University of South Carolina School of Medicine, Department of Pharmacology, Physiology and Neuroscience, 6439 Garners Ferry Road Columbia, SC 29208, USA.
Neuroscience. 2011 Mar 31;178:82-8. doi: 10.1016/j.neuroscience.2011.01.031. Epub 2011 Jan 22.
Aging is associated with many physiological alterations-such as changes in sleep patterns, metabolism and food intake-suggestive of hypothalamic dysfunction, but the effects of senescence on specific hypothalamic nuclei and neuronal groups that mediate these alterations is unclear. The lateral hypothalamus and contiguous perifornical area (LH/PFA) contains several populations of neurons, including those that express the neuropeptides orexin (hypocretin) or melanin-concentrating hormone (MCH). Collectively, orexin and MCH neurons influence many integrative homeostatic processes related to wakefulness and energy balance. Here, we determined the effect of aging on numbers of orexin and MCH neurons in young adult (3-4 months) and old (26-28 months) Fisher 344/Brown Norway F1 hybrid rats. Aged rats exhibited a loss of greater than 40% of orexin-immunoreactive neurons in both the medial and lateral (relative to the fornix) sectors of the LH/PFA. MCH-immunoreactive neurons were also lost in aged rats, primarily in the medial LH/PFA. Neuronal loss in this area was not global as no change in cells immunoreactive for the pan-neuronal marker, NeuN, was observed in aged rats. Combined with other reports of altered receptor expression or behavioral responses to exogenously-administered neuropeptide, these data suggest that compromised orexin (and, perhaps, MCH) function is an important mediator of age-related homeostatic disturbances of hypothalamic origin. The orexin system may represent a crucial substrate linking homeostatic and cognitive dysfunction in aging, as well as a novel therapeutic target for pharmacological or genetic restoration approaches to preventing or ameliorating these disturbances.
衰老是与许多生理变化相关的，例如睡眠模式、代谢和食物摄入的变化，这些变化提示下丘脑功能障碍，但衰老对介导这些变化的特定下丘脑核和神经元群的影响尚不清楚。外侧下丘脑和相邻的peri-fornical 区域 (LH/PFA) 包含几种神经元群体，包括表达神经肽食欲素 (hypocretin) 或黑色素浓缩激素 (MCH) 的神经元。总的来说，食欲素和 MCH 神经元影响许多与觉醒和能量平衡相关的整合性稳态过程。在这里，我们确定了衰老对年轻成年（3-4 个月）和老年（26-28 个月）Fisher 344/Brown Norway F1 杂种大鼠中食欲素和 MCH 神经元数量的影响。老年大鼠在 LH/PFA 的内侧和外侧（相对于穹窿）区域均表现出食欲素免疫反应性神经元丧失超过 40%。MCH 免疫反应性神经元也在老年大鼠中丢失，主要在 LH/PFA 的内侧。该区域的神经元丢失不是全局的，因为在老年大鼠中未观察到对泛神经元标志物 NeuN 免疫反应的细胞发生变化。结合其他关于外源性神经肽给药后受体表达或行为反应改变的报告，这些数据表明，受损的食欲素（也许还有 MCH）功能是下丘脑源性与年龄相关的稳态紊乱的重要介导者。食欲素系统可能代表一个关键的基质，将稳态和认知功能障碍联系起来，也是预防或改善这些紊乱的药理学或遗传恢复方法的一个新的治疗靶点。
