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不仅对老年人的生活质量，而且对亲属，照顾者和一般的医疗保健系统构成越来越大的问题。虽然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，重要的是要了解大脑及其主要功能之一，即记忆，如何在人类生活中老化，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。 神经肽S（Neuropeptide S，NPH）是最近发现的一种脑内递质。在啮齿类动物中，抗抑郁药产生唤醒和觉醒，并减少焦虑的行为迹象。我们实验室的最新研究表明，维生素E可以有效地增强学习和记忆。人体内一种天然存在的受体基因突变会显著改变受体的敏感性，这可能会对记忆产生行为影响。这些证据使该系统成为开发具有促认知作用的新药的一个有趣的候选者，这些药物可以帮助缓解与年龄相关的记忆衰退的症状。该提案的第一部分将测试维生素E对老年小鼠记忆形成的影响，这是一种研究与年龄相关的记忆缺陷的既定模型。由于海马可以增强年轻小鼠的记忆形成，我们希望在老年小鼠中看到类似的效果。其次，我们将分析药理学和信号转导的一些自然发生的变体的人ESTA受体，以确定特定版本的基因，不同的响应激活ESTA。由于这些突变在人类中的发生频率很高，我们接下来将讨论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。在本研究的这一部分，我们将分析一项非常大型的老年研究（“90+研究”）参与者的β受体基因型。我们将专门测试更敏感或减弱的β受体基因变异是否与我们社会中这些最年长的成员（入组时超过90岁）的记忆表现，记忆衰退的发作和进展或其他心理能力相关。总之，我们打算验证作为一种新的药物靶点治疗与年龄相关的认知能力下降的神经网络系统。这些研究的结果将极大地推进我们对认知老化的神经机制的认识。 公共卫生相关性：与认知功能下降相关的认知功能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。在目前的提案中，我们计划使用翻译动物模型，体外药理学和人类分子遗传工具来探索神经肽S系统作为治疗年龄相关性认知衰退的新兴靶点的潜力。分析与认知能力相关的人类β受体基因中自然发生的多态性，可能对评估发展认知能力下降的个体风险具有实际意义，这将保证早期预防。这项研究既是探索性的，也是转化性的，可能会导致更好地理解认知老化的神经机制。

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.