title: Ultrasound of alternating frequencies and variable emotional impact evokes depressive syndrome in mice and rats.
abstract: Emotional stress is primarily triggered by the cognitive processing of negative input; it is regarded as a serious pathogenetic factor of depression that is challenging to model in animals. While available stress paradigms achieve considerable face and construct validity in modelling depressive disorders, broader use of naturalistic stressors instead of the more prevalent models with artificial challenges inducing physical discomfort or pain may substantially contribute to the development of novel antidepressants. Here, we investigated whether a 3-week exposure of Wistar rats and Balb/c mice to unpredictably alternating frequencies of ultrasound between the ranges of 20-25 and 25-45kHz, which are known to correspond with an emotionally negative and with a neutral emotional state, respectively, for small rodents in nature, can induce behavioural and molecular depressive-like changes. Both rats and mice displayed decreased sucrose preference, elevated "despair" behaviour in a swim test, reduced locomotion and social exploration. Rats showed an increased expression of SERT and 5-HT2A receptor, a decreased expression of 5-HT1A receptor in the prefrontal cortex and hippocampus, diminished BDNF on gene and protein levels in the hippocampus. Fluoxetine, administered to rats at the dose of 10mg/kg, largely precluded behavioural depressive-like changes. Thus, the here applied paradigm of emotional stress is generating an experimental depressive state in rodents, which is not related to any physical stressors or pain. In essence, this ultrasound stress model, besides enhancing animal welfare, is likely to provide improved validity in the modelling of clinical depression and may help advance translational research and drug discovery for this disorder.
authors.affiliation: Department of Basic and Applied Neurobiology, V.P. Serbsky Federal Medical Research Center for Psychiatry and Narcology, Moscow, Russia; Department of Medical Nanobiotechnology, Pirogov Russian National Research Medical University (RNRMU), Moscow, Russia.
authors.forename: Anna
authors.initials: A
authors.lastname: Morozova
authors.affiliation: Department of Basic and Applied Neurobiology, V.P. Serbsky Federal Medical Research Center for Psychiatry and Narcology, Moscow, Russia; Department of Medical Nanobiotechnology, Pirogov Russian National Research Medical University (RNRMU), Moscow, Russia.
authors.forename: Eugene
authors.initials: E
authors.lastname: Zubkov
authors.affiliation: Department of Neuroscience, Maastricht University, Maastricht, Netherlands.
authors.forename: Tatyana
authors.initials: T
authors.lastname: Strekalova
authors.affiliation: Department of Basic and Applied Neurobiology, V.P. Serbsky Federal Medical Research Center for Psychiatry and Narcology, Moscow, Russia.
authors.forename: Zurab
authors.initials: Z
authors.lastname: Kekelidze
authors.affiliation: Department of Basic and Applied Neurobiology, V.P. Serbsky Federal Medical Research Center for Psychiatry and Narcology, Moscow, Russia.
authors.forename: Zinaida
authors.initials: Z
authors.lastname: Storozeva
authors.affiliation: Annadal Medical Research Center, Maastricht, Netherlands.
authors.forename: Careen A
authors.initials: CA
authors.lastname: Schroeter
authors.affiliation: Laboratory of Cognitive Dysfunctions, Institute of General Pathology and Pathophysiology, Moscow, Russia.
authors.forename: Nataliia
authors.initials: N
authors.lastname: Bazhenova
authors.affiliation: Division of Molecular Psychiatry, Laboratory of Translational Neuroscience, Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Lesch
authors.affiliation: INSERM U1119, FMTS, Université de Strasbourg, Faculté de Médecine, Strasbourg, France. Electronic address: bhcline@gmail.com.
authors.forename: Brandon H
authors.initials: BH
authors.lastname: Cline
authors.affiliation: Department of Basic and Applied Neurobiology, V.P. Serbsky Federal Medical Research Center for Psychiatry and Narcology, Moscow, Russia; Department of Medical Nanobiotechnology, Pirogov Russian National Research Medical University (RNRMU), Moscow, Russia. Electronic address: chekhoninnew@yandex.ru.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Chekhonin
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D003866:Depressive Disorder / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D004195:Disease Models, Animal; D005473:Fluoxetine / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D013315:Stress, Psychological / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D000069453:Ultrasonic Waves / Q000009:adverse effects*
chemical_list: D005473:Fluoxetine; D011985:Receptors, Serotonin; D017367:Selective Serotonin Reuptake Inhibitors
keywords: Animal welfare; Depression; Emotional stress; Mice; Rats; Ultrasound