Mechanisms and outcomes of stress-induced changes to neurogenesis in zebrafish

鱼类在脊椎动物中是独一无二的，因为它们具有在整个成年大脑中增加和吸收新神经元的高能力。了解鱼类如何以及为什么这样做仍然是一个悬而未决的问题；因此，研究非传统物种的神经发生，比如鱼，可能会为脑损伤、神经退行性疾病和精神疾病带来新的治疗策略。过去的研究表明，鱼类的神经发生可以受到非生物和社会因素的影响，这可能为鱼类适应环境变化提供了一种基础。在这种情况下，理解神经发生的调节和功能将加深这一生态和进化的观点。我的发现项目将研究压力和鱼类成体神经发生之间的机制和功能联系。我们知道压力对大脑有深远的影响，最近的研究表明，主要的压力激素皮质醇可以影响神经发生。因此，应激反应中皮质醇水平的升高可能是中枢神经系统中重要的行为和生理反应固化的重要机制。与此同时，慢性应激源在自然环境中越来越多地出现，但这是否会导致神经发生的长期抑制和适应不良的结果尚不清楚。在接下来的5年里，我将以斑马鱼为模型：(I)建立关于应激对神经发生动态影响的核心知识；（ii）确定大脑神经源性区域内调节皮质醇信号的细胞通路；（iii）通过将细胞命运跟踪实验与行为和生理分析相结合，探索神经源性可塑性的适应性意义。这些实验将通过定义关键的机制和功能指标来突破比较神经发生的界限，这些指标是鱼类产生新神经元并将其融入成人大脑的有趣能力的基础。我的创新研究项目为HQP提供了丰富而刺激的培训环境，学生将从事多学科和综合研究，使用遗传和药理学工具来破译从分子到整个动物的生理途径。

Fish are unique among vertebrates in having a high capacity to add and incorporate new neurons across the entire adult brain. Understanding how and why fish do this remains an open question; and therefore researching neurogenesis in non-traditional species, like fish, may lead to novel treatment strategies for brain injuries, neurodegenerative diseases, and psychiatric disorders. Past studies show that neurogenesis in fish can be modified by abiotic and social factors, and this may provide a substrate by which fish adapt to environmental change. Understanding the regulation and functions of neurogenesis in such contexts will deepen this ecological and evolutionary perspective. My Discovery Program will investigate the mechanistic and functional connections between stress and adult neurogenesis in fish. We know that stress has a profound influence on the brain, and recent studies suggest that the major stress hormone, cortisol, can influence neurogenesis. Increased cortisol levels in response to stress may therefore be an important mechanism by which important behavioural and physiological responses are solidified in the central nervous system. At the same time, chronic stressors are an increasing occurrence in the natural environment, but whether or not this leads to longterm suppression of neurogenesis with maladaptive outcomes is unknown. Over the next 5years, I will use zebrafish as a model to: (i) build core knowledge on the dynamic effects of stress on neurogenesis; (ii) define the cellular pathways that regulate cortisol signalling within neurogenic regions of the brain; and (iii) explore the adaptive significance of neurogenic plasticity by integrating cell fate tracking experiments with behavioural and physiological assays. These experiments will push the boundaries of comparative neurogenesis by defining key mechanistic and functional metrics that underlie the intriguing ability of fish to make and incorporate new neurons into the adult brain. My innovative research program provides a rich and stimulating training environment for HQP, where students will engage in multidisciplinary and integrative research that uses genetic and pharmacological tools to decipher physiological pathways from molecules to whole animals.