Role of adult hippocampal neurogenesis in memory

项目主任/首席调查员(最后、第一、中间)：德鲁，迈克尔·R。 项目总结 海马体是少数几个在成年后保留产生神经元能力的大脑区域之一。 从老鼠到人类，成年神经发生在哺乳动物物种中的保守性表明 神经发生在很大程度上促进了海马区的功能。事实上，对人类患者和 动物模型表明，神经发生的变化改变了记忆功能，并在病因和 情绪障碍的治疗。如果我们要了解海马体是如何调节记忆、情绪、 因此，我们必须了解成年神经发生在海马区功能中的作用。主 该项目的目标是确定成年出生的神经元对海马区做出贡献的机制。 记忆的机制。我们将重点介绍一个研究得很好的神经发生依赖学习模型： 语境恐惧条件作用，一种无处不在的学习形式，其中动物获得对语境的恐惧 厌恶的刺激。我们已经证明，阻止成年海马区的神经发生会损害背景恐惧 条件反射，在没有神经发生的小鼠表现出对电击配对环境的习得恐惧较少。然而， 阻止成人神经发生损害CFCs的简单观察揭示了成人的作用很少 海马区记忆机制中的神经发生。解决关于角色的机械问题 记忆过程中的神经发生需要新的方法来操纵神经发生 蜂窝精确度。为此，我们开发了两种新的方法来控制神经发生。 时间和细胞的特异性。一种是一种新型的转基因小鼠，可以可逆地消融神经 祖细胞。另一种是转基因/病毒相结合的方法，表达光遗传神经 在特定的成年出生神经元队列中的消音器。我们建议使用这些方法来揭示 神经发生有助于潜在的记忆过程，如习得、系统巩固和 取回。具体地说，我们将解决这些关键问题，即年轻的成年出生的神经元在 情景恐惧记忆：(1)成年神经元在情景恐惧条件反射中的作用是否与情景有关 这些学习形式的表征、情绪学习或表达？(2)神经元的相加是如何 对海马体影响现有情景恐惧记忆的维持？(3)成年出生的人扮演什么角色 神经元在它们帮助编码的记忆的长期保持中发挥了作用？这些研究将阐明 成人神经发生调节记忆的基本机制，并通过这样做，将澄清 神经发生改变在情绪性疾病的治疗和病因中的作用机制 精神障碍，如抑郁症和焦虑症。 0925-0001/0002(08/12版)页面续格式页面

Program Director/Principal Investigator (Last, First, Middle): Drew, Michael R. PROJECT SUMMARY The hippocampus is one of a select few brain regions that retain the ability to generate neurons in adulthood. The conservation of adult neurogenesis across mammalian species from mice to humans suggests that neurogenesis contributes to hippocampal function in significant ways. Indeed, research in human patients and animal models suggests that changes in neurogenesis alter memory function and contribute to the etiology and treatment of emotional disorders. If we are to understand how the hippocampus mediates memory, emotion, and disorders thereof, we must understand the role of adult neurogenesis in hippocampal function. The main goal of this project is to identify mechanisms through which adult-born neurons contribute to hippocampal mechanisms of memory. We will focus on one well-studied model of neurogenesis-dependent learning: contextual fear conditioning, a ubiquitous form of learning in which animals acquire fear of a context paired with aversive stimulation. We have shown that arresting adult hippocampal neurogenesis impairs contextual fear conditioning, in that mice without neurogenesis exhibit less learned fear of a shock-paired context. However, the simple observation that arresting adult neurogenesis impairs CFC reveals very little about the role of adult neurogenesis in hippocampal memory mechanisms. Addressing mechanistic questions about the role of neurogenesis in memory processes requires new methods of manipulating neurogenesis with temporal and cellular precision. To this end we developed two new methods of manipulating neurogenesis with high temporal and cellular specificity. One is a novel transgenic mouse that enables reversible ablation of neural progenitor cells. The other is combined transgenic/viral approach that expresses an optogenetic neural silencer in defined cohorts of adult-born neurons. We propose to use these methods to reveal how neurogenesis contributes to underlying memory processes, such as acquisition, systems consolidation, and retrieval. Specifically, we will address these critical questions about the role of young, adult-born neurons in contextual fear memory: (1) Does the role of adult-born neurons in contextual fear conditioning relate to context representation, emotional learning, or expression of these forms of learning? (2) How does addition of neurons to the hippocampus affect maintenance of existing contextual fear memories? (3) What role do adult-born neurons play in long-term retention of the memories they help encode? These studies will elucidate fundamental mechanisms through which adult neurogenesis modulates memory, and, in doing so, will clarify mechanisms through which alterations in neurogenesis contribute to the treatment and etiology of emotional disorders, such as depression and anxiety disorders. 0925-0001/0002 (Rev. 08/12) Page Continuation Format Page