Gerashchenko D, Salin-Pascual R, Shiromani P J
West Roxbury VA Medical Center and Harvard Medical School, 1400 VFW Parkway, West Roxbury, MA 02132, USA.
Brain Res. 2001 Sep 14;913(1):106-15. doi: 10.1016/s0006-8993(01)02792-5.
Neurons containing the peptide hypocretin, also known as orexin, were recently implicated in the human sleep disorder narcolepsy. Hypocretin neurons are located only in the lateral hypothalamus from where they innervate virtually the entire brain and spinal cord. This peptide is believed to be involved in regulating feeding and wakefulness. However, to fully understand what other behaviors are regulated by this peptide it is necessary to investigate each hypocretin target site. In the present study, we focus on one hypocretin target site, the medial septum, where there is a dense collection of hypocretin-2 receptor-containing cells, and degenerating axons are present here in canines with narcolepsy [J. Neurosci. 19 (1999) 248]. We utilize a saporin toxin conjugated to the hypocretin receptor binding ligand, hypocretin-2, and find that when this toxin is injected into the medial septum, it lesions the parvalbumin and cholinergic neurons. We contrast the effects of the hypocretin-saporin with another saporin conjugated toxin, 192 IgG-saporin, that lesions only the cholinergic neurons in the basal forebrain. 192 IgG-saporin reduced theta activity, a finding consistent with previous reports [J. Neurophysiol. 79 (1998) 1633; Neurodegeneration 4 (1995) 61; Neuroscience 62 (1994) 1033]. However, hypocretin-saporin completely eliminated hippocampal theta activity by day 12, indicating that parvalbumin-containing cells in the medial septum generate theta. The daily amount of sleep and wakefulness were not different between hypocretin-saporin, 192 IgG-saporin, or saline-treated rats. The homeostatic response to 12 h prolonged wakefulness was also not affected in hypocretin-saporin lesioned rats. These findings suggest that hypocretin neurons could facilitate theta generation during episodes of purposeful behavior by activating GABAergic neurons in the MS/VDB. In this way, hypocretin, which is implicated in feeding, energy metabolism and wakefulness, serves to influence cognitive processes critical for the animal's survival.
含有肽类物质下丘脑泌素（也称为食欲素）的神经元最近被认为与人类睡眠障碍发作性睡病有关。下丘脑泌素神经元仅位于下丘脑外侧，从这里它们几乎支配整个大脑和脊髓。这种肽被认为参与调节进食和清醒。然而，要全面了解这种肽还调节哪些其他行为，有必要研究每个下丘脑泌素靶位点。在本研究中，我们聚焦于一个下丘脑泌素靶位点——内侧隔区，这里有密集的含下丘脑泌素 - 2受体的细胞群，并且在发作性睡病犬中此处存在轴突退变[《神经科学杂志》19 (1999) 248]。我们使用与下丘脑泌素受体结合配体下丘脑泌素 - 2偶联的皂草素毒素，发现当将这种毒素注入内侧隔区时，它会损伤小白蛋白和胆碱能神经元。我们将下丘脑泌素 - 皂草素的作用与另一种偶联皂草素的毒素192 IgG - 皂草素的作用进行对比，192 IgG - 皂草素仅损伤基底前脑的胆碱能神经元。192 IgG - 皂草素降低了θ波活动，这一发现与先前的报道一致[《神经生理学杂志》79 (1998) 1633；《神经退行性变》4 (1995) 61；《神经科学》62 (1994) 1033]。然而，下丘脑泌素 - 皂草素在第12天时完全消除了海马θ波活动，表明内侧隔区含小白蛋白的细胞产生θ波。下丘脑泌素 - 皂草素处理组、192 IgG - 皂草素处理组或生理盐水处理组大鼠的每日睡眠和清醒时长并无差异。下丘脑泌素 - 皂草素损伤的大鼠对12小时延长清醒的稳态反应也未受影响。这些发现表明，下丘脑泌素神经元可通过激活内侧隔核/垂直对角带核中的γ - 氨基丁酸能神经元，在有目的行为发作期间促进θ波的产生。通过这种方式，与进食、能量代谢和清醒有关的下丘脑泌素有助于影响对动物生存至关重要的认知过程。
