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（由申请人提供）：对神经干细胞的兴奋很大程度上源于人们希望能够利用它们来修复患病的大脑。然而，人们对这些新神经元如何通过建立适当的连接整合到现有的大脑回路中知之甚少——这个过程可以与在行驶时更换汽车的车轮进行比较。此外，关于成年神经发生和功能整合如何受局部因素以及动物经验调节的主要问题在很大程度上仍未得到解答。在这项提案中，我们将进行创新实验，研究新神经元如何整合到小鼠嗅球的突触回路中。啮齿动物嗅球是一个优秀的模型系统，因为其神经发生率高、可接近性、模块化组织和行为相关性。我们将通过使用多光子激光扫描显微镜对活体小鼠完整大脑中的形态和功能进行高分辨率成像，描述成年神经元在其原生环境中的自然历史。我们还将开始揭示利用遗传扰动将新神经元功能整合到现有回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、基因编码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。通过使用体内延时成像在几周内跟踪已识别的神经元，我们将能够发现在每只动物中获取单个快照的传统方法所看不到的结构和功能变化。我们将在“关键”时期改变小鼠的气味体验，在此期间标记的新生细胞整合到灯泡中，并研究这如何改变它们的功能特性和生存。该项目的实验将遵循三个目标。目标 1：使用多光子显微镜确定已识别的成年神经元在发育过程中感觉反应的时间演变。目标 2：确定感官体验如何影响成年神经细胞的功能特性及其存活。目标 3：确定成年神经元功能特性细化的细胞和分子机制。这里提出的研究将更深入地了解新生细胞如何找到合适的突触伙伴并融入成人大脑。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信息。