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（由申请人提供）：成人海马神经发生是一个动态过程，其中新的神经元在成人大脑中不断产生并整合到齿状回中，齿状回是学习、记忆和情绪调节的关键区域。这一过程的失调与各种精神和神经疾病有关，包括重度抑郁症和癫痫。描述这些成年出生的神经元如何发育和获得可以影响局部电路的信号特性，对于理解这种现象在脑功能和病理学中的作用至关重要。许多关于这些新生齿状颗粒细胞发育过程中的电生理特性的知识都来自海马脑片的体外制备。这些研究揭示了可塑性的关键时期，当细胞在4至6周龄左右时，它们表现出增强的突触可塑性。这一惊人的观察结果表明，在成熟的特定时间窗口期间，成年出生的神经元可能具有独特的发育调节作用。因此，一个普遍的假设是，特定年龄的新生颗粒细胞表现出响应环境刺激的活动特征模式。然而，由于技术限制，无法确定体内记录细胞的年龄，因此不可能通过细胞外单个单位记录直接检验这一假设。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），该模型适用于齿状回中的光遗传学引导的四极记录，以确定出生日期，识别并记录自由移动动物中单个成年出生的神经元（目标2）。开发和验证诱导型遗传策略以在狭窄的时间窗口（即2 - 4天）内靶向高度增殖的神经祖细胞将产生一种模型，其中可以以前所未有的精确度鉴定和操纵新生细胞群。这将是一个新的资源，为神经发生研究社区调查的内源性功能，这一人口及其失调可能有助于神经病理。对于当前的项目，该模型将用于表达新生神经元中的光激活视蛋白通道（通道视紫红质），以允许通过植入的光纤刺激和记录体内光响应的假定成年颗粒细胞。完成 这些实验将导致首次描述体内成年颗粒细胞的放电特性，以及首次直接评估切片记录中的可塑性临界期是否转化为行为相关神经活动的变化。这种解决该领域最关键的突出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。