Department of Integrative Physiology, University of Colorado Boulder, USA.
Institute for Behavioral Genetics, University of Colorado Boulder, USA.
Brain Behav Immun. 2024 Oct;121:74-86. doi: 10.1016/j.bbi.2024.07.027. Epub 2024 Jul 21.
Protein Kinase RNA-activated (PKR) is an enzyme that plays a role in many systemic processes, including modulation of inflammation, and is implicated in neurodegenerative diseases, such as Alzheimer's disease (AD). PKR phosphorylation results in the production of several cytokines involved in the regulation / modulation of sleep, including interleukin-1β, tumor necrosis factor-α and interferon-γ. We hypothesized targeting PKR would alter spontaneous sleep of mice, attenuate responses to sleep deprivation, and inhibit responses to immune challenge. To test these hypotheses, we determined the sleep-wake phenotype of mice lacking PKR (knockout; PKR) during undisturbed baseline conditions; in responses to six hours of sleep deprivation; and after immune challenge with lipopolysaccharide (LPS). Adult male mice (C57BL/6J, n = 7; PKR, n = 7) were surgically instrumented with EEG recording electrodes and an intraperitoneal microchip to record core body temperature. During undisturbed baseline conditions, PKR mice spent more time in non-rapid eye movement sleep (NREMS) and rapid-eye movement sleep (REMS), and less time awake at the beginning of the dark period of the light:dark cycle. Delta power during NREMS, a measure of sleep depth, was less in PKR mice during the dark period, and core body temperatures were lower during the light period. Both mouse strains responded to sleep deprivation with increased NREMS and REMS, although these changes did not differ substantively between strains. The initial increase in delta power during NREMS after sleep deprivation was greater in PKR mice, suggesting a faster buildup of sleep pressure with prolonged waking. Immune challenge with LPS increased NREMS and inhibited REMS to the same extent in both mouse strains, whereas the initial LPS-induced suppression of delta power during NREMS was greater in PKR mice. Because sleep regulatory and immune responsive systems in brain are redundant and overlapping, other mediators and signaling pathways in addition to PKR are involved in the responses to acute sleep deprivation and LPS immune challenge.
蛋白激酶 RNA 激活（PKR）是一种在许多全身过程中发挥作用的酶，包括炎症调节，并与神经退行性疾病如阿尔茨海默病（AD）有关。PKR 磷酸化导致几种参与睡眠调节/调制的细胞因子的产生，包括白细胞介素-1β、肿瘤坏死因子-α和干扰素-γ。我们假设靶向 PKR 将改变小鼠的自发睡眠，减弱对睡眠剥夺的反应，并抑制对免疫挑战的反应。为了验证这些假设，我们在未受干扰的基线条件下确定了缺乏 PKR（敲除；PKR）的小鼠的睡眠-觉醒表型；在六小时睡眠剥夺后的反应；以及在脂多糖（LPS）免疫挑战后的反应。成年雄性小鼠（C57BL/6J，n=7；PKR，n=7）接受了 EEG 记录电极和腹腔内微芯片的手术植入，以记录核心体温。在未受干扰的基线条件下，PKR 小鼠在黑暗期的非快速眼动睡眠（NREMS）和快速眼动睡眠（REMS）中花费更多时间，在觉醒时花费更少时间。NREMS 期间的 delta 功率，睡眠深度的一种衡量标准，在黑暗期 PKR 小鼠中较低，而在光照期核心体温较低。两种小鼠品系对睡眠剥夺的反应都是 NREMS 和 REMS 增加，尽管这些变化在品系之间没有实质性差异。睡眠剥夺后 NREMS 期间 delta 功率的初始增加在 PKR 小鼠中更大，这表明在清醒时间延长时，睡眠压力的建立更快。LPS 免疫挑战以相同的程度增加了两种小鼠品系的 NREMS 并抑制了 REMS，而 PKR 小鼠中 NREMS 期间初始 LPS 诱导的 delta 功率抑制更大。由于大脑中的睡眠调节和免疫反应系统是冗余和重叠的，因此除了 PKR 之外，其他介质和信号通路也参与了对急性睡眠剥夺和 LPS 免疫挑战的反应。
