Effects of lateral hypothalamic lesion with the neurotoxin hypocretin-2-saporin on sleep in Long-Evans rats
Effects of lateral hypothalamic lesion with the neurotoxin hypocretin-2-saporin on sleep in Long-Evans rats
复制标题
DOI：
10.1016/s0306-4522(02)00575-4
复制
发表时间：
2003-01-01
期刊：
影响因子：
3.3
通讯作者：
Shiromani, PJ
中科院分区：
文献类型：
--
作者：
Gerashchenko, D;Blanco-Centurion, C;Shiromani, PJ
发作性睡病是一种以白天过度嗜睡、睡眠发作、睡眠碎片、猝倒、入睡快速眼动睡眠和催眠幻觉为特征的致残性神经疾病，最近被认为与含有神经肽下丘脑分泌素的神经元丢失有关。发作性睡病患者的症状严重程度有相当大的差异，这可能与下丘脑外侧区神经元丢失的程度有关。为了研究这种可能性，我们将两种浓度(90 ng或490 ng，体积为0.5微升)的神经毒素下丘脑-2-皂苷、未结合皂苷或生理盐水直接注射到下丘脑外侧核，并监测睡眠、核心体温和活动的自由运动节律。在穹隆周围区、背内侧核和下丘脑腹内侧核计数下丘脑下丘脑底内侧核和下丘脑下丘脑腹内侧核的神经元。与低浓度(-34%)相比，较高浓度的下丘脑-2-皂苷(-55%)破坏更多的神经元核(NeUN)细胞，尽管两种浓度对下丘脑神经元的损害几乎相同(高浓度=91%；低浓度=88%)。高浓度的下丘脑-2-皂苷还损害了下丘脑背内侧核和下丘脑腹内侧核的神经元。两种浓度的下丘脑-2-皂苷都能产生发作性睡病样的睡眠行为。在正常活动的夜间周期中，高浓度比低浓度产生更大的非快速眼动睡眠增加。竹红菌素-2-皂苷的浓度不会扰乱核心温度的阶段或周期或活动节律。低浓度的未结合皂苷不会对下丘脑肌酸或神经元造成明显损害，也不会改变睡眠。高浓度的未结合皂苷导致部分神经元核免疫反应(Neun-ir)神经元和下丘脑肌醇免疫反应神经元的丢失，但非快速眼动睡眠仅有一过性增加。这些结果使我们得出结论，下丘脑下丘脑下部下丘脑下部神经元丢失的程度以及伴随而来的细胞丢失可能解释了人类发作性睡病症状严重程度的差异。(C)2003年IBRO。爱思唯尔科学有限公司出版。版权所有。
Narcolepsy, a disabling neurological disorder characterized by excessive daytime sleepiness, sleep attacks, sleep fragmentation, cataplexy, sleep-onset rapid eye movement sleep periods and hypnagogic hallucinations was recently linked to a loss of neurons containing the neuropeptide hypocretin. There is considerable variability in the severity of symptoms between narcoleptic patients, which could be related to the extent of neuronal loss in the lateral hypothalamus. To investigate this possibility, we administered two concentrations (90 ng or 490 ng in a volume of 0.5 mul) of the neurotoxin hypocretin-2-saporin, unconjugated saporin or saline directly to the lateral hypothalamus and monitored sleep, the entrained and free-running rhythm of core body temperature and activity. Neurons stained for hypocretin or for the neuronal specific marker were counted in the perifornical area, dorsomedial and ventromedial nucleus of the hypothalamus. More neuronal nuclei (NeuN) cells were destroyed by the higher concentration of hypocretin-2-saporin (-55%) compared with the lower concentration (-34%) in the perifornical area, although both concentrations lesioned the hypocretin neurons almost equally well (high concentration=91%; low concentration=88%). The high concentration of hypocretin-2-saporin also lesioned neurons in the dorsomedial nucleus of the hypothalamus and ventromedial nucleus of the hypothalamus. Narcoleptic-like sleep behavior was produced by both concentrations of the hypocretin-2-saporin. The high concentration produced a larger increase in non-rapid eye movement sleep amounts during the normally active night cycle than low concentration. Neither concentration of hypocretin-2-saporin disrupted the phase or period of the core temperature or activity rhythms. The low concentration of unconjugated saporin did not significantly lesion hypocretin or neurons and did not alter sleep. The high concentration of unconjugated saporin produced some loss of neuronal nuclei-immunoreactive (NeuN-ir) neurons and hypocretin immunoreactive neurons, but only a transient increase in non-rapid eye movement sleep. These results led us to conclude that the extent of hypocretin neuronal loss together with an accompanying loss of cells in the lateral hypothalamus may explain the differences in severity of symptoms seen in human narcolepsy. (C) 2003 IBRO. Published by Elsevier Science Ltd. All rights reserved.