Longitudinal analysis of the electroencephalogram and sleep phenotype in the R6/2 mouse model of Huntington's disease
Longitudinal analysis of the electroencephalogram and sleep phenotype in the R6/2 mouse model of Huntington's disease
复制标题
DOI：
10.1093/brain/awt132
复制
发表时间：
2013-07-01
期刊：
影响因子：
14.5
通讯作者：
Morairty, Stephen R.
中科院分区：
文献类型：
--
作者：
Fisher, Simon P.;Black, Sarah W.;Morairty, Stephen R.
睡眠和昼夜节律组织缺陷已被确定为亨廷顿病患者的常见早期特征，与症状严重程度相关，并可能有助于疾病进展。对亨廷顿氏病基因携带者的研究表明，脑电图的改变可能反映了在表现前阶段存在的潜在神经元功能障碍。我们在亨廷顿病的R6/2小鼠模型中进行了睡眠/觉醒和脑电图活动的纵向表征，以确定是否可以在疾病进展的早期识别类似的脑电图“签名”。R6/2和野生型小鼠被植入用于脑电图记录，沿着遥测用于连续记录活动和体温。在R6/2小鼠中，昼夜活动模式和核心体温逐渐被破坏，到13周龄时，这些节律的幅度明显大幅降低。相对于野生型小鼠，随着睡眠变得更加碎片化和总睡眠时间减少，睡眠/觉醒状态的昼夜变化逐渐减弱。这些基因型差异在17周时增加，并且在整个24小时期间都很明显。定量脑电图分析显示，在R6/2小鼠的所有睡眠/清醒状态下，高β和γ活动（25-60 Hz）异常增加，沿着非快速眼动和快速眼动睡眠期间θ活动增加，以及非快速眼动睡眠中δ功率减少。在我们最早的记录（9周）中，定量脑电图测量的这些戏剧性变化是明显的，在昼夜生理或睡眠/觉醒行为发生任何重大差异之前。此外，对睡眠剥夺的稳态反应随着疾病进展而大大减弱。这些研究结果表明定量脑电图分析的敏感性，以确定早期病理生理学改变的R6/2模型的亨廷顿舞蹈病，并建议纵向研究在其他临床前亨廷顿舞蹈病模型，以确定这些意见作为一个潜在的辅助治疗发展的一般性。
Deficits in sleep and circadian organization have been identified as common early features in patients with Huntington's disease that correlate with symptom severity and may be instrumental in disease progression. Studies in Huntington's disease gene carriers suggest that alterations in the electroencephalogram may reflect underlying neuronal dysfunction that is present in the premanifest stage. We conducted a longitudinal characterization of sleep/wake and electroencephalographic activity in the R6/2 mouse model of Huntington's disease to determine whether analogous electroencephalographic 'signatures' could be identified early in disease progression. R6/2 and wild-type mice were implanted for electroencephalographic recordings along with telemetry for the continuous recording of activity and body temperature. Diurnal patterns of activity and core body temperature were progressively disrupted in R6/2 mice, with a large reduction in the amplitude of these rhythms apparent by 13 weeks of age. The diurnal variation in sleep/wake states was gradually attenuated as sleep became more fragmented and total sleep time was reduced relative to wild-type mice. These genotypic differences were augmented at 17 weeks and evident across the entire 24-h period. Quantitative electroencephalogram analysis revealed anomalous increases in high beta and gamma activity (25-60 Hz) in all sleep/wake states in R6/2 mice, along with increases in theta activity during both non-rapid eye movement and rapid eye movement sleep and a reduction of delta power in non-rapid eye movement sleep. These dramatic alterations in quantitative electroencephalographic measures were apparent from our earliest recording (9 weeks), before any major differences in diurnal physiology or sleep/wake behaviour occurred. In addition, the homeostatic response to sleep deprivation was greatly attenuated with disease progression. These findings demonstrate the sensitivity of quantitative electroencephalographic analysis to identify early pathophysiological alterations in the R6/2 model of Huntington's disease and suggest longitudinal studies in other preclinical Huntington's disease models are needed to determine the generality of these observations as a potential adjunct in therapeutic development.