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

项目总结：细胞中环核苷酸信号传导的区室化 海马 60岁以后，几乎所有的人都会经历某种形式的认知能力下降--尤其是记忆力 而且没有药物能够阻止或逆转这种损失。与糖尿病相关的认知障碍，即使在 没有痴呆症，增加了医疗保健费用和残疾风险。认知能力下降不是一个统一的 过程，在个体和认知领域之间观察到症状严重程度的变异性。 联想性长期记忆（aLTMs）-特别是那些涉及与家人和朋友的经历- 与认知长期记忆（rLTMs）相比， 原因不太清楚。对控制年龄的分子机制缺乏了解- 相关的衰退减缓了新疗法的发展。 磷酸二酯酶11 A（PDE 11 A）是分解cAMP和cGMP的酶，并且PDE 11 A 可能是调节社会性aLTMs的重要分子机制。PDE 11 A几乎完全是 在大脑中一个叫做腹侧海马体的小区域表达，这是一个大脑区域， 来正确存储社交活动我们已经证明海马PDE 11 A4的表达显著地 在小鼠、大鼠和人类的整个生命周期中都会增加。这就提出了一个问题， 增加反映了海马体生理控制的崩溃或大脑试图保护 本身在初步的研究中，我们已经表明，缺乏或表达很少的PDE 11 A的小鼠完全是 防止与年龄相关的社交aLTM认知能力下降。根据这些和其他初步研究， 我们假设海马PDE 11 A4与年龄相关的增加发生在一个亚细胞内， 隔室特定的方式和损害社会aLTM。在这三个目标中，我们采取了一个综合的 通过将体内遗传操作与体内行为测试以及离体 分子和生化终点。在具体目标1中，我们将确定是否预防或逆转年龄- PDE 11 A4的相关增加可以挽救社交aLTM中与年龄相关的损伤。在第二阶段，我们将 确定PDE 11 A4表达与年龄相关增加的回路、细胞类型和亚细胞区室 发生并识别驱动这些区室特异性效应的翻译后修饰。在特定 目的3，我们将定义驱动PDE 11 A4表达的年龄相关性增加的信号。这些创新 这些研究也将为我们提供对社会记忆基本机制的深入了解 PDE 11 A在大脑中的功能和调节。靶向PDE 11 A可能是一种选择性地 在调节社交记忆的特定大脑区域恢复环核苷酸信号， 影响其他地方的信号。这可能会缓解社会赤字，而不会造成不必要的副作用。

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.