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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

基本信息

批准号：
10629324
负责人：
Amar Sahay
金额：
$ 72.71万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
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/10629324
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

项目摘要

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.

项目总结