Identifying the physiological correlates of adult-born granule cells in vivo

识别体内成年颗粒细胞的生理相关性

• 批准号: 9062521
• 负责人: Kimberly Christian
• 金额: $ 20.25万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9062521
• 关键词: Acute; Adaptive Behaviors; Address; Adult; Affect; Age; Animals; Behavior; Birth; Brain; Cell Aging; Cell Survival; Cells; Cerebral cortex; Communities; Cytoplasmic Granules; Data; Data Set; Date of birth; Developmental Process; Electrodes; Electrophysiology (science); Embryo; Employee Strikes; Environment; Evaluation; Exhibits; Foundations; Functional disorder; Genetic; Genetic Models; Genetic Recombination; Health; Heterogeneity; Hippocampus (Brain); Implant; Investigation; Knowledge; Learning; Light; Major Depressive Disorder; Mediating; Memory; Mental disorders; Methods; Modeling; Molecular; Mus; Nervous system structure; Neurons; Newborn Infant; Opsin; Pathology; Pattern; Physiological; Population; Preparation; Process; Property; Proteins; Reporting; Reproducibility; Research; Resolution; Resources; Response Latencies; Rest; Role; Seminal; Signal Transduction; Slice; Specificity; Stimulus; Synaptic plasticity; System; Tamoxifen; Techniques; Testing; Time; Tonic-Clonic Epilepsy; Transgenic Model; Translating; Validation; adult neurogenesis; base; cognitive function; cohort; critical period; dentate gyrus; design; extracellular; genetic approach; granule cell; in vivo; innovation; microbial; mood regulation; mouse model; nerve stem cell; nervous system disorder; neurodevelopment; neurogenesis; newborn neuron; novel; optical fiber; optogenetics; prevent; reconstruction; relating to nervous system; research study; response

 DESCRIPTION (provided by applicant): Adult hippocampal neurogenesis is a dynamic process in which new neurons are continuously generated in the adult brain and integrated into the dentate gyrus, a region that is critical for learning, memory and mood regulation. Dysregulation of this process has been implicated in various psychiatric and neurological disorders, including major depression and epilepsy. Characterizing how these adult- born neurons develop and acquire signaling properties that can affect the local circuitry is important to understand the role of this phenomenon in brain function and pathology. Much of what is known about the electrophysiological properties of these newborn dentate granule cells as they develop has been derived from ex vivo preparations of hippocampal slices. These studies revealed a critical period of plasticity when the cells are around 4 to 6 weeks of age in which they exhibit enhanced synaptic plasticity. This striking observation suggests that there may be a unique, developmentally-regulated role of adult born neurons during a specific time window of maturation. Consequently, a prevalent hypothesis is that newborn granule cells of a particular age exhibit signature patterns of activity in response to environmental stimuli. A direct test of this hypothesis through extracellular single unit recordings has not been possible, however, due to technical limitations that prohibited determining the age of the recorded cell in vivo. To overcome this obstacle, this project is designed to produce a highly specific genetic mouse model (Aim 1) that is amenable to optogenetically-guided tetrode recordings in the dentate gyrus to birthdate, identify and record from single adult-born neurons in freely moving animals (Aim 2). Developing and validating an inducible genetic strategy to target highly proliferative neural progenitors within a narrow time window (i.e. 2 - 4 days) will generate a model in which cohorts of newborn cells can be identified and manipulated with unprecedented precision. This will be a novel resource for the neurogenesis research community to investigate the endogenous function of this population and how its dysregulation may contribute to neural pathology. For the current project, this model will be used to express light-activated opsin channels (channelrhodopsin) in newborn neurons to allow for stimulation and recording of light-responsive putative adult-born granule cells in vivo, via an implanted optical fiber. Completion of these experiments will result in the first description of the firing properties of adult-born granue cells in vivo and the first direct evaluation of whether the critical period of plasticity observedin slice recordings translates to changes in behaviorally relevant neural activity. This innovative approach to address one of the most critical outstanding questions in the field will provide a new genetic model, technique, and dataset to facilitate investigations into the function and dysfunction of adult neurogenesis.

 描述（由申请人提供）：成人海马神经发生是一个动态过程，其中新神经元在成人大脑中不断产生并整合到齿状回中，该区域对于学习、记忆和情绪调节至关重要。与各种精神和神经系统疾病有关，包括重度抑郁症和癫痫症，了解这些成年神经元如何发育和获得影响局部回路的信号特性对于了解这种现象在大脑功能中的作用非常重要。关于这些新生齿状颗粒细胞发育过程中的电生理学特性的大部分知识都来自海马切片的离体制备，这些研究揭示了细胞在 4 至 6 周左右时的可塑性关键时期。这一惊人的观察结果表明，在特定的成熟时间窗口内，成年神经元可能具有独特的发育调节作用，一个普遍的假设是，新生颗粒细胞在成熟过程中发挥着独特的作用。然而，由于无法克服技术限制，无法克服特定年龄对环境刺激作出反应的活动特征模式。为了克服这一障碍，该项目旨在产生一种高度特异性的遗传小鼠模型（目标 1），该模型能够在齿状回中进行光遗传学引导的四极管记录，从自由活动的动物中识别和记录单个成年出生的神经元的出生日期（目标 2）。开发和验证在狭窄的时间窗口（即 2-4 天）内针对高度增殖的神经祖细胞的诱导遗传策略将生成一个模型，在该模型中可以以前所未有的精度识别和操作新生细胞群。将成为神经发生研究界研究该群体的内源性功能及其失调如何导致神经病理学的新资源。对于当前的项目，该模型将用于表达光激活。新生神经元中的视蛋白通道（视紫红质通道）可通过植入的光纤来刺激和记录体内假定的成年颗粒细胞的光响应。 这些实验将首次描述体内成年颗粒细胞的放电特性，并首次直接评估切片记录中观察到的可塑性关键期是否会转化为行为相关神经活动的变化，这是解决一个问题的创新方法。该领域最关键的突出问题将提供新的遗传模型、技术和数据集，以促进对成人神经发生的功能和功能障碍的研究。