Regulating brain development through sensorimotor experience-dependent neurogenesis

通过感觉运动经验依赖的神经发生调节大脑发育

• 批准号: RGPIN-2020-04373
• 负责人: Hall, Zachary
• 金额: $ 2.99万
• 依托单位: University of Alberta
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=716999
• 关键词: Regulating; brain; development; through; sensorimotor

Postembryonic development marks the period in life when sensory experience has its greatest impact on brain development. Experience-dependent changes in brain development are often assumed to occur via synaptic plasticity. However, the effects of sensory experience on other forms of neuroplasticity, such as neurogenesis, are largely unexplored. Understanding the capacity of the sensory environment to modulate neurogenesis is important because perturbations in developmental neurogenesis are thought to initiate aberrant neurodevelopmental trajectories that culminate in neuropsychiatric illness. Accordingly, the long-term goal of my research is to understand how sensory experience shapes brain development through the modulation of neurogenesis. Previously, I found that somatosensory feedback from the body during movement stimulates neurogenesis in the forebrain of zebrafish larvae. I believe this form of movement-dependent neurogenesis represents a fundamental form of sensorimotor feedback coupling motor and brain development early in life. The short-term goal of my research is to elucidate the mechanism through which motor experience modulates neurogenic brain development. I will achieve this goal by answering three questions: How does sensorimotor feedback reach the brain? Dorsal root ganglia (DRG), sensory cells in the body, convey feedback during movement to regulate forebrain neurogenesis. However, the pathway carrying DRG input to the brain is unknown. Using both anatomical mapping of isolated DRG neurites and functional mapping of neuronal activity evoked by DRG activation I will identify hindbrain nuclei that receive and process DRG ascending input. Upon reaching the hindbrain, how does sensorimotor feedback then reach the forebrain? DRG neurites terminate within the hindbrain where nuclei must then convey this ascending sensory input to regulate forebrain neurogenesis. I hypothesize that the locus coeruleus (LC), a noradrenergic hindbrain nucleus, mediates movement-dependent neurogenesis. Using transgenically modified zebrafish, in which LC can be ablated or optogenetically stimulated, I will test the importance of LC signaling in movement-dependent forebrain neurogenesis. How does motor experience modulate neurogenic development? Neurogenesis encapsulates processes including cell proliferation, fate, and survival, and how motor experience affects these different processes is unknown. Using intersectional transgenic approaches to isolate neural stem cell lineages in vivo and histologically, I will test how motor experience shapes the forebrain neurodevelopmental trajectory via the modulation of different neurogenic processes. Answering these questions will elucidate the neural circuitry through which ascending motor feedback affects early brain growth. This work will greatly expand our understanding of the importance of sensory experience in shaping the neurodevelopmental trajectory through the modulation of neurogenesis.

胚后发育标志着生命中感官体验对大脑发育影响最大的时期。通常认为大脑发育中的经验依赖性变化是通过突触可塑性发生的。然而，感觉经验对其他形式的神经可塑性的影响，如神经发生，在很大程度上是未知的。了解感觉环境调节神经发生的能力是很重要的，因为发育神经发生的扰动被认为会引发异常的神经发育轨迹，最终导致神经精神疾病。因此，我研究的长期目标是了解感觉经验如何通过调节神经发生来塑造大脑发育。 以前，我发现运动过程中来自身体的体感反馈刺激斑马鱼幼虫前脑的神经发生。我相信这种形式的运动依赖性神经发生代表了一种基本形式的感觉运动反馈耦合运动和大脑的发展在生命早期。我研究的短期目标是阐明运动经验调节神经源性大脑发育的机制。我将通过回答三个问题来实现这一目标： 感觉运动反馈如何到达大脑？背根神经节（DRG）是人体内的感觉细胞，在运动过程中传递反馈，调节前脑神经发生。然而，携带DRG输入到大脑的途径是未知的。使用分离的DRG神经突起的解剖映射和DRG激活诱发的神经元活动的功能映射，我将确定接受和处理DRG上行输入的后脑核。 感觉运动反馈到达后脑后，如何到达前脑？DRG神经突终止于后脑内，那里的核必须传递这种上行的感觉输入以调节前脑神经发生。我假设蓝斑（LC），去甲肾上腺素能后脑核，介导运动依赖性神经发生。使用转基因修饰的斑马鱼，其中LC可以被消融或光遗传学刺激，我将测试LC信号在运动依赖性前脑神经发生的重要性。 运动经验如何调节神经性发育？神经发生包括细胞增殖、命运和存活等过程，运动体验如何影响这些不同的过程尚不清楚。使用交叉转基因方法分离神经干细胞谱系在体内和组织学上，我将测试如何运动的经验形状前脑神经发育轨迹，通过调制不同的神经发生过程。 提出这些问题将阐明上行运动反馈影响早期大脑发育的神经回路。这项工作将极大地扩展我们的理解的重要性，通过神经发生的调制塑造神经发育轨迹的感觉经验。