Role of adult hippocampal neurogenesis in memory

描述(申请人提供)：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的研究表明，神经发生的变化会改变记忆功能，并有助于情感障碍的病因和治疗。如果我们想要了解海马体是如何调节记忆、情绪及其紊乱的，我们就必须了解成年神经发生在海马体功能中的作用。这个项目的主要目标是确定成年出生的神经元对海马区记忆机制的贡献机制。我们将专注于一个研究得很好的神经发生依赖学习模型：情境恐惧条件作用，这是一种普遍存在的学习形式，在这种学习中，动物会对伴随着厌恶刺激的情境产生恐惧。我们已经证明，阻止成年海马神经发生会损害背景恐惧条件反射，因为没有神经发生的小鼠对休克配对的背景表现出较少的习得性恐惧。然而，简单的观察表明，阻止成人神经发生损害了CFC，对成人神经发生在海马区记忆机制中的作用揭示得很少。解决有关神经发生在记忆过程中的作用的机械性问题，需要新的方法来精确地操纵时间和细胞上的神经发生。为此，我们开发了两种新的方法来操纵神经发生，具有高度的时间和细胞特异性。一种是一种新型的转基因小鼠，可以可逆地消融神经前体细胞。另一种是转基因/病毒相结合的方法，在特定的成年出生神经元队列中表达一种光遗传神经沉默因子。我们建议使用这些方法来揭示神经发生如何对潜在的记忆过程做出贡献，如获得、系统巩固和提取。具体地说，我们将解决这些关于成年出生的年轻神经元在情景恐惧记忆中所扮演的角色的关键问题：(1)成年出生的神经元在情景恐惧条件反射中的作用是否与情景表征、情绪学习或这些形式的学习的表达有关？(2)增加神经元到海马区是如何影响现有情景恐惧记忆的维持？(3)成年出生的神经元在帮助编码的记忆的长期保持中扮演什么角色？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，将阐明神经发生变化有助于情绪障碍(如抑郁症和焦虑症)的治疗和病因的机制。0925-0001/0002(08/12版)页面续格式页面

DESCRIPTION (provided by applicant): 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