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

项目摘要：腹侧环核苷酸信号的区隔 海马体 60岁以后，几乎所有人都会经历某种形式的认知衰退--尤其是记忆力衰退 赤字--没有任何药物能够预防或扭转这种损失。与年龄相关的认知障碍，即使在 没有痴呆症，增加了医疗保健费用和残疾风险。认知衰退并不是一成不变的 过程，在不同个体和不同认知域观察到症状严重程度的差异。 联想长期记忆(ALTM)--尤其是那些涉及与家人和朋友的经历的记忆-- 与认知长期记忆(RLTM)相比，更容易受到与年龄相关的认知衰退的影响 原因还不是很清楚。对支配年龄的分子机制缺乏了解- 相关的下降减缓了新疗法的发展。 磷酸二酯酶11A(PDE11A)是一种分解cAMP和cGMP的酶，PDE11A 可能是调节社会性aLTM的重要分子机制。PDE11A几乎是独有的 在大脑中称为腹侧海马体的一小块区域表达，这是大脑中需要 用于社交aLTM的适当存储。我们已经证明了海马区PDE11A4的显著表达 延长小鼠、大鼠和人类的寿命。这就提出了这样一个问题：这种与年龄有关的 增加反映了海马体生理控制的崩溃或大脑试图保护 它本身。在初步研究中，我们已经表明，缺乏或表达很少PDE11A的小鼠完全是 防止社交aLTM的年龄相关认知能力下降。基于这些和其他初步研究， 我们假设海马区PDE11A4中与年龄相关的增加发生在一个亚细胞中 隔间特有的举止和损害社交行为。在三个目标中，我们采取了综合的 将体内遗传操作与体内行为测试和体外实验相结合的实验方法 分子和生化终点。在具体目标1中，我们将确定是否防止或逆转年龄-- PDE11A4的相关增加可以挽救社交aLTM中与年龄相关的损害。在具体目标2中，我们将 识别与年龄相关的PDE11A4表达增加的回路、细胞类型和亚细胞室 发生并识别驱动这些隔室特定效应的翻译后修饰。具体而言 目的3，我们将定义驱动PDE11A4表达随年龄增加的信号。这些创新之处 研究也将对社会记忆的基本机制提供亟需的洞察力 作为PDE11A在大脑中的功能和调节。瞄准PDE11A可能是一种选择性地 恢复特定大脑区域中调节社会记忆的环核苷酸信号，而不是 影响其他地方的信号。这可能会缓解社会赤字，而不会产生不受欢迎的副作用。

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.