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

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

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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.

项目摘要海马通过产生情节记忆的形成中起着至关重要的作用（空间和社会）经验的独特，连词的表示，并将其转移前额叶皮质位点的表示，用于存储或整合。与年龄有关认知能力下降和轻度认知障碍（MCI）的特征是记忆增加干扰，记忆表示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动物的证据表明海马神经发生，海马多动和僵化的重塑相关的认知下降和MCI。白蛋白抑制性中间神经元（PV INS）发挥关键性通过调节神经元兴奋性和同步神经元发射的神经元集合和锋利波纹波（SWR）。因此，降低了海马CA2招募的PV，这是一个社交记忆处理的枢纽，可能有助于与年龄相关的社会记忆障碍。在这里，我们提出了一个角色齿状回-CA2中的神经发生抑制耦合作为候选电路机制哪个成年神经元在成年和衰老中促进社会记忆的巩固。在对FOA的响应，我们将开发并验证一个体内功能获得平台以迭代抑制神经发生的新型候选调节剂的亲认知潜力的测试衰老期间的耦合。为了实现这一目标，我们将建立广泛的初步并发表数据并整合了增强神经发生的遗传方法，输入特异性操纵 PV INS，PV INS的活性依赖性分子分析，靶向病毒表达中的PV，光遗传学，离体和体内局部现场潜在录音以及对衰老敏感的社会内存行为范式。这些目标将共同为小说建立概念概念针对抑制神经发生耦合机制以改善社交记忆的平台在衰老和MCI中。