Functional reconstruction of the basal ganglia neural circuit by human striatal neurons in hypoxic-ischaemic injured brain.
Functional reconstruction of the basal ganglia neural circuit by human striatal neurons in hypoxic-ischaemic injured brain.
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缺氧性损伤的大脑中人纹状体神经元基底神经神经回路的功能重建。
DOI：
10.1093/brain/awac358
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发表时间：
2023-02-13
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围产期缺氧缺血性脑病是导致新生儿死亡和永久性神经功能障碍的主要原因，而基底节是缺氧缺血性脑病患者脑内选择性和高度受累的主要核团之一，尤其是重症患者。人类胚胎干细胞来源的神经元在成人不同类型的脑部疾病中显示出巨大的潜力。然而，目前尚不清楚移植的人类胚胎干细胞来源的神经元是否以及如何修复患有缺氧缺血性脑病的未成熟大脑。在这里，通过将基因标记的人胚胎干细胞来源的纹状体神经前体细胞注入缺氧缺血性脑病小鼠同侧纹状体，我们发现移植的细胞在形态和电生理上逐渐成熟为GABA刺状投射神经元，并显著挽救了缺氧缺血性脑病损伤脑的面积损失。有趣的是，利用免疫组织化学染色结合增强的抗坏血酸过氧化物酶免疫电子显微镜和狂犬病病毒介导的跨突触示踪，我们发现移植物开始向内源性靶区(苍白球外球、苍白球内侧区、黑质)延伸轴突投射，与宿主纹状体、苍白球和黑质神经元形成突触，并在移植后2个月接受广泛而稳定的突触输入。重要的是，我们通过光遗传学结合电生理记录，进一步证明了移植后3-6个月，移植神经元与宿主皮质、纹状体和黑质神经元之间的功能神经回路在缺氧缺血性脑病损伤的脑中重新建立。最后，移植的纹状体棘投射神经元而不是脊髓GABA神经元恢复了缺氧缺血性脑病的运动缺陷，这种缺陷可以被氯氮平-N-氧化物抑制移植物功能所逆转。这些发现表明，在缺氧缺血性脑病损伤的未成熟脑中，纹状体棘突投射神经元对包括多个环的基底节神经回路进行了解剖和功能重建，这增加了这种细胞替代治疗新生儿缺氧缺血性脑病的可能性。Jiet al.人胚胎干细胞来源的纹状体神经前体细胞移植到缺氧缺血性脑病脑损伤小鼠的纹状体内。这些细胞成熟为GABA能棘突投射神经元，重新填充受损的纹状体，从解剖和功能上修复基底节回路，并修复运动缺陷。
Perinatal hypoxic–ischaemic encephalopathy is the leading cause of neonatal death and permanent neurological deficits, while the basal ganglia is one of the major nuclei that is selectively and greatly affected in the brains of hypoxic–ischaemic encephalopathy patients, especially in severe cases. Human embryonic stem cell-derived neurons have shown great potential in different types of brain disorders in adults. However, it remains unknown whether and how grafted human embryonic stem cell-derived neurons can repair immature brains with hypoxic–ischaemic encephalopathy. Here, by administrating genetically labelled human embryonic stem cell-derived striatal neural progenitors into the ipsilateral striatum of hypoxic–ischaemic encephalopathy-injured mice, we found that the grafted cells gradually matured into GABA spiny projection neurons morphologically and electrophysiologically, and significantly rescued the area loss of hypoxic–ischaemic encephalopathy-injured brains. Intriguingly, using immunohistochemical staining combined with enhanced ascorbate peroxidase-based immunoelectron microscopy and rabies virus-mediated trans-synaptic tracing, we show that the grafts start to extend axonal projections to the endogenous target areas (globus pallidus externa, globus pallidus internus, substantia nigra), form synapses with host striatal, globus pallidus and nigra neurons, and receive extensive and stable synaptic inputs as early as 2 months post-transplantation. Importantly, we further demonstrated functional neural circuits re-established between the grafted neurons and host cortical, striatal and substantial nigra neurons at 3–6 months post-transplantation in the hypoxic–ischaemic encephalopathy-injured brain by optogenetics combined with electrophysiological recording. Finally, the transplanted striatal spiny projection neurons but not spinal GABA neurons restored the motor defects of hypoxic–ischaemic encephalopathy, which were reversed by clozapine-N-oxide-based inhibition of graft function. These findings demonstrate anatomical and functional reconstruction of the basal ganglia neural circuit including multiple loops by striatal spiny projection neurons in hypoxic–ischaemic encephalopathy-injured immature brains, which raises the possibility of such a cell replacement therapeutic strategy for hypoxic–ischaemic encephalopathy in neonates. Ji et al. graft striatal neural progenitors derived from hESCs into the striatum of mice with brain injury caused by hypoxic–ischaemic encephalopathy. The cells mature into GABAergic spiny projection neurons that repopulate the injured striatum, repair basal ganglia circuits anatomically and functionally and rescue motor defects.
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DOI：
10.1523/jneurosci.3833-10.2011
发表时间：
2011-01-26
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
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