Regeneration of dopaminergic neurons in adult zebrafish depends on immune system activation and differs for distinct populations
Regeneration of dopaminergic neurons in adult zebrafish depends on immune system activation and differs for distinct populations
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成年斑马鱼多巴胺能神经元的再生取决于免疫系统的激活，并且不同种群的再生有所不同
DOI：
10.1101/367151
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Caldwell L
中科院分区：
文献类型：
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作者：
Caldwell L
与哺乳动物相比，成年斑马鱼在大脑中再生神经元，但这种能力的程度和可变性尚不清楚。在这里，我们问是否各种多巴胺能神经元群体的损失是足以触发其功能再生。分析了斑马鱼的两种性别。遗传谱系追踪显示，特定的间脑室管膜放射状神经胶质（ERG）祖细胞产生新的多巴胺能[酪氨酸羟化酶阳性（TH+）]神经元。消融消除了免疫应答，增加了ERG祖细胞的增殖，并增加了组成性添加新神经元的群体中新TH+神经元的添加（例如，间脑人群5/6）。抑制免疫反应会将神经发生减弱到控制水平。增强免疫应答增强ERG增殖，但不增加TH+神经元。相反，在组成性神经发生不可检测的人群中（例如，后结节和蓝斑），细胞替代和组织整合是不完全和短暂的。这与脊髓TH+轴突的损失以及浅水和生殖行为的永久性缺陷有关。因此，多巴胺能神经元群体在成年斑马鱼大脑中显示出巨大的差异，再生能力与组成性添加的神经元和依赖于免疫系统activation.Significance声明尽管事实上，斑马鱼显示出高倾向于再生神经元在大脑中，这项研究表明，并不是所有类型的多巴胺能神经元功能再生后，特定的消融。因此，在相同的成年脊椎动物大脑中，可以研究成功和不完全再生的机制。我们鉴定了多巴胺能神经元的祖细胞，并表明激活免疫系统可促进这些细胞的增殖。然而，在大脑的某些区域，这只会导致功能重要的多巴胺能神经元的替代不足，这些神经元后来消失。了解斑马鱼的再生机制可能会为针对非再生哺乳动物内源性祖细胞再生功能重要神经元（如多巴胺能神经元）的干预提供信息。
Adult zebrafish, in contrast to mammals, regenerate neurons in their brain, but the extent and variability of this capacity is unclear. Here we ask whether the loss of various dopaminergic neuron populations is sufficient to trigger their functional regeneration. Both sexes of zebrafish were analyzed. Genetic lineage tracing shows that specific diencephalic ependymo-radial glial (ERG) progenitor cells give rise to new dopaminergic [tyrosine hydroxylase-positive (TH+)] neurons. Ablation elicits an immune response, increased proliferation of ERG progenitor cells, and increased addition of new TH+neurons in populations that constitutively add new neurons (e.g., diencephalic population 5/6). Inhibiting the immune response attenuates neurogenesis to control levels. Boosting the immune response enhances ERG proliferation, but not addition of TH+neurons. In contrast, in populations in which constitutive neurogenesis is undetectable (e.g., the posterior tuberculum and locus ceruleus), cell replacement and tissue integration are incomplete and transient. This is associated with a loss of spinal TH+axons, as well as permanent deficits in shoaling and reproductive behavior. Hence, dopaminergic neuron populations in the adult zebrafish brain show vast differences in regenerative capacity that correlate with constitutive addition of neurons and depend on immune system activation.SIGNIFICANCE STATEMENTDespite the fact that zebrafish show a high propensity to regenerate neurons in the brain, this study reveals that not all types of dopaminergic neurons are functionally regenerated after specific ablation. Hence, in the same adult vertebrate brain, mechanisms of successful and incomplete regeneration can be studied. We identify progenitor cells for dopaminergic neurons and show that activating the immune system promotes the proliferation of these cells. However, in some areas of the brain this only leads to insufficient replacement of functionally important dopaminergic neurons that later disappear. Understanding the mechanisms of regeneration in zebrafish may inform interventions targeting the regeneration of functionally important neurons, such as dopaminergic neurons, from endogenous progenitor cells in nonregenerating mammals.