title: Mouse social stress induces increased fear conditioning, helplessness and fatigue to physical challenge together with markers of altered immune and dopamine function.
abstract: In neuropsychiatry, animal studies demonstrating causal effects of environmental manipulations relevant to human aetiology on behaviours relevant to human psychopathologies are valuable. Such valid models can improve understanding of aetio-pathophysiology and preclinical discovery and development of new treatments. In depression, specific uncontrollable stressful life events are major aetiological factors, and subsequent generalized increases in fearfulness, helplessness and fatigue are core symptoms or features. Here we exposed adult male C57BL/6 mice to 15-day psychosocial stress with loss of social control but minimal physical wounding. One cohort was assessed in a 3-day test paradigm of motor activity, fear conditioning and 2-way avoid-escape behaviour on days 16-18, and a second cohort was assessed in a treadmill fatigue paradigm on days 19 and 29, followed by the 3-day paradigm on days 30-32. All tests used a physical aversive stimulus, namely mild, brief electroshocks. Socially stressed mice displayed decreased motor activity, increased fear acquisition, decreased 2-way avoid-escape responding (increased helplessness) and increased fatigue. They also displayed increased plasma TNF and spleen hypertrophy, and adrenal hypertrophy without hyper-corticoidism. In a third cohort, psychosocial stress effects on brain gene expression were assessed using next generation sequencing. Gene expression was altered in pathways of inflammation and G-protein coupled receptors in prefrontal cortex and amygdala; in the latter, expression of genes important in dopamine function were de-regulated including down-regulated Drd2, Adora2a and Darpp-32. This model can be applied to identify targets for treating psychopathologies such as helplessness or fatigue, and to screen compounds/biologics developed to act at these targets.
authors.affiliation: Preclinical Laboratory for Translational Research into Affective Disorders, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland; Neuroscience Center Zurich, University of Zurich and ETH Zurich, Switzerland. Electronic address: damiano.azzinnari@bli.uzh.ch.
authors.forename: Damiano
authors.initials: D
authors.lastname: Azzinnari
authors.affiliation: Preclinical Laboratory for Translational Research into Affective Disorders, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland.
authors.forename: Hannes
authors.initials: H
authors.lastname: Sigrist
authors.affiliation: Preclinical Laboratory for Translational Research into Affective Disorders, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland.
authors.forename: Simon
authors.initials: S
authors.lastname: Staehli
authors.affiliation: Institute of Medical Biochemistry, Department of Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria.
authors.forename: Rupert
authors.initials: R
authors.lastname: Palme
authors.affiliation: Target Discovery, Boehringer Ingelheim Pharma GmbH & Co. KG., Biberach an der Riss, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Hildebrandt
authors.affiliation: Target Discovery, Boehringer Ingelheim Pharma GmbH & Co. KG., Biberach an der Riss, Germany.
authors.forename: German
authors.initials: G
authors.lastname: Leparc
authors.affiliation: CNS Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG., Biberach an der Riss, Germany.
authors.forename: Bastian
authors.initials: B
authors.lastname: Hengerer
authors.affiliation: Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland; Neuroscience Center Zurich, University of Zurich and ETH Zurich, Switzerland.
authors.forename: Erich
authors.initials: E
authors.lastname: Seifritz
authors.affiliation: Preclinical Laboratory for Translational Research into Affective Disorders, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland; Neuroscience Center Zurich, University of Zurich and ETH Zurich, Switzerland. Electronic address: christopher.pryce@bli.uzh.ch.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Pryce
mesh_terms: D000311:Adrenal Glands / Q000473:pathology / Q000503:physiopathology; D000679:Amygdala / Q000503:physiopathology*; D000818:Animals; D003213:Conditioning, Psychological / Q000502:physiology; D004195:Disease Models, Animal; D004291:Dominance-Subordination; D004298:Dopamine / Q000378:metabolism*; D004924:Escape Reaction / Q000502:physiology; D005221:Fatigue / Q000473:pathology / Q000503:physiopathology; D005239:Fear / Q000502:physiology; D015870:Gene Expression; D006380:Helplessness, Learned; D008297:Male; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000502:physiology; D015213:Neuroimmunomodulation / Q000502:physiology*; D017397:Prefrontal Cortex / Q000503:physiopathology*; D013154:Spleen / Q000473:pathology / Q000503:physiopathology; D013315:Stress, Psychological / Q000473:pathology / Q000503:physiopathology*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D014409:Tumor Necrosis Factor-alpha; D004298:Dopamine
keywords: Chronic social defeat; Dopamine; Fatigue; Generalized helplessness; Inflammation; Next generation sequencing