Hagar Janel M, Macht Victoria A, Wilson Steven P, Fadel James R
Department of Pharmacology, Physiology & Neuroscience, University of South Carolina School of Medicine, Columbia, SC 29208, USA.
Department of Pharmacology, Physiology & Neuroscience, University of South Carolina School of Medicine, Columbia, SC 29208, USA; Department of Psychology, University of South Carolina School of Medicine, Columbia, SC 29208, USA.
Neuroscience. 2017 May 14;350:124-132. doi: 10.1016/j.neuroscience.2017.03.021. Epub 2017 Mar 24.
Aging is associated with changes in numerous homeostatic functions, such as food intake, that are thought to be mediated by the hypothalamus. Orexin/hypocretin neurons of the hypothalamus regulate several physiological functions, including feeding, sleep and wakefulness. Evidence from both clinical and animal studies supports the notion that aging is associated with loss or dysregulation of the orexin system. Here, we used virus-mediated gene transfer to manipulate expression of orexin peptides in young and aged rats and examined behavioral and neurochemical correlates of food intake in these animals. Aged rats showed slower feeding latencies when presented with palatable food compared to young control rats, and these deficits were ameliorated by upregulation of orexin expression. Similarly, young animals treated with a virus designed to decrease preproorexin expression showed longer feeding latencies reminiscent of aged control rats. Feeding was also associated with increased acetylcholine, glutamate and GABA efflux in insular cortex of young control animals. Orexin upregulation did not restore deficits in feeding-elicited release of these neurotransmitters in aged rats, but did enhance basal neurotransmitter levels which may have contributed to the behavioral correlates of these genetic manipulations. These studies demonstrate that age-related deficits in behavioral and neurochemical measures of feeding are likely to be mediated, in part, by the orexin system. Because these same neurotransmitter systems have been shown to underlie orexin effects on cognition, treatments which increase orexin function may have potential for improving both physiological and cognitive manifestations of certain age-related disorders.
衰老与众多稳态功能的变化相关，如食物摄入，而这些变化被认为是由下丘脑介导的。下丘脑的食欲素/下丘脑泌素神经元调节多种生理功能，包括进食、睡眠和觉醒。临床和动物研究的证据均支持衰老与食欲素系统的丧失或失调相关这一观点。在此，我们利用病毒介导的基因转移来操纵年轻和老年大鼠中食欲素肽的表达，并研究这些动物进食行为和神经化学方面的相关性。与年轻对照大鼠相比，老年大鼠在面对美味食物时进食潜伏期更长，而食欲素表达上调可改善这些缺陷。同样，用旨在降低前食欲素原表达的病毒处理的年轻动物表现出更长的进食潜伏期，这与老年对照大鼠相似。进食还与年轻对照动物岛叶皮质中乙酰胆碱、谷氨酸和γ-氨基丁酸外流增加有关。食欲素上调并未恢复老年大鼠进食引发的这些神经递质释放的缺陷，但确实提高了基础神经递质水平，这可能有助于解释这些基因操作的行为相关性。这些研究表明，与年龄相关的进食行为和神经化学指标缺陷可能部分由食欲素系统介导。由于这些相同的神经递质系统已被证明是食欲素对认知产生影响的基础，增强食欲素功能的治疗方法可能有潜力改善某些与年龄相关疾病的生理和认知表现。
