Department of Pharmacology, Physiology and Neuroscience, University of South Carolina School of Medicine, Columbia, South Carolina, USA.
J Neurochem. 2018 May;145(3):232-244. doi: 10.1111/jnc.14279. Epub 2018 Jan 12.
Orexin/hypocretin neurons of the lateral hypothalamus and perifornical area are integrators of physiological function. Previous work from our laboratory and others has shown the importance of orexin transmission in cognition. Age-related reductions in markers of orexin function further suggest that this neuropeptide may be a useful target for the treatment of age-related cognitive dysfunction. Intranasal administration of orexin-A (OxA) has shown promise as a therapeutic option for cognitive dysfunction. However, the neurochemical mechanisms of intranasal OxA administration are not fully understood. Here, we use immunohistochemistry and in vivo microdialysis to define the effects of acute intranasal OxA administration on: (i) activation of neuronal populations in the cortex, basal forebrain, and brainstem and (ii) acetylcholine (ACh) and glutamate efflux in the prefrontal cortex (PFC) of Fischer 344/Brown Norway F1 rats. Acute intranasal administration of OxA significantly increased c-Fos expression, a marker for neuronal activation, in the PFC and in subpopulations of basal forebrain cholinergic neurons. Subsequently, we investigated the effects of acute intranasal OxA on neurotransmitter efflux in the PFC and found that intranasal OxA significantly increased both ACh and glutamate efflux in this region. These findings were independent from any changes in c-Fos expression in orexin neurons, suggesting that these effects are not resultant from direct activation of orexin neurons. In total, these data indicate that intranasal OxA may enhance cognition through activation of distinct neuronal populations in the cortex and basal forebrain and through increased neurotransmission of ACh and glutamate in the PFC.
下丘脑外侧区和peri 穹窿区的食欲素/下丘脑分泌素神经元是生理功能的整合者。我们实验室和其他实验室的先前工作表明，食欲素传递在认知中起着重要作用。与年龄相关的食欲素功能标志物减少进一步表明，这种神经肽可能是治疗与年龄相关的认知功能障碍的有用靶点。鼻内给予食欲素-A（OxA）已显示出作为认知功能障碍治疗选择的潜力。然而，鼻内 OxA 给药的神经化学机制尚未完全阐明。在这里，我们使用免疫组织化学和体内微透析来定义急性鼻内 OxA 给药对以下方面的影响：（i）大脑皮层、基底前脑和脑干中神经元群体的激活，以及（ii）前额叶皮层（PFC）中乙酰胆碱（ACh）和谷氨酸的外排在 Fischer 344/Brown Norway F1 大鼠中。急性鼻内给予 OxA 可显著增加 PFC 中 c-Fos 表达，c-Fos 是神经元激活的标志物，并且在基底前脑胆碱能神经元的亚群中也是如此。随后，我们研究了急性鼻内 OxA 对 PFC 中神经递质外排的影响，发现鼻内 OxA 可显著增加该区域的 ACh 和谷氨酸外排。这些发现与食欲素神经元中 c-Fos 表达的任何变化无关，表明这些影响不是源自食欲素神经元的直接激活。总的来说，这些数据表明，鼻内 OxA 可能通过激活皮层和基底前脑中的不同神经元群体以及增加 PFC 中的 ACh 和谷氨酸神经传递来增强认知。
