Chronic mild stress-induced alterations of clock gene expression in rat prefrontal cortex: modulatory effects of prolonged lurasidone treatment
Chronic mild stress-induced alterations of clock gene expression in rat prefrontal cortex: modulatory effects of prolonged lurasidone treatment
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DOI：
10.1016/j.phrs.2015.12.023
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发表时间：
2016-02-01
影响因子：
9.3
通讯作者：
Riva, Marco A.
中科院分区：
文献类型：
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作者：
Calabrese, Francesca;Savino, Elisa;Riva, Marco A.
已知生物节律的中断与抑郁症有关，这表明分子钟的异常可能导致这些疾病的发展。这些机制已经在视交叉上核中得到了广泛的表征，但对个体时钟基因在抑郁症重要的大脑结构中所发挥的作用知之甚少。通过慢性轻度应激模型，我们发现CMS大鼠前额皮质核室中BMAL1和CLOCK蛋白水平显著降低，与此同时，多个靶基因（包括Pers和Crys）以及Reverb β和Ppar α表达下调。有趣的是，多受体调节剂鲁拉西酮（3mg /kg，持续5周）的慢性治疗能够使CMS暴露引起的前额皮质分子变化正常化，但它也能够调节海马中的一些基因。我们认为，CMS暴露后时钟基因表达的变化可能导致与抑郁症相关的紊乱，而慢性鲁拉西酮使这种改变正常化的能力可能与其改善重度抑郁症和其他压力相关疾病患者恶化的功能的治疗特性有关。(C) 2015 Elsevier Ltd.版权所有。
Disruptions of biological rhythms are known to be associated with depressive disorders, suggesting that abnormalities in the molecular clock may contribute to the development of these disorders. These mechanisms have been extensively characterized in the suprachiasmatic nucleus, but little is know about the role exerted by individual clock genes in brain structures that are important for depressive disorders. Using the chronic mild stress model we found a significant reduction of BMAL1 and CLOCK protein levels in the nuclear compartment of the prefrontal cortex of CMS rats, which was paralleled by a down-regulation of the expression of several target genes, including Pers and Crys but also Reverb beta and Ppar alpha.Interestingly, chronic treatment with the multi receptor modulator lurasidone (3 mg/kg for 5 weeks) was able to normalize the molecular changes induced by CMS exposure in prefrontal cortex, but it was also able to regulate some of these genes within the hippocampus.We believe that changes in clock genes expression after CMS exposure may contribute to the disturbances associated with depressive disorders and that the ability of chronic lurasidone to normalize such alterations may be relevant for its therapeutic properties in ameliorating functions that are deteriorated in patients with major depression and other stress-related disorders. (C) 2015 Elsevier Ltd. All rights reserved.