Neural Signaling in Age-related Cognitive Impairment

描述（由申请人提供）：正常衰老可导致外显记忆和执行功能的丧失，这些功能分别依赖于海马/内侧颞叶和前额叶皮质的完整性。可以在大鼠中测量由海马和前额叶皮质介导的认知域，以提供功能输出，我们可以根据该输出评估与年龄相关的神经生物学变化对记忆障碍的重要性以及干预措施的效果。在老年大鼠和人类的海马和皮质中，毒蕈碱M1和代谢型谷氨酸受体（mGluR）1型与Galphaq/11偶联，下游磷酸肌醇周转信号减弱。重要的是，在记忆力受损最严重的大鼠中，受体偶联是最迟钝的，并且有一些迹象表明，阿尔茨海默病患者也是如此。在体外和体内的研究可以重现老化对毒蕈碱受体/G-蛋白偶联的影响，通过两个明显无关的机制：增加氧化应激或清除胆碱能传入。我们在这个项目中的目标是确定哪些机制有助于衰老的这些影响，并随后干预和预防机械性改变和认知能力下降。我们将结合联合收割机行为评估与神经生物学分析，以确定通过生长激素/IGF-1干预预防受体偶联缺陷是否与预防年龄相关的认知能力下降有关。这些实验的结果将提供关于与年龄相关的认知衰退的基本机制的新信息，并揭示向老年受试者施用生长激素是否将防止认知衰退的出现，沿着分子机制的相关改变。铺设说明：该项目将确定大脑中细胞信号的某些变化是否会导致衰老中的记忆丧失，以及驱动这些变化的机制是什么。该项目还将确定生长激素的早期干预是否会防止细胞信号变化和相关的年龄相关的认知能力下降。公共卫生相关性30%的65岁或65岁以上的人会表现出认知能力下降的迹象，从轻度认知障碍到严重痴呆。本提案中描述的大鼠研究将重点关注导致非病理性记忆丧失的机制因素，这种记忆丧失是正常衰老的结果，并将提供临床前数据，旨在开发潜在的治疗方法，以对抗正常的、与年龄相关的记忆衰退。

DESCRIPTION (provided by applicant): Normal aging can produce a loss of explicit memory and executive function, functions dependent upon the integrity of the hippocampus/medial temporal lobe and the prefrontal cortex, respectively. The cognitive domains mediated by the hippocampus and the prefrontal cortex can be measured in rats to provide a functional output against which we can assess the importance of age-related neurobiological changes on memory impairment and the effects of interventions. In the hippocampus and cortex of aged rats and humans, muscarinic M1 and metabotropic glutamate receptor (mGluR) Type 1 coupling to Galphaq/11 and downstream phosphoinositide turnover signaling is blunted. Importantly, the receptor coupling is most blunted in the rats with the most impaired memory, and there is some indication that this is also the case in Alzheimer's disease patients. In vitro and in vivo studies can reproduce the effects of aging on muscarinic receptor/G-protein coupling by two apparently unrelated mechanisms: increasing oxidative stress or removal of cholinergic afferents. Our goal in this project is to determine which mechanism(s) contribute to these effects of aging, and subsequently to intervene and prevent both the mechanistic alterations and cognitive decline. We will combine behavioral assessment with neurobiological analysis to determine if the prevention of receptor coupling deficits via growth hormone/IGF-1 intervention is relevant in the prevention of age-related cognitive decline. The outcome of these experiments will provide new information with regards to the basic mechanisms of age related cognitive decline and reveal if growth hormone administration to aged subjects will prevent the emergence of cognitive decline along with associated alterations in molecular mechanisms. Lay description: This project will determine if certain changes in cell signaling in the brain contribute to a loss of memory in aging and what mechanisms drive these changes. This project will also determine if early intervention with growth hormone will prevent cell signaling changes and the associated age-related cognitive decline. PUBLIC HEALTH RELEVANCE Thirty percent of individuals aged 65 or older will show signs of cognitive decline ranging from mild cognitive impairment to severe dementia. The rat studies described in this proposal will focus on the mechanistic factors that contribute to the non-pathological loss of memory that occurs as a consequence of normal aging and will provide pre-clinical data aimed at the development of potential therapies to counteract normal, age-related memory decline.