Mechanisms of experience-dependent hippocampal neurogenesis

这个研究项目调查了生活经历是如何塑造大脑的。事实上，半个多世纪以来，人们已经知道，大脑的解剖结构、化学成分和功能受到压力、体育活动和认知训练等经历的强烈影响。大脑受经验影响的能力被称为可塑性，这是大脑的决定性特征之一。了解这是如何发生的将有助于我们理解关键的大脑功能，如学习和记忆的能力。我们的长期目标是建立一个综合模型，从生活经历到基因，生活经历如何调节大脑的可塑性。我们关注的是海马体，这是成人大脑中少有的能够产生神经发生（脑干细胞产生新脑细胞的过程）的区域之一。值得注意的是，只需将小鼠置于不同的住房环境中，这些环境中充满了跑步轮、社会互动和/或压力源，就可以明显地改变海马神经发生。这一发现为我们在这里探讨的基本问题提供了一个模型。在我们之前的工作中，我们从行为层面开始，开发住房模型，使我们能够证明丰富环境中的个体因素（如体育活动，认知刺激，压力和社会互动）以不同的方式影响海马体。这项先前的工作确定了这些经历与大脑“对话”的潜在途径。基于我们的发现，我们现在建议在细胞和分子水平上扩大我们的工作。我们将使用最先进的技术来描述当动物暴露于运动中时，海马体中数千个细胞中的每一个细胞是如何表现的，并使用先进的动物模型来确定介导这些运动反应的细胞过程。这个研究项目将产生对大脑可塑性机制的基本生物学见解，这是我们大脑如何运作的基本特征。重要的是，该项目还将为未来的学术、工业和监管职位提供有价值的、专业的和多才多艺的高素质人才。

This research program investigates how the brain is shaped by life experiences. Indeed, it has been known for over half a century that the brain's anatomy, chemistry, and function are powerfully influenced by experiences such as stress, physical activity, and cognitive training. The ability of the brain to be shaped by experience is called plasticity, and it is one of the brain's defining features. Understanding how this occurs will help us understand key brain functions, such as the ability to learn and remember. Our long-term goal is to develop an integrated model, from life experiences to gene, of how life experience regulates brain plasticity. We focus on the hippocampus, one of the rare regions of the adult brain that is capable of neurogenesis (the process by which brain stem cells produce new brain cells). Remarkably, hippocampal neurogenesis can be measurably changed simply by placing mice in different housing environments that are enriched with a running wheel, social interactions and/or stressors. This discovery serves as a model for the fundamental questions we are pursuing here. In our prior work, we started at the behavioral level, developing housing models that allowed us to demonstrate that individual elements within an enriched environment (such as physical activity, cognitive stimulation, stress, and social interactions) affect the hippocampus in different ways. This prior work identified potential pathways by which such experiences "talk" to the brain. Based on our findings, we now propose to expand our work at the cellular and molecular levels. We will use state of the art technologies that describe how each of the thousands of cells in the hippocampus is behaving when an animal is exposed to exercise, and use advanced animal models to identify the cellular processes that are mediating these responses to exercise. This research program will generate fundamental biological insights into the mechanisms of brain plasticity, which is an essential feature of how our brains function. Importantly, this project will also provide highly qualified personnel with valuable, specialized and versatile expertise for future academic, industrial and regulatory positions.