title: Time-dependent miR-16 serum fluctuations together with reciprocal changes in the expression level of miR-16 in mesocortical circuit contribute to stress resilient phenotype in chronic mild stress - An animal model of depression.
abstract: MicroRNAs (miRNAs) are involved in stress-related pathologies. However, the molecular mechanisms underlying stress resilience are elusive. Using chronic mild stress (CMS), an animal model of depression, we identified animals exhibiting a resilient phenotype. We investigated serum levels of corticosterone, melatonin and 376 mature miRNAs to find peripheral biomarkers associated with the resilient phenotype. miR-16, selected during screening step, was assayed in different brain regions in order to find potential relationship between brain and peripheral alterations in response to stress. Two CMS experiments that lasted for 2 and 7 consecutive weeks were performed. During both CMS procedures, sucrose consumption levels were significantly decreased in anhedonic-like animals (p<0.0001) compared with unstressed animals, whereas the drinking profiles of resilient rats did not change despite the rats being stressed. Serum corticosterone measurements indicated that anhedonic-like animals had blunted hypothalamic-pituitary-adrenal (HPA) axis activity, whereas resilient animals exhibited dynamic responses to stress. miRNA profiling revealed that resilient animals had elevated serum levels of miR-16 after 7 weeks of CMS (adjusted p-value<0.007). Moreover, resilient animals exhibited reciprocal changes in miR-16 expression level in mesocortical pathway after 2 weeks of CMS (p<0.008). A bioinformatic analysis showed that miR-16 regulates genes involved in the functioning of the nervous system in both humans and rodents. Resilient animals can actively cope with stress on a biochemical level and miR-16 may contribute to a "stress-resistant" behavioral phenotype by pleiotropic modulation of the expression of genes involved in the function of the nervous system.
authors.affiliation: Institute of Pharmacology Polish Academy of Sciences, Department of Pharmacology, Smetna Street 12, Kraków 31-343, Poland. Electronic address: zurawek@if-pan.krakow.pl.
authors.forename: Dariusz
authors.initials: D
authors.lastname: Zurawek
authors.affiliation: Institute of Pharmacology Polish Academy of Sciences, Department of Pharmacology, Smetna Street 12, Kraków 31-343, Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Kusmider
authors.affiliation: Institute of Pharmacology Polish Academy of Sciences, Department of Pharmacology, Smetna Street 12, Kraków 31-343, Poland.
authors.forename: Agata
authors.initials: A
authors.lastname: Faron-Gorecka
authors.affiliation: Institute of Pharmacology Polish Academy of Sciences, Department of Pharmacology, Smetna Street 12, Kraków 31-343, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Gruca
authors.affiliation: Institute of Pharmacology Polish Academy of Sciences, Department of Pharmacology, Smetna Street 12, Kraków 31-343, Poland.
authors.forename: Paulina
authors.initials: P
authors.lastname: Pabian
authors.affiliation: Institute of Pharmacology Polish Academy of Sciences, Department of Pharmacology, Smetna Street 12, Kraków 31-343, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Kolasa
authors.affiliation: Institute of Pharmacology Polish Academy of Sciences, Department of Pharmacology, Smetna Street 12, Kraków 31-343, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Solich
authors.affiliation: Institute of Pharmacology Polish Academy of Sciences, Department of Pharmacology, Smetna Street 12, Kraków 31-343, Poland.
authors.forename: Kinga
authors.initials: K
authors.lastname: Szafran-Pilch
authors.affiliation: Institute of Pharmacology Polish Academy of Sciences, Department of Pharmacology, Smetna Street 12, Kraków 31-343, Poland.
authors.forename: Mariusz
authors.initials: M
authors.lastname: Papp
authors.affiliation: Institute of Pharmacology Polish Academy of Sciences, Department of Pharmacology, Smetna Street 12, Kraków 31-343, Poland.
authors.forename: Marta
authors.initials: M
authors.lastname: Dziedzicka-Wasylewska
mesh_terms: D059445:Anhedonia / Q000502:physiology; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002908:Chronic Disease; D003345:Corticosterone / Q000097:blood; D003866:Depressive Disorder / Q000378:metabolism*; D019422:Dietary Sucrose; D004195:Disease Models, Animal; D005247:Feeding Behavior; D008032:Limbic System / Q000378:metabolism*; D008297:Male; D008550:Melatonin / Q000097:blood; D035683:MicroRNAs / Q000378:metabolism*; D011897:Random Allocation; D017208:Rats, Wistar; D055500:Resilience, Psychological; D013315:Stress, Psychological / Q000378:metabolism*; D013995:Time
chemical_list: D015415:Biomarkers; D019422:Dietary Sucrose; C547573:MIRN16 microRNA, rat; D035683:MicroRNAs; D008550:Melatonin; D003345:Corticosterone
keywords: Biomarker; Chronic mild stress; Depression; MicroRNA; Rats; Stress resilience