Chemogenetic activation of orexin/hypocretin neurons ameliorates aging-induced changes in behavior and energy expenditure.
Chemogenetic activation of orexin/hypocretin neurons ameliorates aging-induced changes in behavior and energy expenditure.
复制标题
食欲素/下丘脑分泌素神经元的化学遗传学激活可改善衰老引起的行为和能量消耗的变化。
DOI：
10.1152/ajpregu.00383.2018
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Kotz,Catherine
中科院分区：
文献类型：
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作者：
Stanojlovic,Milos;PallaisYllescasJr,JeanPierre;Mavanji,Vijaya;Kotz,Catherine
衰老影响许多生理过程以及行为。这些过程中的大量调节，至少部分，由下丘脑食欲素神经元，食欲素张力可能会随着正常衰老而下降。在这项研究中，我们假设设计师受体专门激活设计师药物（DREADD）刺激食欲素神经元活性将改善衰老对年轻和中年小鼠行为和代谢改变的影响。通过将AAV载体（AAV 2-hSyn-DIO-hM 3D（Gq）-mCherry）立体定位注射到5和12月龄食欲素-cre雌性小鼠的外侧下丘脑中来实现DREADD靶向，并通过食欲素A和mCherry表达的免疫组织化学（IHC）分析来证实。恢复后，对动物进行行为测试组合，包括高架十字迷宫（ESTA）、旷场（OFT）和新物体识别测试（NORT），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，食欲素神经元的激活减轻了中年小鼠中焦虑样行为的衰老诱导的减少（P< 0.005），并增加了年轻和中年小鼠中的运动（P< 0.05）。增食欲素神经元的激活增加了中年小鼠的SPA（P< 0.01）和EE（P< 0.005），恢复到年轻动物中观察到的水平。这项研究的结果确定了食欲素神经元作为认知和焦虑相关行为以及能量平衡中与年龄相关的损伤的潜在治疗靶点。
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(Gq)-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 (P< 0.005) and increases locomotion in both young and middle-aged mice (P< 0.05). Activation of orexin neurons increases SPA (P< 0.01) and EE (P< 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.