Dissecting the dynamics of vertebrate brain regeneration

摘要 成人大脑的创伤性损伤导致终身功能丧失。相比之下，成年斑马鱼 大脑在受伤后具有惊人的有效再生能力。控制这一过程的分子机制 现象不清楚，研究不足。了解导致激活和迁移的事件 斑马鱼脑再生过程中的干细胞受到不精确的损伤模型， 传统上研究的大脑区域和有限的实时成像平台。这项研究将建立 斑马鱼嗅球（OB）作为脑再生的模型。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 输出，并且在脊椎动物中在解剖学和功能上是保守的。具体目标是 一项提案试图（1）从基因上消除斑马鱼OB的区域，并剖析细胞生物学的动力学 在再生过程中通过活体成像;（2）识别控制激活的转录程序， 脑再生过程中神经元祖细胞沿着单独谱系的进展;以及（3）鉴定和 询问大脑再生所需的信号通路。最后，发现的生物学事件 这一建议可能是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.