Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, Translational Health Sciences, Faculty of Health Sciences, School of Medicine, University of Bristol, Bristol BS1 3NY, United Kingdom.
School of Physiology, Pharmacology and Neuroscience, Faculty of Life Sciences, University of Bristol, Bristol BS8 1TD, United Kingdom.
Proc Natl Acad Sci U S A. 2023 Apr 11;120(15):e2211996120. doi: 10.1073/pnas.2211996120. Epub 2023 Apr 6.
Disrupted circadian activity is associated with many neuropsychiatric disorders. A major coordinator of circadian biological systems is adrenal glucocorticoid secretion which exhibits a pronounced preawakening peak that regulates metabolic, immune, and cardiovascular processes, as well as mood and cognitive function. Loss of this circadian rhythm during corticosteroid therapy is often associated with memory impairment. Surprisingly, the mechanisms that underlie this deficit are not understood. In this study, in rats, we report that circadian regulation of the hippocampal transcriptome integrates crucial functional networks that link corticosteroid-inducible gene regulation to synaptic plasticity processes via an intrahippocampal circadian transcriptional clock. Further, these circadian hippocampal functions were significantly impacted by corticosteroid treatment delivered in a 5-d oral dosing treatment protocol. Rhythmic expression of the hippocampal transcriptome, as well as the circadian regulation of synaptic plasticity, was misaligned with the natural light/dark circadian-entraining cues, resulting in memory impairment in hippocampal-dependent behavior. These findings provide mechanistic insights into how the transcriptional clock machinery within the hippocampus is influenced by corticosteroid exposure, leading to adverse effects on critical hippocampal functions, as well as identifying a molecular basis for memory deficits in patients treated with long-acting synthetic corticosteroids.
昼夜节律活动的紊乱与许多神经精神疾病有关。肾上腺糖皮质激素的分泌是昼夜生物系统的主要协调者，它表现出明显的觉醒前峰值，调节代谢、免疫和心血管过程，以及情绪和认知功能。皮质类固醇治疗期间这种昼夜节律的丧失常常与记忆障碍有关。令人惊讶的是，这种缺陷的机制尚不清楚。在这项研究中，我们在大鼠中报告说，海马转录组的昼夜节律调节整合了关键的功能网络，这些网络通过海马内的昼夜转录时钟将皮质类固醇诱导的基因调节与突触可塑性过程联系起来。此外，这些昼夜节律的海马功能受到通过 5 天口服给药方案给予皮质类固醇治疗的显著影响。海马转录组的节律表达以及突触可塑性的昼夜调节与自然光/暗的昼夜节律传入线索失去同步，导致在海马依赖行为中出现记忆障碍。这些发现提供了关于海马内转录时钟机制如何受到皮质类固醇暴露影响的机制见解，导致对关键海马功能的不利影响，并确定了长期使用合成皮质类固醇治疗的患者记忆缺陷的分子基础。
