Targeting neurogenesis-inhibition coupling to improve memory in aging

靶向神经发生-抑制耦合以改善衰老记忆

• 批准号: 10851086
• 负责人: Amar Sahay
• 金额: $ 10.34万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10851086
• 关键词: Adult; Affect; Age; Age-associated memory impairment; Aging; Behavioral Paradigm; CHD7 gene; Cells; Chromatin; Cognitive; Communities; Coupling; Data; Development; Discrimination; Episodic memory; Female; Frequencies; Genetic; Goals; Grant; Hippocampus; Human; Hyperactivity; Hypothalamic structure; Impairment; Interneurons; Maps; Mediating; Memory; Memory Loss; Memory impairment; Molecular; Molecular Profiling; Mus; Neurons; Neurosciences; Parvalbumins; Play; Prefrontal Cortex; Property; Publishing; Resources; Rodent; Role; Route; Site; Testing; Update; Viral; aged; candidate validation; dentate gyrus; design; experience; gain of function; genetic approach; granule cell; improved; in vivo; male; memory consolidation; memory process; memory recognition; middle age; mild cognitive impairment; neural circuit; neurogenesis; neuronal excitability; nonhuman primate; novel; optogenetics; overexpression; patch clamp; programs; recruit; response; ribosome profiling; social; tool

Project Summary 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.

项目摘要 海马体在情景记忆的形成中起着关键作用，它通过产生 对(空间和社会)体验的不同的、联合的表示，并传递这些 前额叶皮质部位的表征，用于记忆存储或巩固。与年龄相关的 认知功能减退和轻度认知障碍(MCI)的特征是记忆力增强 干扰、内存表示的稳定性降低和内存效率低下 整合。来自人类、非人类灵长类和啮齿动物的证据表明 增龄过程中海马神经发生、海马多动和顽固的重新定位 认知功能减退与MCI相关。小白蛋白抑制中间神经元(PV INS)起着关键作用 调节神经元兴奋性与记忆的辨别和巩固 同步神经元放电潜在的神经元集合和尖波纹波(SWR)。 因此，社会记忆处理中枢--海马CA2的PV IN募集减少可能 会导致与年龄相关的社会记忆障碍。在这里，我们建议扮演以下角色 齿状回-CA2区神经发生-抑制偶联作为候选回路机制的研究 哪些成年出生的神经元在成年和衰老时促进社会记忆的巩固。在……里面 作为对FOA的回应，我们将开发和验证体内功能增益平台，用于迭代 神经发生抑制新候选调节剂的前认知潜能测试 老化过程中的耦合。为了这个目标，我们将在广泛的初步和出版的基础上再接再厉 数据和集成的遗传方法，以增强神经发生，输入特定的操作 PV INS，依赖活性的PV INS分子图谱，PV IN靶向病毒表达， 光遗传学、体外和活体局部场电位记录和对衰老敏感的社会 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-抑制耦合机制以改善社会记忆的平台 在老龄化和MCI方面。