title: Severe, multimodal stress exposure induces PTSD-like characteristics in a mouse model of single prolonged stress.
abstract: Appropriate animal models of posttraumatic stress disorder (PTSD) are needed because human studies remain limited in their ability to probe the underlying neurobiology of PTSD. Although the single prolonged stress (SPS) model is an established rat model of PTSD, the development of a similarly-validated mouse model emphasizes the benefits and cross-species utility of rodent PTSD models and offers unique methodological advantages to that of the rat. Therefore, the aims of this study were to develop and describe a SPS model for mice and to provide data that support current mechanisms relevant to PTSD. The mouse single prolonged stress (mSPS) paradigm, involves exposing C57Bl/6 mice to a series of severe, multimodal stressors, including 2h restraint, 10 min group forced swim, exposure to soiled rat bedding scent, and exposure to ether until unconsciousness. Following a 7-day undisturbed period, mice were tested for cue-induced fear behavior, effects of paroxetine on cue-induced fear behavior, extinction retention of a previously extinguished fear memory, dexamethasone suppression of corticosterone (CORT) response, dorsal hippocampal glucocorticoid receptor protein and mRNA expression, and prefrontal cortex glutamate levels. Exposure to mSPS enhanced cue-induced fear, which was attenuated by oral paroxetine treatment. mSPS also disrupted extinction retention, enhanced suppression of stress-induced CORT response, increased mRNA expression of dorsal hippocampal glucocorticoid receptors and decreased prefrontal cortex glutamate levels. These data suggest that the mSPS model is a translationally-relevant model for future PTSD research with strong face, construct, and predictive validity. In summary, mSPS models characteristics relevant to PTSD and this severe, multimodal stress modifies fear learning in mice that coincides with changes in the hypothalamo-pituitary-adrenal (HPA) axis, brain glucocorticoid systems, and glutamatergic signaling in the prefrontal cortex.
authors.affiliation: Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI, USA. Electronic address: sperrine@med.wayne.edu.
authors.forename: Shane A
authors.initials: SA
authors.lastname: Perrine
authors.affiliation: Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Eagle
authors.affiliation: Department of Psychiatry, Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Sophie A
authors.initials: SA
authors.lastname: George
authors.affiliation: Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Kostika
authors.initials: K
authors.lastname: Mulo
authors.affiliation: Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Kohler
authors.affiliation: Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Gerard
authors.affiliation: Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Arman
authors.initials: A
authors.lastname: Harutyunyan
authors.affiliation: Research and Development Service, John D. Dingell VA Medical Center, Detroit, MI, USA,; Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Hool
authors.affiliation: Research and Development Service, John D. Dingell VA Medical Center, Detroit, MI, USA,; Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Laura L
authors.initials: LL
authors.lastname: Susick
authors.affiliation: Research and Development Service, John D. Dingell VA Medical Center, Detroit, MI, USA,; Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Brandy L
authors.initials: BL
authors.lastname: Schneider
authors.affiliation: Department of Anesthesiology, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Farhad
authors.initials: F
authors.lastname: Ghoddoussi
authors.affiliation: Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI, USA; Department of Anesthesiology, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Galloway
authors.affiliation: Department of Psychiatry, Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, USA,; Department of Psychiatry, VA Medical Center, Ann Arbor, MI, USA.
authors.forename: Israel
authors.initials: I
authors.lastname: Liberzon
authors.affiliation: Research and Development Service, John D. Dingell VA Medical Center, Detroit, MI, USA,; Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Alana C
authors.initials: AC
authors.lastname: Conti
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003214:Conditioning, Classical; D003345:Corticosterone / Q000097:blood; D003463:Cues; D004195:Disease Models, Animal; D005108:Extinction, Psychological; D005239:Fear / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017374:Paroxetine / Q000008:administration & dosage; D017397:Prefrontal Cortex / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D012149:Restraint, Physical; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage; D013313:Stress Disorders, Post-Traumatic / Q000209:etiology / Q000378:metabolism* / Q000523:psychology*; D013315:Stress, Psychological / Q000150:complications*; D013550:Swimming
chemical_list: D003345:Corticosterone; D018698:Glutamic Acid; D017374:Paroxetine; D011965:Receptors, Glucocorticoid; D017367:Selective Serotonin Reuptake Inhibitors
keywords: Fear conditioning; Glucocorticoid; Glutamate; Mice; Posttraumatic stress disorder; Single prolonged stress