Integrative Biology and Physiology, University of Minnesota , Minneapolis, Minnesota.
Minneapolis Veterans Affairs Health Care System, Geriatric Research Education and Clinical Center , Minneapolis, Minnesota.
Am J Physiol Regul Integr Comp Physiol. 2019 May 1;316(5):R571-R583. doi: 10.1152/ajpregu.00383.2018. Epub 2019 Feb 6.
Aging affects numerous physiological processes, as well as behavior. A large number of these processes are regulated, at least partially, by hypothalamic orexin neurons, and orexin tone may decrease with normal aging. In this study, we hypothesized that designer receptors exclusively activated by designer drugs (DREADD) stimulation of orexin neuronal activity will ameliorate the effect of aging on behavioral and metabolic alterations in young and middle-aged mice. DREADD targeting was achieved by stereotaxic injection of AAV vectors (AAV2-hSyn-DIO-hM3D(G)-mCherry) into the lateral hypothalamus of 5- and 12-mo old orexin-cre female mice and was confirmed by immunohistochemistry (IHC) analysis of orexin A and mCherry expression. After recovery, animals were subjected to a behavioral test battery consisting of the elevated plus maze (EPM), open field (OFT), and novel object recognition tests (NORT) to assess effects of aging on anxiety-like behavior, general locomotion, and working memory. A comprehensive laboratory animal monitoring system (CLAMS) was used to measure spontaneous physical activity (SPA) and energy expenditure (EE). The results indicate that activation of orexin neurons mitigates aging-induced reductions in anxiety-like behavior in middle-aged mice ( < 0.005) and increases locomotion in both young and middle-aged mice ( < 0.05). Activation of orexin neurons increases SPA ( < 0.01) and EE ( < 0.005) in middle-aged mice, restoring the levels to that observed in young animals. Results from this study identify orexin neurons as potential therapeutic targets for age-related impairments in cognitive and anxiety-related behavior, and energy balance.
衰老是许多生理过程的影响因素，也会影响行为。这些过程中有大量过程受到下丘脑食欲素神经元的调节，而且食欲素的活动可能会随着正常衰老而降低。在这项研究中，我们假设，通过专门激活设计药物的受体（DREADD）刺激食欲素神经元的活动，将改善年轻和中年小鼠衰老对行为和代谢改变的影响。通过立体定向注射 AAV 载体（AAV2-hSyn-DIO-hM3D(G)-mCherry）到外侧下丘脑，实现了 DREADD 靶向，通过食欲素 A 和 mCherry 表达的免疫组织化学（IHC）分析进行了确认。恢复后，动物接受了包括高架十字迷宫（EPM）、旷场（OFT）和新物体识别测试（NORT）在内的行为测试，以评估衰老对焦虑样行为、一般运动和工作记忆的影响。使用综合实验室动物监测系统（CLAMS）测量自发体力活动（SPA）和能量消耗（EE）。结果表明，激活食欲素神经元可以减轻中年小鼠衰老引起的焦虑样行为减少（<0.005），并增加年轻和中年小鼠的运动（<0.05）。激活食欲素神经元增加 SPA（<0.01）和 EE（<0.005）在中年小鼠中，将水平恢复到年轻动物的水平。这项研究的结果表明，食欲素神经元可能是治疗与年龄相关的认知和焦虑相关行为以及能量平衡受损的潜在治疗靶点。
