Amini-Khoei Hossein, Mohammadi-Asl Ali, Amiri Shayan, Hosseini Mir-Jamal, Momeny Majid, Hassanipour Mahsa, Rastegar Mojgan, Haj-Mirzaian Arya, Mirzaian Arvin Haj-, Sanjarimoghaddam Hossein, Mehr Shahram Ejtemaei, Dehpour Ahmad Reza
Medical Plants Research Center, Shahrekord University of Medical Sciences, Shahrekord, Iran; Department of Physiology and Pharmacology, School of Medicine, Shahrekord University of Medical Sciences, Shahrekord, Iran.
Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Prog Neuropsychopharmacol Biol Psychiatry. 2017 Jun 2;76:169-178. doi: 10.1016/j.pnpbp.2017.02.022. Epub 2017 Mar 1.
Mother-infant contact has a critical role on brain development and behavior. Experiencing early-life adversities (such as maternal separation stress or MS in rodents) results in adaptations of neurotransmission systems, which may subsequently increase the risk of depression symptoms later in life. In this study, we show that Oxytocin (OT) exerted antioxidant and anti-inflammatory properties. Previous studies indicate that neuroinflammation and mitochondrial dysfunction are associated with the pathophysiology of depression. To investigate the antidepressant-like effects of OT, we applied MS paradigm (as a valid animal model of depression) to male mice at postnatal day (PND) 2 to PND 14 (3h daily, 9AM to 12AM) and investigated the depressive-like behaviors of these animals at PND 60 in different groups. Animals in this work were divided into 4 experimental groups: 1) saline-treated, 2) OT-treated, 3) atosiban (OT antagonist)-treated and, 4) OT+ atosiban-treated mice. We used forced swimming test (FST), splash test, sucrose preference test (SPT) and open field test (OFT) for behavioral assessment. Additionally, we used another set of animals to investigate the effects of MS and different treatments on mitochondrial function and the expression of the relevant genes for neuroinflammation. Our results showed that MS provoked depressive- like behaviors in the FST, SPT and splash test. In addition, our molecular findings revealed that MS is capable of inducing abnormal mitochondrial function and immune-inflammatory response in the hippocampus. Further, we observed that treating stressed animals with OT (intracerebroventricular, i.c.v. injection) attenuated the MS-induced depressive-like behaviors through improving mitochondrial function and decreasing the hippocampal expression of immune-inflammatory genes. In conclusion, we showed that MS-induced depressive-like behaviors in adult male mice are associated with abnormal mitochondrial function and immune-inflammatory responses in the hippocampus, and activation of OTergic system has protective effects against negative effects of MS on brain and behavior of animals.
母婴接触对大脑发育和行为起着关键作用。经历早期生活逆境（如啮齿动物中的母婴分离应激或MS）会导致神经传递系统的适应性变化，这可能会增加日后患抑郁症症状的风险。在本研究中，我们表明催产素（OT）具有抗氧化和抗炎特性。先前的研究表明，神经炎症和线粒体功能障碍与抑郁症的病理生理学有关。为了研究OT的抗抑郁样作用，我们在出生后第2天至第14天（每天3小时，上午9点至中午12点）对雄性小鼠应用MS范式（作为抑郁症的有效动物模型），并在第60天研究不同组这些动物的抑郁样行为。本研究中的动物分为4个实验组：1）生理盐水处理组，2）OT处理组，3）阿托西班（OT拮抗剂）处理组，4）OT + 阿托西班处理组小鼠。我们使用强迫游泳试验（FST）、泼水试验、蔗糖偏好试验（SPT）和旷场试验（OFT）进行行为评估。此外，我们使用另一组动物来研究MS和不同处理对线粒体功能以及神经炎症相关基因表达的影响。我们的结果表明，MS在FST、SPT和泼水试验中引发了抑郁样行为。此外，我们的分子研究结果表明，MS能够在海马体中诱导异常的线粒体功能和免疫炎症反应。此外，我们观察到用OT（脑室内注射，i.c.v.）治疗应激动物可通过改善线粒体功能和降低海马体中免疫炎症基因的表达来减轻MS诱导的抑郁样行为。总之，我们表明成年雄性小鼠中MS诱导的抑郁样行为与海马体中异常的线粒体功能和免疫炎症反应有关，并且OT能系统的激活对MS对动物大脑和行为的负面影响具有保护作用。
