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 海马体通过产生记忆，在情景记忆的形成中起着至关重要的作用。 （空间和社会）经验的不同的、联合的表征，并将这些表征 前额叶皮质部位的记忆储存或巩固。年龄相关 认知能力下降和轻度认知障碍（MCI）的特征是记忆力增强 干扰，记忆表征的稳定性降低和记忆效率低下 合并。来自人类、非人类灵长类动物和啮齿类动物的证据表明， 海马神经发生、海马活动过度和年龄过程中不灵活的重新映射 认知能力下降和MCI。小清蛋白抑制性中间神经元（PVINs）在神经元内起关键作用。 通过调节神经元兴奋性在记忆辨别和巩固中的作用， 同步神经元放电潜在的神经元集合和尖锐波波纹（SWR）。 因此，海马CA 2（社会记忆处理的中枢）中PV IN募集的减少可能 会导致与年龄相关的社交记忆障碍在这里，我们提出了一个角色， 齿状回-CA 2中的神经发生-抑制偶联作为候选回路机制， 成年后出生的神经元在成年和衰老时促进社会记忆的巩固。在 响应FOA，我们将开发和验证一个体内功能获得平台，用于迭代 神经发生抑制的新候选调节剂的促认知潜力的测试 老化过程中的耦合。为了实现这一目标，我们将建立在广泛的初步和出版的 数据和整合的遗传方法，以加强神经发生，输入特定的操纵， PV IN、PV IN的活性依赖性分子特征分析、PV IN靶向病毒表达， 光遗传学、离体和体内局部场电位记录以及老化敏感的社会 记忆行为范式总之，这些目标将为一部小说建立概念验证 用于靶向神经发生-抑制偶联机制以改善社会记忆的平台 在衰老和轻度认知障碍方面。