Role of Cyclic Nucleotide Signaling in Age-related Decline of Social Memories

环核苷酸信号传导在年龄相关的社交记忆衰退中的作用

• 批准号: 10541235
• 负责人: Michy Patrice Kelly
• 金额: $ 47.51万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-15 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10541235
• 关键词: Affect; Age; Age-associated memory impairment; Aging; Anterior; Area; Automobile Driving; Biochemical; Brain; Brain region; CREB1 gene; Cell Nucleus; Cognitive; Compensation; Controlled Study; Coupling; Cyclic AMP; Cyclic GMP; Cyclic Nucleotides; Cytosol; Dementia; Development; Enzymes; Exoribonucleases; Family; Food Preferences; Fractionation; Friends; Generations; Genetic Transcription; Goals; Health Care Costs; Hippocampal Formation; Hippocampus; Homodimerization; Human; Immunofluorescence Immunologic; Impaired cognition; Impairment; In Vitro; Individual; Knockout Mice; Knowledge; Longevity; Measures; Medicine; Membrane; Memory; Memory impairment; Messenger RNA; Molecular; Mus; Mutation; Neurons; Outcome; Pharmaceutical Preparations; Phosphorylation; Physiological; Pilot Projects; Post-Translational Protein Processing; Predisposition; Primates; Process; Protein Isoforms; Proteins; Rattus; Regulation; Reporter; Reporting; Rodent; Role; Serine; Severities; Signal Transduction; Social Behavior; Structure; Symptoms; System; Therapeutic; Tissues; Transcript; Transgenic Organisms; age related; aged; behavior test; cell type; demented; disability risk; experience; genetic manipulation; in vivo; innovation; insight; long term memory; mRNA Transcript Degradation; neural circuit; new therapeutic target; non-demented; novel; novel therapeutics; overexpression; phosphodiesterase 11a; prevent; promoter; protein expression; public health relevance; side effect; social; social deficits; symptom treatment; therapeutic target; trafficking; transmission process

PROJECT SUMMARY: Compartmentalization of Cyclic Nucleotide Signaling in the Ventral Hippocampus After the age of 60, nearly all individuals experience some form of cognitive decline—particularly memory deficits—and no drugs are able to prevent or reverse this loss. Age-related cognitive impairment, even in absence of dementia, increases health care costs and risk for disability. Cognitive decline is not a uniform process, with variability in symptom severity observed across individuals and across cognitive domains. Associative long-term memories (aLTMs)—particularly those involving experiences with family and friends— are more susceptible to age-related cognitive decline than are recognition long-term memories (rLTMs) for reasons that are not well understood. The lack of knowledge of the molecular mechanisms that govern age- related decline slows the development of novel therapeutics. Phosphodiesterase 11A (PDE11A) is an enzyme that breaks down cAMP and cGMP, and PDE11A may be an important molecular mechanism for regulating social aLTMs. PDE11A is almost exclusively expressed in a small area of the brain called the ventral hippocampus, which is a brain region that is required for the proper storage of social aLTMs. We have shown that hippocampal PDE11A4 expression dramatically increases across the lifespan in mice, rats, and humans. This raises the question of whether this age-related increase reflects a breakdown in physiological control of the hippocampus or an attempt of the brain to protect itself. In preliminary studies, we have shown that mice that lack or express very little PDE11A are completely protected against age-related cognitive decline of social aLTMs. Based on these and other preliminary studies, we hypothesize that age-related increases in hippocampal PDE11A4 occur in a subcellular compartment-specific manner and impair social aLTM. Across the 3 aims, we take an integrative experimental approach by coupling in vivo genetic manipulations with in vivo behavioral tests as well as ex vivo molecular and biochemical endpoints. In Specific Aim 1, we will determine if preventing or reversing age- related increases in PDE11A4 can rescue age-related impairments in social aLTMs. In Specific Aim 2, we will identify the circuit, cell type, and subcellular compartment where age-related increases in PDE11A4 expression occur and identify the posttranslational modifications that drive these compartment-specific effects. In Specific Aim 3, we will define the signals that drive age-related increases in PDE11A4 expression. These innovative studies will provide much needed insight into the fundamental mechanisms of social memory as well as the function and regulation of PDE11A in the brain. Targeting PDE11A may be a way to selectively restore cyclic nucleotide signaling in a specific brain region that regulates social memories, without affecting signaling elsewhere. This may relieve social deficits without causing unwanted side effects.

项目摘要：腹侧循环核苷酸信号的隔室化 海马 60岁以后，几乎所有个人都经历了某种形式的认知下降 - 特别是记忆 缺陷 - 没有药物能够预防或扭转这种损失。即使在 缺乏痴呆，增加医疗保健成本和残疾风险。认知能力下降不是统一的 过程，跨个体和跨认知领域观察到症状严重程度的差异。 协会长期记忆（ALTMS） - 尤其是那些与家人和朋友的经验 比认识长期记忆（RLTMS）更容易受到与年龄相关的认知能力的影响 理解的原因。缺乏对支配年龄的分子机制的了解 相关下降会减慢新疗法的发展。 磷酸二酯酶11A（PDE11A）是一种分解营地和CGMP的酶，PDE11A 可能是调节社会ALTMS的重要分子机制。 PDE11A几乎是完全 在大脑的小区域中表达，称为腹侧海马，这是需要的大脑区域 为了正确存储社交altms。我们已经证明海马PDE11A4表达很大 在小鼠，大鼠和人类中，整个寿命的增加。这就提出了这个与年龄有关的问题 增加反映了对海马的物理控制的崩溃或大脑保护的尝试 本身。在初步研究中，我们已经表明缺乏或表达的小鼠完全是完全的PDE11a 免受与年龄相关的社会ALTMS认知衰落的保护。基于这些和其他初步研究， 我们假设海马PDE11A4与年龄相关的增加发生在亚细胞中 特定于室的方式并损害社交ALTM。在这三个目标中，我们进行了一个集成的 实验方法通过在体内遗传操作与体内行为测试以及Ex Vivo耦合 分子和生化终点。在特定目标1中，我们将确定是否预防或逆转年龄 PDE11A4的相关增加可以挽救社交ALTMS中与年龄相关的障碍。在特定的目标2中，我们将 确定电路，单元类型和亚细胞室，其中与年龄相关的PDE11A4表达增加 发生并确定驱动这些隔室特异性效应的翻译后修饰。具体 AIM 3，我们将定义信号，即PDE11A4表达中与年龄相关的增加。这些创新的 研究也将提供急需的洞察力，了解社会记忆的基本机制 作为大脑中PDE11A的功能和调节。定位PDE11A可能是选择性的 恢复调节社会记忆的特定大脑区域中的环状核丁基信号传导 影响其他地方的信号。这可能会挽救社会缺陷而不会造成不良副作用。