Newborn Neurons in the Adult Hippocampal Network

 描述(申请人提供)：神经发生持续存在于所有成年哺乳动物的齿状回，包括人类。神经产生受到许多生理和病理条件的干扰，对神经发生的选择性操作表明，成年出生的神经元有助于海马体依赖的行为。尽管对指导神经发生的细胞生物学过程的了解越来越多，但对可能赋予少数成年出生神经元对海马区功能做出贡献的生理特性的了解较少。一种可能性是，不断更新的未成熟神经元群体显示出与先前存在的更大群体神经元截然不同的特性，导致了独特的功能。尽管相当多的注意力集中在内在兴奋性的瞬时差异上，但不同回路的潜在后果还没有被探索。该项目的目标是确定在成熟过程中突触连接的变化如何影响齿状神经元的激活，从而潜在地允许未成熟和成熟神经元处理海马网活动的不同组成部分。齿状神经元接受两种主要的兴奋性传入投射：穿支通路来自内嗅觉皮质，联合/连合通路来自海马区内的肺门苔藓细胞。我们将使用体外切片生理学、各种转基因小鼠模型和光遗传学来解决不断变化的突触连接和内在特性如何控制逐渐成熟阶段的招募。首先，我们将重点了解控制兴奋性驱动和突触整合的穿支通路和联合/连合通路的机制(目标1和2)。这些单细胞研究将扩展到在突触和回路水平上测试选择性通路刺激的功能后果(目标3)。我们将超越电路映射，了解特定阶段的突触属性如何与内在兴奋性相互作用，以决定皮质和海马区传入活动的整合。综上所述，这些目标的结果将揭示突触连接如何有助于未成熟神经元参与齿状回路，并提供对成人神经发生产生异质性齿状神经元群体的潜力的洞察，这些齿状神经元可以在海马区功能中扮演不同的角色。了解成年出生神经元的生理功能是解剖成人神经发生的意义和目的的重要组成部分，成年神经发生是大脑可塑性的一种戏剧性形式，可能成为许多大脑疾病的治疗靶点。

 DESCRIPTION (provided by applicant): Neurogenesis persists in the dentate gyrus of all adult mammals, including humans. Neural production is perturbed by many physiological and pathological conditions, and selective manipulation of neurogenesis suggests that adult born neurons contribute to hippocampal-dependent behaviors. Despite growing knowledge of the cell biological processes directing neurogenesis, less is known about the physiological properties that may endow the small population of adult born neurons to contribute to hippocampal function. One possibility is that the continually renewing population of immature neurons exhibits distinct properties from the larger population of pre-existing neurons, resulting in unique functionality. Although considerable attention has focused on transient differences in intrinsic excitability, the potential consequences of distinct circuitry have not been explored. The goal of this project is to determine how changes in synaptic connectivity across maturation affect activation of dentate neurons, potentially allowing immature and mature neurons to process distinct components of hippocampal network activity. Dentate neurons receive two main excitatory afferent projections; the perforant path originating from the entorhinal cortex and the associational/commissural pathway arising from hilar mossy cells within the hippocampus itself. We will use in vitro slice physiology, a variety of transgenic mouse models and optogenetics to address how changing synaptic connectivity and intrinsic properties control recruitment at progressive stages of maturation. First we will focus on understanding the mechanisms controlling excitatory drive and synaptic integration of the perforant path and associational/commissural pathways (Aims 1 & 2).These single cell studies will be extended to test functional consequences of selective pathway stimulation at the synaptic and circuit level (Aim 3). We will go beyond circuit mapping to understand how stage-specific synaptic properties interact with intrinsic excitability to dictate integration of cortical and hippocampal afferent activity. Together the results of these Aims will reveal how synaptic connectivity contributes to the participation of immature neurons in dentate circuitry and provide insight into the potential for adult neurogenesis to produce a heterogeneous population of dentate neurons that can play diverse roles in hippocampal function. Understanding the physiological function of adult born neurons is an essential component of dissecting the significance and purpose of adult neurogenesis, a dramatic form of brain plasticity that may be a therapeutic target for numerous brain disorders.