Regulating brain development through sensorimotor experience-dependent neurogenesis

胚胎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。大脑发育中依赖经验的变化通常被认为是通过突触可塑性发生的。然而，感觉体验对其他形式的神经可塑性的影响，如神经发生，在很大程度上还没有被探索。了解感觉环境调节神经发生的能力很重要，因为发育神经发生的扰动被认为启动了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体验如何通过调节神经发生来塑造大脑发育。此前，我发现身体在运动时的体感反馈会刺激斑马鱼幼体前脑的神经发生。我认为这种形式的运动依赖神经发生代表了感觉运动反馈的一种基本形式，耦合了生命早期的运动和大脑发育。我研究的短期目标是阐明运动体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信息，调节前脑神经发生。然而，将DRG输入到大脑的途径尚不清楚。利用分离的DRG神经突起的解剖图谱和DRG激活引起的神经元活动的功能图谱，我将识别接受和处理DRG上行输入的后脑核团。在到达后脑后，感觉运动反馈是如何到达前脑的？背根神经节轴突终止于后脑，在那里，核团必须传递这种上升的感觉输入，以调节前脑神经发生。我推测，蓝斑(LC)是去甲肾上腺素能的后脑核团，参与运动依赖型神经发生。利用转基因斑马鱼，在这种斑马鱼中，LC可以被消融或光遗传刺激，我将测试LC信号在运动依赖型前脑神经发生中的重要性。运动经验是如何调节神经源性发育的？神经发生包括细胞增殖、命运和生存等过程，而运动经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体内和组织学上的神经干细胞谱系，我将测试运动体验如何通过调节不同的神经发生过程来塑造前脑神经发育轨迹。回答这些问题将阐明提升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对感官体验在通过调节神经发生来塑造神经发育轨迹方面的重要性的理解。

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.