Role of adult hippocampal neurogenesis in memory

项目主任/主要研究者（最后，第一，中间）：德鲁，迈克尔R。 项目摘要 海马体是少数几个在成年后仍能产生神经元的大脑区域之一。 从小鼠到人类的哺乳动物物种中成年神经发生的保守性表明， 神经发生以重要的方式促进海马功能。事实上，在人类患者和 动物模型表明，神经发生的变化改变记忆功能，并有助于病因学， 治疗情绪障碍如果我们要了解海马体是如何调节记忆，情绪， 和疾病，我们必须了解成年神经发生在海马功能中的作用。主要 该项目的目标是确定成年出生的神经元对海马神经元的作用机制。 记忆的机制。我们将重点关注一个经过充分研究的神经发生依赖性学习模型： 情境恐惧条件反射，一种普遍存在的学习形式，动物在这种学习中获得对与之配对的情境的恐惧， 厌恶性刺激我们已经证明，阻止成年海马神经发生会削弱背景恐惧 条件反射，因为没有神经发生的小鼠表现出对电击配对环境的学习恐惧较少。然而，在这方面， 简单地观察到成体神经发生的停止会损害CFC， 海马记忆机制中的神经发生。解决关于妇女作用的机械性问题 记忆过程中的神经发生需要新的方法来操纵神经发生， 细胞精度为此，我们开发了两种新的方法来操纵神经发生， 时间和细胞特异性。一种是一种新的转基因小鼠，它能够可逆地消融神经元， 祖细胞另一种是组合的转基因/病毒方法，其表达光遗传学神经元。 成年出生的神经元的特定队列中的沉默者。我们建议使用这些方法来揭示如何 神经发生有助于潜在的记忆过程，如获得，系统巩固， 检索具体来说，我们将解决这些关键问题的作用，年轻的，成年出生的神经元， 情境恐惧记忆：（1）成人神经元在情境恐惧条件反射中的作用是否与情境有关 表征，情感学习，或这些学习形式的表达？(2)神经元的加入 影响现有的情境恐惧记忆的维持吗(3)成年人出生后 神经元在长期记忆保持中发挥的作用？这些研究将阐明 成人神经发生调节记忆的基本机制，并在这样做时，将阐明 神经发生的改变有助于情绪障碍的治疗和病因学的机制 例如抑郁症和焦虑症。 0925-0001/0002（2012年8月修订版）续页格式页

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