Dissecting the dynamics of vertebrate brain regeneration

摘要 对成人大脑的创伤性损伤会导致终生功能丧失。相比之下，成年斑马鱼 大脑具有惊人的能力，能够在受伤后有效地再生。控制这一现象的分子机制 这一现象还不清楚，也没有得到充分的研究。了解导致激活和迁移的事件 斑马鱼大脑再生过程中的干细胞受到不精确损伤模型的挑战， 传统上研究的大脑区域和有限的实时成像平台。这项拟议的研究将建立 斑马鱼嗅球(OB)作为大脑再生的模型。OB有很大的能力 再生和神经可塑性，包含大的和形态上不同的轴突，控制行为 在脊椎动物中，在解剖学和功能上都是保守的。这样做的具体目的是 建议寻求(1)通过基因消融斑马鱼OB的区域并剖析细胞生物学的动力学 通过实时成像在再生过程中；(2)识别控制激活和 神经前体细胞在脑再生过程中沿着不同谱系的进展；以及(3)识别和 询问大脑再生所需的信号通路。最终，发现的生物事件 这一建议可能成为人类脑损伤和中风治疗策略的潜在靶点。

ABSTRACT Traumatic injury to the adult human brain results in life-long loss of function. By contrast, the adult zebrafish brain has a striking ability to efficiently regenerate after injury. The molecular mechanisms controlling this phenomenon are unclear and understudied. Understanding the events that lead to activation and migration of stem cells during zebrafish brain regeneration is challenged by imprecise injury models, complexity of the brain regions traditionally studied and limited platforms for live imaging. This proposed research will establish the zebrafish olfactory bulb (OB) as a model for brain regeneration. The OB has a great capacity for regeneration and neuroplasticity, contains large and morphologically distinct axons, controls behavioral outputs, and is anatomically and functionally conserved among vertebrates. The specific aims of this proposal seek to (1) genetically ablate regions of the zebrafish OB and dissect dynamics of cell biology during regeneration via live imaging; (2) identify the transcriptional programs that control the activation and progression of neuronal progenitors along separate lineages during brain regeneration; and (3) identify and interrogate signaling pathways required for brain regeneration. Ultimately, the biological events discovered in this proposal may be potential targets for therapeutic strategies in human brain injury and stroke.