title: Oxytocin mitigated the depressive-like behaviors of maternal separation stress through modulating mitochondrial function and neuroinflammation.
abstract: 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.
authors.affiliation: 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.
authors.forename: Hossein
authors.initials: H
authors.lastname: Amini-Khoei
authors.affiliation: Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Ali
authors.initials: A
authors.lastname: Mohammadi-Asl
authors.affiliation: Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Regenerative Medicine Program, Department of Biochemistry and Medical Genetics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.
authors.forename: Shayan
authors.initials: S
authors.lastname: Amiri
authors.affiliation: Zanjan Applied Pharmacology Research Center, Zanjan University of Medical sciences, Zanjan, Iran; Department of Pharmacology and Toxicology, School of Pharmacy, Zanjan University of Medical Sciences, Zanjan, Iran.
authors.forename: Mir-Jamal
authors.initials: MJ
authors.lastname: Hosseini
authors.affiliation: Hematology/Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Majid
authors.initials: M
authors.lastname: Momeny
authors.affiliation: Department of Physiology and Pharmacology, School of Medicine, Rafsanjan University of Medical Sciences, Kerman, Iran; Physiology-Pharmacology Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.
authors.forename: Mahsa
authors.initials: M
authors.lastname: Hassanipour
authors.affiliation: Regenerative Medicine Program, Department of Biochemistry and Medical Genetics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.
authors.forename: Mojgan
authors.initials: M
authors.lastname: Rastegar
authors.affiliation: Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Arya
authors.initials: A
authors.lastname: Haj-Mirzaian
authors.affiliation: Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Arvin Haj-
authors.initials: AH
authors.lastname: Mirzaian
authors.affiliation: Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Hossein
authors.initials: H
authors.lastname: Sanjarimoghaddam
authors.affiliation: Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Shahram Ejtemaei
authors.initials: SE
authors.lastname: Mehr
authors.affiliation: Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. Electronic address: Dehpour@yahoo.com.
authors.forename: Ahmad Reza
authors.initials: AR
authors.lastname: Dehpour
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D003863:Depression / Q000188:drug therapy* / Q000209:etiology*; D004195:Disease Models, Animal; D006624:Hippocampus / Q000276:immunology* / Q000378:metabolism*; D006727:Hormone Antagonists / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy*; D008297:Male; D008426:Maternal Deprivation; D051379:Mice; D028361:Mitochondrial Diseases / Q000188:drug therapy*; D010121:Oxytocin / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D014668:Vasotocin / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D006727:Hormone Antagonists; C047046:atosiban; D010121:Oxytocin; D014668:Vasotocin
keywords: Depression; Maternal separation stress; Mitochondrial function; Neuroinflammation; Oxytocin