Circadian regulation of hippocampal function is disrupted with corticosteroid treatment.
Circadian regulation of hippocampal function is disrupted with corticosteroid treatment.
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海马功能的昼夜节律调节被皮质类固醇治疗中断。
DOI：
10.1073/pnas.2211996120
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发表时间：
2023-04-11
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
糖皮质激素的昼夜振荡是所有哺乳动物肾上腺激素分泌的基本特征。这些节律可能被慢性压力或合成糖皮质激素治疗打乱，导致包括记忆、情绪和睡眠受损在内的副作用。在这里，我们发现用甲基强的松龙治疗5天可以延长糖皮质激素受体的激活时间，并导致海马核心时钟基因周期1中糖皮质激素调节元件的结合。此外，随着海马长期增强（LTP）昼夜节律变化的丧失和海马记忆受损，海马昼夜节律基因调控明显中断。总之，这些数据表明在长效糖皮质激素治疗期间海马功能失调，并进一步支持设计改进的糖皮质激素治疗方案的重要性，这些方案可以重现内源性糖皮质激素节律性。昼夜节律活动中断与许多神经精神疾病有关。昼夜节律生物系统的一个主要协调者是肾上腺糖皮质激素分泌，它在觉醒前表现出明显的峰值，调节代谢、免疫和心血管过程，以及情绪和认知功能。在皮质类固醇治疗期间，这种昼夜节律的丧失通常与记忆障碍有关。令人惊讶的是，这种缺陷背后的机制尚不清楚。在这项研究中，我们报告了在大鼠中，海马转录组的昼夜节律调节整合了通过海马内昼夜节律转录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的关键功能网络。此外，这些昼夜节律海马功能受到5天口服皮质类固醇治疗方案的显著影响。海马转录组的节律性表达以及突触可塑性的昼夜节律调节与自然光/暗昼夜节律引导线索不一致，导致海马依赖行为的记忆障碍。这些发现提供了关于海马体内的转录时钟机制如何受到皮质类固醇暴露的影响的机制见解，从而导致对关键海马功能的不利影响，并确定了长效合成皮质类固醇治疗患者记忆缺陷的分子基础。
Circadian oscillations of glucocorticoids are a fundamental characteristic of adrenal hormone secretion in all mammals. These rhythms can be disrupted by chronic stress or synthetic glucocorticoid therapy, resulting in side effects including impaired memory, mood, and sleep. Here, we show that 5-d treatment with methylprednisolone induces prolonged activation of glucocorticoid receptors and consequent binding at glucocorticoid regulatory elements in the core clock gene Period 1, in the hippocampus. Furthermore, disruption of circadian hippocampal gene regulation was evident, along with loss of circadian variation in hippocampal long-term potentiation (LTP) and impaired hippocampal memory. Together, these data demonstrate dysregulated hippocampal function during long-acting glucocorticoid treatment and further support the importance of devising improved regimens of glucocorticoid therapy that recapitulate endogenous glucocorticoid rhythmicity. 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.
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影响因子：
4.5
作者：
Flynn BP;Birnie MT;Kershaw YM;Pauza AG;Kim S;Baek S;Rogers MF;Paterson AR;Stavreva DA;Murphy D;Hager GL;Lightman SL;Conway-Campbell BL
通讯作者：
Conway-Campbell BL
影响因子：
15.9
作者：
Dillon DG;Pizzagalli DA
通讯作者：
Pizzagalli DA
影响因子：
4.1
作者：
Coutinho, Agnes E.;Chapman, Karen E.
通讯作者：
Chapman, Karen E.
影响因子：
25
作者：
Busche, Marc Aurel;Kekus, Maja;Konnerth, Arthur
通讯作者：
Konnerth, Arthur
影响因子：
56.9
作者：
Balsalobre, A;Brown, SA;Schibler, U
通讯作者：
Schibler, U