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: 8978461
• 负责人: Kimberly Christian
• 金额: $ 24.3万
• 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 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8978461
• 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; Embryo; Employee Strikes; Environment; Evaluation; Exhibits; Foundations; Functional disorder; Genetic; Genetic Models; Genetic Recombination; 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; public health relevance; 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（由适用提供）：成人海马神经发生是一个动态过程，在成人大脑中不断产生新的神经元并整合到牙科回旋中，该区域对于学习，记忆和情绪调节至关重要。该过程的失调与包括严重抑郁症和癫痫在内的各种精神病和神经系统疾病有关。表征这些成年神经元如何发展和获取可能影响局部电路的信号传导特性对于了解这种现象在脑功能和病理学中的作用很重要。这些新生儿牙齿颗粒细胞发育的电生理特性所知道的许多已知是从海马切片的离体制剂中得出的。这些研究表明，当细胞大约4至6周龄时，它们表现出增强的合成可塑性时的关键时期。该罢工观察表明，在特定的成熟时间窗口中，成年出生神经元可能存在独特的，发达的作用。因此，一个普遍的假设是，特定年龄的新生颗粒细胞响应环境刺激而表现出活性的特征模式。但是，由于禁止确定体内记录的细胞年龄的技术局限性，无法通过细胞外单个单位记录对该假设进行直接检验。为了克服这一障碍，该项目旨在产生一个高度特异的遗传小鼠模型（AIM 1），该模型可容纳齿状回的光遗传学引导的四极管记录至生日，识别和记录自由移动动物的单个成人神经元的记录（AIM 2）。在狭窄的时间窗口内（即2-4天），开发和验证一种可诱导的遗传策略，以靶向高度增殖的神经元，将生成一个模型，在该模型中，可以用前所未有的精度来识别和操纵新生细胞的同类。对于神经发生研究界来说，这将是研究该人群的内源性功能以及其失调可能导致神经病理学的新资源。对于当前项目，该模型将用于在新生神经元中表达光激活的OPSIN通道（通道Rhopopsin），以通过植入的光纤在体内刺激和记录体内光反应性假定的成人颗粒细胞。完成 这些实验将导致对体内成人花岗岩细胞的发射特性的首次描述，并首先直接评估切片记录中观察到的可塑性的关键时期是否转化为行为相关的神经发生的变化。这种用于解决该领域最关键问题之一的创新方法将提供一种新的遗传模型，技术和数据集，以促进对成人神经发生功能和功能障碍的研究。