Functional integration of adult-born neurons into the mammalian brain

成年神经元与哺乳动物大脑的功能整合

• 批准号: 8851561
• 负责人: VENKATESH N MURTHY
• 金额: $ 35.55万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8851561
• 关键词: Adult; Affect; Animals; Appearance; Behavioral; Biological Models; Brain; Brain Diseases; Cells; Characteristics; Chronic; Development; Environment; Environmental Risk Factor; Evolution; Exhibits; Functional Imaging; Generations; Genetic; Goals; Health; Human; Image; Individual; Injection of therapeutic agent; Interneurons; Knockout Mice; Label; Laser Scanning Microscopy; Left; Life; Measures; Methods; Microscopy; Molecular; Molecular Genetics; Morphology; Mus; Natural History; Neurons; Neurosciences; Newborn Infant; Odors; Olfactory Learning; Optical Methods; Parahippocampal Gyrus; Process; Property; Proteins; Replacement Therapy; Research; Resolution; Rodent; Running; Sensory; Signal Pathway; Signal Transduction; Site; Speed; Stimulus; Stream; Synapses; System; Time; Viral; adult neurogenesis; base; brain repair; calcium indicator; critical period; dentate gyrus; deprivation; experience; gamma-Aminobutyric Acid; granule cell; in vivo; innovation; insight; learned behavior; nerve stem cell; neural circuit; neurogenesis; newborn neuron; olfactory bulb; olfactory sensory neurons; repaired; research study; response; sensory stimulus; subventricular zone; time use

DESCRIPTION (provided by applicant): The excitement about neural stem cells arises in large part from the hope that they can be harnessed therapeutically to repair diseased brains. Very little is known, however, about how these new neurons integrate into existing brain circuits by making appropriate connections - this process can be compared to changing the wheels of a car while it is running. In addition, major questions of how adult neurogenesis and functional integration are regulated by local factors as well as by an animal's experience remain largely unanswered. In this proposal, we will conduct innovative experiments to investigate how new neurons are integrated into synaptic circuits in the mouse olfactory bulb. The rodent olfactory bulb is an excellent model system because of the high rate of neurogenesis, its accessibility, modular organization and behavioral relevance. We will describe the natural history of adult-born neurons in their native environment by imaging their morphology and function at high resolution in the intact brains of living mice using multiphoton laser scanning microscopy. We will also begin to uncover the cellular and molecular processes involved in the functional integration of new neurons into existing circuits using genetic perturbations. To achieve our goals, we will use stereotaxic viral injections, genetically-encoded calcium indicators and chronic multiphoton microscopy to examine in real time how newborn granule cells develop their morphological and functional properties. By tracking identified neurons over several weeks using time-lapse imaging in vivo, we will be able to uncover structural and functional changes that are not visible to conventional methods that obtain single snapshots in each animal. We will alter the odor experience of mice in a "critical" period during which labeled newborn cells are integrated into the bulb and investigate how this alters their functional properties and their survival. Experiments in this project will be guided by three Aims. Aim 1: To determine the time evolution of sensory responses of identified adult-born neurons over their development using multiphoton microscopy. Aim 2: To determine how sensory experience affects the functional properties of adult-born neurons cells and their survival. Aim 3: To determine the cellular and molecular mechanisms in the refinement of functional properties of adult-born neurons. The research proposed here will provide a deeper understanding about how newborn cells find appropriate synaptic partners and integrate into the adult brain. Insights gained from this study will inform efforts to treat human brain disorders using neuron replacement therapies.

描述(申请人提供)：对神经干细胞的兴奋在很大程度上是因为希望它们能够被利用来治疗疾病的大脑。然而，对于这些新神经元如何通过适当的连接整合到现有的大脑回路中，人们知之甚少--这个过程可以比作在汽车行驶时改变车轮。此外，关于成年神经发生和功能整合如何受到当地因素以及动物经验的调控的主要问题在很大程度上仍未得到解答。在这个方案中，我们将进行创新的实验，以研究新的神经元如何整合到小鼠嗅球的突触电路中。啮齿动物嗅球是一种很好的模型系统，因为它具有很高的神经形成率、可及性、模块化组织和行为相关性。我们将描述成年出生的神经元在其自然环境中的自然历史，方法是使用多光子激光扫描显微镜在活着的小鼠的完整大脑中以高分辨率成像它们的形态和功能。我们还将开始揭示使用遗传扰动将新神经元功能整合到现有电路中所涉及的细胞和分子过程。为了实现我们的目标，我们将使用立体定位病毒注射、遗传编码的钙指示剂和慢性多光子显微镜来实时检查新生颗粒细胞如何发展其形态和功能特性。通过在活体内使用延时成像在几周内跟踪识别出的神经元，我们将能够发现传统方法无法看到的结构和功能变化，这些方法在每种动物身上都获得了单一的快照。我们将在标记的新生细胞整合到球茎中的“关键”时期改变小鼠的气味体验，并研究这如何改变它们的功能特性和生存。这个项目的实验将以三个目标为指导。目的1：用多光子显微镜研究成年出生神经元感觉反应在发育过程中的时间演化。目的2：确定感觉体验如何影响成年神经细胞的功能特性及其存活。目的：研究成体神经元功能特性改变的细胞和分子机制。这里提出的研究将提供对新生细胞如何找到合适的突触伙伴并整合到成人大脑中的更深层次的理解。从这项研究中获得的见解将为使用神经元替代疗法治疗人类大脑疾病的努力提供参考。