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.

海马体在情景记忆的形成中起着至关重要的作用