Neural Signaling in Age-related Cognitive Impairment

项目摘要 正常的衰老会导致外显记忆和执行功能的丧失，这些功能依赖于 海马/内侧颞叶和前额叶皮质的完整性。认知 可以在大鼠中测量由海马和前额皮质介导的区域， 功能输出，据此我们可以评估与年龄相关的神经生物学变化的重要性， 记忆障碍和干预的效果。 在老年大鼠和人类的海马和皮层中，毒蕈碱M1和代谢型谷氨酸受体 （mGluR）1型与Galphaq/11偶联和下游磷酸肌醇周转信号传导被钝化。 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， 一些迹象表明，这也是阿尔茨海默病患者的情况。体外和体内研究可以 通过两个明显不相关的基因， 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， 随后进行干预并防止机械性改变和认知能力下降。我们将联合收割机 行为评估与神经生物学分析，以确定是否预防受体偶联缺陷 通过生长激素/IGF-1干预与预防年龄相关的认知能力下降有关。的 这些实验的结果将提供关于年龄的基本机制的新信息 相关的认知能力下降，并揭示是否生长激素管理老年受试者将防止 认知能力下降的出现沿着分子机制的相关改变。 该项目将确定大脑中细胞信号的某些变化是否会导致大脑功能的丧失。 以及是什么机制驱动了这些变化。该项目还将确定， 生长激素的干预将防止细胞信号的变化和相关的年龄相关的认知功能障碍。 下降

Project Summary 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.