Targeting neurogenesis-inhibition coupling to improve memory in aging\Diversity Supplement

海马体在情景记忆的形成中起着关键作用，它产生不同的、合取的 (空间和社会)经验的表征及其向前额叶皮质的迁移 用于存储或整合内存的站点。年龄相关性认知功能减退与轻度认知功能障碍 其特征是内存干扰增加，内存表示的稳定性降低，以及 内存整合效率低下。来自人类、非人灵长类和啮齿动物的证据表明 在与年龄相关的过程中，海马神经发生减少、海马过度活跃和不灵活的重新映射 认知功能减退和MCI。小白蛋白抑制中间神经元在记忆中起着关键作用 调节神经元兴奋性和同步神经元放电的辨别和巩固 神经元群和尖波纹波(SWR)。因此，减少了海马CA2区的PV IN募集，a 社会记忆处理中枢，可能会导致与年龄相关的社会记忆障碍。在这里，我们 提出齿状回-CA2区神经发生-抑制耦合的作用作为候选回路机制 成年出生的神经元通过这种方式在成年和衰老时促进社会记忆的巩固。为回应这一事件 FOA，我们将开发和验证一个体内功能增益平台，用于前认知的迭代测试 衰老过程中神经发生-抑制耦合的新候选调节因子的潜力。为了实现这个目标，我们 将建立在广泛的初步和已公布数据的基础上，并整合遗传方法以增强 神经发生，PV INS的输入特异性操作，PV INS的活性依赖的分子图谱 靶向病毒表达，光遗传学，体外和体内局部场电位记录和老化- 敏感的社会记忆行为范式。这些目标加在一起，将为一部小说建立概念验证 靶向神经发生-抑制偶联机制以改善衰老和社会记忆的平台 MCI。

The hippocampus plays a critical role in the formation of episodic memories by generating distinct, conjunctive representations of (spatial and social) experiences and transferring these representations to prefrontal cortical sites for memory storage or consolidation. Age-related cognitive decline and mild-cognitive impairment (MCI) are characterized by increased memory interference, decreased stability of memory representations and inefficient memory consolidation. Evidence from humans, non-human primates and rodents demonstrate reduced hippocampal neurogenesis, hippocampal hyperactivity and inflexible remapping during age- related cognitive decline and MCI. Parvalbumin inhibitory interneurons (PV INs) play a pivotal role in memory discrimination and consolidation by regulating neuronal excitability and synchronizing neuronal firing underlying neuronal ensembles and sharp-wave ripples (SWRs). Thus, reduced PV IN recruitment in hippocampal CA2, a hub for social memory processing, may contribute to age-associated social memory impairments. Here, we propose a role for neurogenesis-inhibition coupling in the dentate gyrus-CA2 as a candidate circuit mechanism by which adult-born neurons promote social memory consolidation in adulthood and aging. In response to the FOA, we will develop and validate an in vivo gain-of-function platform for iterative testing of pro-cognitive potential of novel candidate regulators of neurogenesis-inhibition coupling during aging. Towards this goal, we will build on extensive preliminary and published data and integrate a genetic approach to enhance neurogenesis, input-specific manipulation of PV INs, activity-dependent molecular profiling of PV INs, PV IN targeted viral expression, optogenetics, ex vivo and in vivo local field potential recordings and an aging- sensitive social memory behavioral paradigm. Together, these Aims will establish proof-of-concept for a novel platform for targeting a neurogenesis-inhibition coupling mechanism to improve social memory in aging and MCI.