Role of Neuropeptide S in age-related cognitive decline

描述（由申请人提供）：随着我们的社会逐渐老龄化，与年龄相关的记忆丧失日益成为一个日益严重的问题，不仅影响老年人的生活质量，而且影响亲属、护理人员和整个医疗保健系统。虽然人们对认知能力下降的生物学机制知之甚少，但已知环境和遗传因素都有影响。因此，了解大脑及其主要功能之一（即记忆）如何影响人类生命中的年龄，并确定与年龄相关的学习和记忆障碍相关的特定生化目标和机制非常重要。 神经肽 S (NPS) 是最近在大脑中发现的一种递质。 NPS 可以产生兴奋和觉醒，并减少啮齿动物的焦虑行为迹象。我们实验室最近的研究表明，NPS 可以有效增强学习和记忆能力。人类 NPS 受体基因中自然发生的突变会显着改变受体的敏感性，这可能会对记忆产生行为影响。这些证据使 NPS 系统成为开发具有促认知作用的新药物的有趣候选者，可以帮助缓解与年龄相关的记忆衰退症状。该提案的第一部分将测试 NPS 对高龄小鼠记忆形成的影响，这是研究与年龄相关的记忆缺陷的既定模型。由于 NPS 可以增强年轻小鼠的记忆形成，因此我们期望在老年小鼠中看到类似的效果。其次，我们将分析人类 NPS 受体的许多天然变体的药理学和信号转导，以确定对 NPS 激活有不同反应的特定基因版本。由于 NPS 受体的这些突变在人群中发生频率很高，因此我们接下来将解决不同形式的受体是否可能导致与年龄相关的认知能力下降或发挥保护功能的问题。在这部分研究中，我们将分析一项大型老年研究“90 研究”参与者的 NPS 受体基因型。我们将专门测试更敏感或减弱的 NPS 受体基因变异是否与我们社会中这些最年长的成员（入组时年龄超过 90 岁）的记忆表现、记忆衰退的发生和进展或其他心理能力相关。我们打算共同验证 NPS 系统作为治疗与年龄相关的认知衰退的新药物靶点。这些研究的结果将极大地增进我们对认知衰老神经机制的认识。 公共卫生相关性：与年龄相关的认知能力下降对受影响的个人、社会和医疗保健系统来说是一个巨大的负担，而潜在的神经生物学机制在很大程度上仍然未知。在当前的提案中，我们计划利用转化动物模型、体外药理学和人类分子遗传学工具来探索神经肽S系统作为治疗与年龄相关的认知衰退的新兴靶点的潜力。分析与认知表现相关的人类 NPS 受体基因中自然发生的多态性可能对评估个体发生认知能力下降的风险具有实际意义，从而需要早期预防。这项研究既是探索性的，也是转化性的，可以帮助人们更好地理解认知衰老背后的神经机制。

DESCRIPTION (provided by applicant): As our society grows progressively older, age-related memory loss is posing an increasing problem, not only for quality of life of elderly people, but also for relatives, caregivers and the health care system in general. While the biological mechanisms of cognitive decline are poorly understood, both environmental and genetic factors are known to contribute. It is therefore important to understand how the brain and one of its major functions, i.e. memory, age during human life and identify specific biochemical targets and mechanisms that are associated with age-related impairment of learning and memory. Neuropeptide S (NPS) is a recently identified transmitter in the brain. NPS produces arousal and wakefulness and reduces behavioral signs of anxiety in rodents. Recent studies in our lab demonstrate that NPS can potently enhance learning and memory. A naturally occurring mutation in the human NPS receptor gene changes the sensitivity of the receptor significantly, which may have a behavioral impact on memory. These evidences make the NPS system an interesting candidate for development of new drugs with pro-cognitive effects that can help to alleviate symptoms of age-related memory decline. The first part of this proposal will test the effects of NPS on memory formation in very old mice, which are an established model to study age-related memory deficits. Since NPS can enhance memory formation in young mice, we expect to see similar effects in aged mice. Second, we will analyze the pharmacology and signal transduction of a number of naturally occurring variants of the human NPS receptor in order to identify particular versions of the gene that respond differently to activation by NPS. Since these mutations in the NPS receptor occur with high frequency in the human population, we will next address the question whether different forms of the receptor may contribute to age-related cognitive decline or exert a protective function. For this part of the study, we will analyze NPS receptor genotypes in participants of a very large geriatric study: the "90+ Study". We will specifically test whether more sensitive or attenuated NPS receptor gene variants are associated with memory performance, onset and progression of memory decline, or other mental capabilities in these oldest-old members of our society (over 90 years old at time of enrollment). Together, we intend to validate the NPS system as a novel drug target for treatment of age-related cognitive decline. Results from these studies will greatly advance our knowledge about neural mechanisms underlying cognitive aging. PUBLIC HEALTH RELEVANCE: Age-related cognitive decline is a tremendous burden for affected individuals, society, and the health care system, while the underlying neurobiological mechanisms remain largely unknown. In the current proposal, we plan to use translational animal models, in vitro pharmacology, and human molecular genetic tools to explore the potential of the Neuropeptide S system as an emerging target for treatment of age-related cognitive decline. Analyzing naturally occurring polymorphisms in the human NPS receptor gene that are associated with cognitive performance may have practical implications to assess individual risk for developing cognitive decline that would warrant early prevention. The study is both exploratory and translational and could lead to a better understanding of neural mechanisms underlying cognitive aging.