Role of adult hippocampal neurogenesis in memory

描述（由申请人提供）：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，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，并有助于情绪障碍的病因和治疗。如果我们要了解海马体是如何调节记忆、情绪及其紊乱的，我们必须了解成年神经发生在海马体功能中的作用。该项目的主要目标是确定成年神经元对海马记忆机制的贡献机制。我们将重点关注一个研究得很好的神经发生依赖性学习模型：情境恐惧条件反射，这是一种普遍存在的学习形式，在这种学习中，动物对与厌恶刺激配对的情境产生恐惧。我们已经证明，阻止成年海马神经发生会损害情境恐惧条件反射，因为没有神经发生的小鼠表现出对电击配对情境的学习恐惧较少。然而，简单的观察，阻止成年神经发生损害CFC揭示很少成年神经发生在海马记忆机制中的作用。要解决记忆过程中神经发生作用的机制问题，需要新的方法来操纵神经发生的时间和细胞精度。为此，我们开发了两种新的方法，操纵神经发生具有高度的时间和细胞特异性。一个是一种新的转基因小鼠，能够可逆地消融神经祖细胞。另一种是组合的转基因/病毒方法，其在成年出生的神经元的限定群组中表达光遗传学神经沉默子。我们建议使用这些方法来揭示神经发生如何有助于潜在的记忆过程，如收购，系统巩固和检索。具体来说，我们将解决这些关键问题的作用，年轻的，成年人出生的神经元在情境恐惧记忆：（1）成年人出生的神经元在情境恐惧条件反射的作用是否与情境表征，情绪学习，或表达这些形式的学习？(2)在海马体中添加神经元如何影响现有情境恐惧记忆的维持？(3)成年人的神经元在帮助编码的记忆的长期保留中扮演什么角色？这些研究将阐明成人神经发生调节记忆的基本机制，并在这样做的过程中，将阐明神经发生的改变有助于情绪障碍（如抑郁症和焦虑症）的治疗和病因学的机制。0925-0001/0002（2012年8月修订版）续页格式页

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