Neuroscience Department, The Scripps Research Institute, La Jolla, CA, 92037, USA.
Neuroscience Department, The Scripps Research Institute, La Jolla, CA, 92037, USA.
Neuropharmacology. 2023 May 1;228:109455. doi: 10.1016/j.neuropharm.2023.109455. Epub 2023 Feb 10.
The neuroimmune system of the brain, which is comprised primarily of astrocytes and microglia, regulates a variety of homeostatic mechanisms that underlie normal brain function. Numerous conditions, including alcohol consumption, can disrupt this regulatory process by altering brain levels of neuroimmune factors. Alcohol and neuroimmune factors, such as proinflammatory cytokines IL-6 and TNF-alpha, act at similar targets in the brain, including excitatory and inhibitory synaptic transmission. Thus, alcohol-induced production of IL-6 and/or TNF-alpha could be important contributing factors to the effects of alcohol on the brain. Recent studies indicate that IL-6 plays a role in alcohol drinking and the effects of alcohol on the brain activity following the cessation of alcohol consumption (post-alcohol period), however information on these topics is limited. Here we used homozygous and heterozygous female and male transgenic mice with increased astrocyte expression of IL-6 to examined further the interactions between alcohol and IL-6 with respect to voluntary alcohol drinking, brain activity during the post-alcohol period, IL-6 signal transduction, and expression of synaptic proteins. Wildtype littermates (WT) served as controls. The transgenic mice model brain neuroimmune status with respect to IL-6 in subjects with a history of persistent alcohol use. Results showed a genotype dependent reduction in voluntary alcohol consumption in the Drinking in the Dark protocol and in frequency-dependent relationships between brain activity in EEG recordings during the post-alcohol period and alcohol consumption. IL-6, TNF-alpha, IL-6 signal transduction partners pSTAT3 and c/EBP beta, and synaptic proteins were shown to play a role in these genotypic effects.
大脑的神经免疫系统主要由星形胶质细胞和小胶质细胞组成，它调节着许多基础脑功能的稳态机制。许多情况，包括饮酒，都可以通过改变大脑中神经免疫因子的水平来破坏这种调节过程。酒精和神经免疫因子，如促炎细胞因子 IL-6 和 TNF-α，在大脑中作用于相似的靶点，包括兴奋性和抑制性突触传递。因此，酒精诱导的 IL-6 和/或 TNF-α的产生可能是酒精对大脑影响的重要因素。最近的研究表明，IL-6 在酒精摄入和酒精戒断后（酒精后期）对大脑活动的影响中起作用，但关于这些主题的信息有限。在这里，我们使用表达 IL-6 的星形胶质细胞增加的纯合和杂合雌性和雄性转基因小鼠，进一步研究了酒精和 IL-6 之间的相互作用，涉及到自愿饮酒、酒精后期大脑活动、IL-6 信号转导和突触蛋白的表达。野生型同窝仔（WT）作为对照。该转基因小鼠模型针对有持续饮酒史的个体的大脑神经免疫状态与 IL-6 有关。结果显示，在黑暗中饮酒协议中，自愿饮酒量存在依赖于基因型的减少，在酒精后期 EEG 记录中的大脑活动与饮酒之间的频率依赖性关系也存在依赖于基因型的减少。IL-6、TNF-α、IL-6 信号转导伙伴 pSTAT3 和 c/EBPβ以及突触蛋白在这些基因型效应中起作用。
