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

 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，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。表征这些成年神经元如何发育和获得影响局部电路的信号特性对于理解这种现象在大脑功能和病理学中的作用非常重要。关于这些新生齿状颗粒细胞发育时的电生理学特性的大部分知识都来自于海马切片的离体制备。这些研究揭示了可塑性的关键时期，即细胞在 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，成年神经元在成熟的特定时间窗口内可能具有独特的、发育调节的作用。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标志性活动模式。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元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），该模型适合于齿状回中的光遗传学引导四极记录到出生日期，识别和记录自由活动动物中单个成年出生的神经元（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。这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，该模型将用于在新生神经元中表达光激活视蛋白通道（视紫红质通道），以便通过植入的光纤在体内刺激和记录光响应假定的成年颗粒细胞。完成 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的功能和功能障碍的研究。

 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.