The locus coeruleus (LC) provides the primary noradrenergic input to the forebrain and hippocampus, and may be vulnerable to degeneration and contribute to age-related cognitive decline and neuroinflammation. Additionally, inhibition of noradrenergic transmission by brain-permeable beta-blockers could exacerbate cognitive impairment. This study examined effects of age and acute beta-blocker administration on LC and hippocampus pathology, neuroinflammation and learning and memory behavior in mice. Male mice, 3 and 18 months old, were administered propranolol (beta-blocker) or mabuterol (beta-adrenergic agonist) acutely around behavioral assessment. Terminal inflammatory markers in plasma, hippocampus and LC were assessed alongside histopathology. An increase in hippocampal and LC microgliosis and inflammatory proteins in the hippocampus was detected in aged mice. We report pathological hyperphosphorylation of the postsynaptic NMDA receptor subunit 2B (NR2B) in the hippocampus, suggesting neuronal hyperexcitability. Furthermore, the aged proteome revealed an induction in proteins related to energy metabolism, and mitochondria dysfunction in the LC and hippocampus. In a series of hippocampal dependent behavioral assessment tasks acute beta-adrenergic agonist or beta blocker administration altered learning and memory behavior in both aged and young mice. In Y-maze, propranolol and mabuterol differentially altered time spent in novel versus familiar arms in young and aged mice. Propranolol impaired Novel Object Recognition in both young and aged mice. Mabuterol enhanced trace learning in fear conditioning. Aged mice froze more to context and less to cue. Propranolol impaired contextual recall in aged mice. Concluding, aged mice show LC and hippocampus pathology and heightened effects of beta-adrenergic pharmacology on learning and memory.

蓝斑 (LC) 为前脑和海马提供主要的去甲肾上腺素能输入，并且可能容易发生退化，并导致与年龄相关的认知能力下降和神经炎症。此外，脑渗透性β受体阻滞剂抑制去甲肾上腺素能传递可能会加剧认知障碍。本研究探讨了年龄和急性 β 受体阻滞剂给药对小鼠 LC 和海马病理、神经炎症以及学习和记忆行为的影响。 3 个月和 18 个月大的雄性小鼠在行为评估前后立即服用普萘洛尔（β 受体阻滞剂）或马布特罗（β 肾上腺素能激动剂）。血浆、海马和 LC 中的终末炎症标志物与组织病理学一起进行评估。在老年小鼠中检测到海马和 LC 小胶质细胞增生以及海马炎症蛋白的增加。我们报告了海马突触后 NMDA 受体亚基 2B (NR2B) 的病理性过度磷酸化，表明神经元过度兴奋。此外，衰老的蛋白质组揭示了与能量代谢相关的蛋白质的诱导，以及 LC 和海马中的线粒体功能障碍。在一系列海马依赖性行为评估任务中，急性β-肾上腺素能激动剂或β-受体阻滞剂的给药改变了老年和年轻小鼠的学习和记忆行为。在 Y 迷宫中，普萘洛尔和马布特罗对年轻和老年小鼠在新臂和熟悉臂上花费的时间有不同的改变。普萘洛尔会损害年轻和老年小鼠的新物体识别能力。马布特罗增强了恐惧条件反射的痕迹学习。年老的老鼠对周围环境的反应更多，而对提示的反应更少。普萘洛尔损​​害老年小鼠的情境记忆。 结论是，老年小鼠表现出 LC 和海马病理学，并且 β-肾上腺素能药理学对学习和记忆的影响增强。