University of South Carolina School of Medicine, Columbia, SC 29208, USA.
Neuroscience. 2011 Nov 10;195:70-9. doi: 10.1016/j.neuroscience.2011.08.033. Epub 2011 Aug 22.
GABAergic neurons of the medial septum of the basal forebrain make up a substantial portion of the septo-hippocampal pathway fibers, and are known to modulate hippocampal amino acid neurotransmission and support cognitive function. Importantly, these neurons are also implicated in age-related cognitive decline. Hypothalamic orexin/hypocretin neurons innervate and modulate the activity of these basal forebrain neurons and also provide direct inputs to the hippocampus. However, the precise role of orexin inputs in modulating hippocampal amino acid neurotransmission--as well as how these interactions are altered in aging--has not been defined. Here, orexin A (OxA) was administered to CA1 and the medial septum of young (3-4 months) and aged (27-29 months) Fisher 344 Brown Norway rats, and hippocampal GABA and glutamate efflux was analyzed by in vivo microdialysis. Following CA1 infusion of OxA, extracellular GABA and glutamate efflux was increased, but the magnitude of orexin-mediated efflux was not altered as a function of age. However, medial septum infusion of OxA did not impact hippocampal efflux in young rats, while aged rats exhibited a significant enhancement in GABA and glutamate efflux compared to young counterparts. Furthermore, immunohistochemical characterization of the medial septum revealed a significant decrease in parvalbumin (PV)-positive cell bodies in aged animals, and a significant reduction in orexin fiber innervation to the remaining GABAergic cells within the septum, while orexin innervation to the hippocampus was unaltered by the aging process. These findings indicate that: (1) OxA directly modulates hippocampal amino acid neurotransmission in young animals, (2) Aged animals show enhanced responsivity to exogenous OxA activation of the septo-hippocampal pathway, and (3) Aged animals undergo an intrinsic reduction in medial septum PV-immunoreactivity and a decrease in orexin innervation to remaining septal PV neurons. Alterations in orexin regulation of septo-hippocampal activity may contribute to age-related dysfunctions in arousal, learning, and memory.
基底前脑内侧隔核的 GABA 能神经元构成了隔海马通路纤维的重要部分，已知其调节海马氨基酸神经传递并支持认知功能。重要的是，这些神经元也与年龄相关的认知衰退有关。下丘脑食欲素/下丘脑泌素神经元支配并调节这些基底前脑神经元的活动，并且还直接向海马体输入。然而，食欲素输入在调节海马氨基酸神经传递中的精确作用——以及这些相互作用在衰老过程中是如何改变的——尚未确定。在这里，给予年轻（3-4 个月）和年老（27-29 个月）Fisher344 棕褐挪威大鼠 CA1 和内侧隔核食欲素 A（OxA），并通过体内微透析分析海马 GABA 和谷氨酸的外排。在 CA1 输注 OxA 后，细胞外 GABA 和谷氨酸外排增加，但食欲素介导的外排量的大小不因年龄而改变。然而，在年轻大鼠中，内侧隔核输注 OxA 不会影响海马体的外排，而年老大鼠与年轻大鼠相比，GABA 和谷氨酸的外排量显著增加。此外，内侧隔核的免疫组织化学特征表明，年老动物的 PV 阳性细胞体数量显著减少，并且剩余 GABA 能细胞内的食欲素纤维支配到隔核的数量显著减少，而海马体的食欲素支配不受衰老过程的影响。这些发现表明：（1）OxA 直接调节年轻动物的海马氨基酸神经传递，（2）年老动物对隔海马通路的外源性 OxA 激活表现出增强的反应性，（3）年老动物经历内侧隔核 PV 免疫反应性的内在减少和剩余隔核 PV 神经元的食欲素支配减少。食欲素对隔海马活动的调节改变可能导致与年龄相关的觉醒、学习和记忆功能障碍。
