植的人mDA神经元是否特异性地投射到黑质。 纹状体形成功能回路，以及是否通过调节移植物活性加速重新连接（目的1）。 此外，我们将探索通过表达调控移植细胞修复的神经回路， hPSC中DREADD的活性或抑制形式（仅由设计药物激活的设计受体） 从而使治疗结果得到改善（目标2）。本研究获得的信息将 有助于恢复和调节PD和其他神经系统疾病的神经回路。

ABSTRACT Cell therapy holds promise for CNS disorders. This is suggested by clinical benefits in some Parkinson's disease (PD) patients who received transplantation of human fetal mesencephalic tissues to replace degenerated midbrain dopamine (mDA) neurons. The ability to produce functional neurons efficiently from human pluripotent stem cells (PSCs) expands the prospect of cell therapy. However, cell therapy for many neurological conditions faces major hurdles. In particular, transplanted neurons often fail to reconstruct a functional circuit that is specific to lost function. In PD, DA neurons are often transplanted directly into the striatum, rather than their home location substantial nigra. Consequently, the grafted cells and their repaired circuit lose appropriate inputs for functional modulation. To address these critical issues, we will reconstruct the nigra-striatal circuit by cell transplantation to the nigra in a PD model mouse and determine if the grafted human mDA neurons project specifically to the striatum to form functional circuit and if the reconnection is sped up by regulating graft activity (Aim 1). Furthermore, we will explore to regulate the neural circuit repaired by transplanted cells by expressing active or inhibitory form of DREADD (designer receptor exclusively activated by designer drug) in hPSCs so that the therapeutic outcomes may be refined (Aim 2). Information gained from this study will be instrumental for restoring and regulating neural circuitry in PD and other neurological conditions.