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.

项目概要海马体通过产生情景记忆，在情景记忆的形成中发挥着关键作用。（空间和社会）经验的独特的、联合的表征，并将这些经验转移用于记忆存储或巩固的前额皮质部位的表征。与年龄相关认知能力下降和轻度认知障碍 (MCI) 的特点是记忆力增强干扰、记忆表征稳定性下降和记忆效率低下合并。来自人类、非人类灵长类动物和啮齿动物的证据表明，年龄阶段的海马神经发生、海马过度活跃和不灵活的重新映射相关的认知能力下降和MCI。小白蛋白抑制性中间神经元 (PV IN) 发挥着关键作用通过调节神经元兴奋性和记忆辨别和巩固的作用同步神经元群的神经元放电和尖波波纹（SWR）。因此，海马 CA2（社会记忆处理中心）PV IN 募集的减少可能导致与年龄相关的社会记忆障碍。在这里，我们建议一个角色齿状回-CA2 中的神经发生-抑制耦合作为候选电路机制成年出生的神经元促进成年和衰老过程中的社会记忆巩固。在为了响应 FOA，我们将开发并验证一个体内迭代功能获得平台神经发生抑制的新型候选调节剂的促认知潜力测试老化过程中的耦合。为了实现这一目标，我们将在广泛的初步和已发表的数据并整合遗传方法来增强神经发生，输入特定的操作 PV IN、PV IN 的活性依赖性分子分析、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衰老敏感的社会记忆行为范式。这些目标共同将为小说建立概念验证针对神经发生-抑制耦合机制以改善社交记忆的平台在衰老和 MCI 方面。