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

靶向神经发生-抑制耦合以改善衰老多样性补充剂的记忆力

• 批准号: 10670533
• 负责人: Amar Sahay
• 金额: $ 2.58万
• 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/10670533
• 关键词: Adult; Age; Age-associated memory impairment; Aging; Behavioral Paradigm; Cognitive; Coupling; Data; Discrimination; Episodic memory; Goals; Hippocampus; Human; Hyperactivity; Interneurons; Maps; Memory; Memory impairment; Molecular Profiling; Neurons; Parvalbumins; Play; Prefrontal Cortex; Publishing; Rodent; Role; Site; Testing; Viral; dentate gyrus; experience; gain of function; genetic approach; improved; in vivo; memory consolidation; memory process; mild cognitive impairment; neural circuit; neurogenesis; neuronal excitability; nonhuman primate; novel; optogenetics; recruit; response; social

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.

海马体通过产生不同的、连接的记忆， （空间和社会）经验的表征，并将这些表征转移到前额叶皮层 用于存储或巩固记忆的场所。脑卒中相关认知功能减退和轻度认知功能障碍（MCI） 其特征在于记忆干扰增加，记忆表征的稳定性降低， 内存整合效率低。来自人类、非人类灵长类动物和啮齿类动物的证据表明， 海马神经发生减少，海马活动过度， 认知能力下降和MCI。小清蛋白抑制性中间神经元（PVINs）在记忆中起着关键作用 通过调节神经元兴奋性和同步神经元放电来区分和巩固 神经元系综和尖波波纹（SWR）。因此，海马CA 2区PV IN募集减少， 社交记忆处理中枢，可能会导致与年龄相关的社交记忆障碍。这里我们 提出齿状回-CA 2中神经发生-抑制偶联作为候选回路机制的作用 通过这种机制，成年人出生的神经元促进了成年和衰老过程中社会记忆的巩固。响应于 FOA，我们将开发和验证一个体内功能获得平台，用于前认知的迭代测试。 潜在的新的候选调节剂的神经发生抑制耦合在老化过程中。为了实现这一目标，我们 将建立在广泛的初步和公布的数据，并整合遗传方法，以提高 神经发生，PV IN的输入特异性操作，PV IN的活性依赖性分子谱，PV IN 靶向病毒表达、光遗传学、离体和体内局部场电位记录和老化- 敏感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衰老中的社会记忆的平台， MCI。