Center for Behavioral Neuroscience, Institute of Experimental Psychology, University of Düsseldorf, 40225 Düsseldorf, Germany.
Proc Natl Acad Sci U S A. 2013 Sep 10;110(37):15097-102. doi: 10.1073/pnas.1306884110. Epub 2013 Aug 27.
Impaired learning and memory performance is often found in aging as an early sign of dementia. It is associated with neuronal loss and reduced functioning of cholinergic networks. Here we present evidence that the neurokinin3 receptors (NK3-R) and their influence on acetylcholine (ACh) release may represent a crucial mechanism that underlies age-related deficits in learning and memory. Repeated pharmacological stimulation of NK3-R in aged rats was found to improve learning in the water maze and in object-place recognition. This treatment also enhanced in vivo acetylcholinergic activity in the frontal cortex, hippocampus, and amygdala but reduced NK3-R mRNA expression in the hippocampus. Furthermore, NK3-R agonism incurred a significantly higher increase in ACh levels in aged animals that showed superior learning than in those that were most deficient in learning. Our findings suggest that the induced activation of ACh, rather than basal ACh activity, is associated with superior learning in the aged. To test whether natural variation in NK3-R function also determines learning and memory performance in aged humans, we investigated 209 elderly patients with cognitive impairments. We found that of the 15 analyzed single single-nucleotide ploymorphism (SNPs) of the NK3-R-coding gene, TACR3, the rs2765 SNP predicted the degree of impairment of learning and memory in these patients. This relationship could be partially explained by a reduced right hippocampus volume in a subsample of 111 tested dementia patients. These data indicate the NK3-R as an important target to predict and improve learning and memory performance in the aged organism.
学习和记忆表现受损在衰老中经常被发现，是痴呆症的早期迹象。它与神经元丧失和胆碱能网络功能降低有关。在这里，我们提供的证据表明，神经激肽 3 受体（NK3-R）及其对乙酰胆碱（ACh）释放的影响可能是导致学习和记忆与年龄相关的缺陷的关键机制。在老年大鼠中反复给予 NK3-R 药理学刺激被发现可改善水迷宫和物体位置识别中的学习。这种治疗方法还增强了前额叶皮层、海马体和杏仁核中的体内乙酰胆碱活性，但降低了海马体中的 NK3-R mRNA 表达。此外，NK3-R 激动剂在表现出优异学习能力的老年动物中引起 ACh 水平的显著增加，而在学习能力最差的动物中则没有。我们的研究结果表明，诱导的 ACh 激活而不是基础 ACh 活性与老年动物的优异学习有关。为了测试 NK3-R 功能的自然变异是否也决定了老年人群的学习和记忆表现，我们研究了 209 名认知障碍的老年患者。我们发现，在分析的 NK3-R 编码基因 TACR3 的 15 个单核苷酸多态性（SNP）中，rs2765 SNP 预测了这些患者学习和记忆损伤的程度。这种关系可以部分解释为在测试的 111 名痴呆症患者的亚样本中右海马体体积减少。这些数据表明 NK3-R 是一个重要的靶点，可以预测和改善老年机体的学习和记忆表现。
