Role of adult hippocampal neurogenesis in memory

成人海马神经发生在记忆中的作用

基本信息

批准号：
8788555
负责人：
MICHAEL R DREW
金额：
$ 37.43万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-01-01 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8788555
关键词：
Ablation Address Adult Affect Age Amygdaloid structure Animal Model Animals Antidepressive Agents Anxiety Disorders Behavior Behavioral Biological Preservation Birth Brain Brain region Cells Disease Drug effect disorder Emotional Emotional disorder Emotions Etiology Exhibits Fright Genetic Goals Health Hippocampus (Brain)Human Impairment Individual Learning Length Limited Stage Link Maintenance Mediating Memory Mental Depression Methods Modification Mus Neurons Patients Pattern Play Principal Investigator Procedures Process Research Retirement Retrieval Rodent Role Shock Specificity Staging Study models System Testing Time Transgenic Mice Transgenic Organisms Viral adult neurogenesis cohort conditioned fear fear memory improved memory acquisition memory process memory retention memory retrieval mental representation nerve stem cell neurogenesis novel optogenetics programs relating to nervous system tool young adult

项目摘要

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

描述（由申请人提供）：海马是保留在成年后产生神经元的少数大脑区域之一。从小鼠到人类的哺乳动物种类的成年神经发生的保存表明，神经发生以重要的方式有助于海马功能。实际上，对人类患者和动物模型的研究表明，神经发生的变化改变了记忆功能，并有助于情绪障碍的病因和治疗。如果我们要了解海马如何介导记忆，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。该项目的主要目的是确定成年神经元对海马记忆机制有助于的机制。我们将重点关注一个依赖神经发生的学习的一个充分研究的模型：上下文恐惧调节，一种无处不在的学习形式，在其中，动物会恐惧与厌恶性刺激相结合。我们已经表明，逮捕成年海马神经发生会损害上下文恐惧调节，而没有神经发生的小鼠对震动的恐惧较少。然而，简单的观察结果是，逮捕成人神经发生会损害CFC的CFC几乎没有关于成年神经发生在海马记忆机制中的作用。解决有关神经发生在记忆过程中的作用的机理问题，需要使用时间和细胞精度来操纵神经发生的新方法。为此，我们开发了两种新方法来操纵具有高时间和细胞特异性的神经发生。一种是一种新型的转基因小鼠，可以使神经祖细胞的可逆消融。另一个是合并的转基因/病毒方法，在定义的成年神经元中表达了光遗传学的神经消音器。我们建议使用这些方法来揭示神经发生如何促进基本记忆过程，例如采集，系统巩固和检索。具体来说，我们将解决有关年轻，成年神经元在上下文恐惧记忆中的作用的关键问题：（1）成年神经元在上下文恐惧条件中的作用是否与上下文表示，情感学习或这些形式的学习形式有关？（2）在海马中添加神经元如何影响现有上下文恐惧记忆的维持？（3）成人出生的神经元在长期保留它们的记忆中起着什么作用？这些研究将阐明成年神经发生调节记忆的基本机制，并在此过程中阐明神经发生的改变有助于情绪障碍的治疗和病因，例如抑郁和焦虑症。 0925-0001/0002（修订版08/12）页面延续格式页面