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. AbstractIn neuropsychiatric research, animal studies that demonstrate causal effects of environmental manipulations relevant to human aetiological factors on emotional and cognitive behaviours relevant to human psychopathologies are valuable. Such valid animal models can be useful for improved 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 psychopathology symptoms or features. In the present study we exposed adult male C57BL/6 mice to an environmental manipulation of 15-day psychosocial stress with loss of social control but with minimal physical wounding. One cohort of stressed and control mice was assessed in a novel 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. The socially stressed mice displayed dec...

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Psychosocial stress is a major risk factor for mood and anxiety disorders, in which excessive reactivity to aversive events/stimuli is a major psychopathology. In terms of pathophysiology, immuneinflammation is an important candidate, including high blood and brain levels of metabolites belonging to the kynurenine pathway. Animal models are needed to study causality between psychosocial stress, immune-inflammation and hyper-reactivity to aversive stimuli. The present mouse study investigated effects of psychosocial stress as chronic social defeat (CSD) versus control-handling (CON) on: Pavlovian tone-shock fear conditioning, activation of the kynurenine pathway, and efficacy of a specific inhibitor (IDOInh) of the tryptophan-kynurenine catabolizing enzyme indoleamine 2,3-dioxygenase (IDO1), in reversing CSD effects on the kynurenine pathway and fear. CSD led to excessive fear learning and memory, whilst repeated oral escitalopram (antidepressant and anxiolytic) reversed excessive fear memory, indicating predictive validity of the model. CSD led to higher blood levels of TNF-, IFN-, kynurenine (KYN), 3-hydroxykynurenine (3-HK) and kynurenic acid, higher KYN and 3-HK in amygdala and hippocampus. However, CSD was without effect on IDO1 gene or protein expression in spleen, ileum and liver, whilst increasing liver TDO2 gene expression. Nonetheless, oral IDOInh reduced blood and brain levels of KYN and 3-HK in CSD mice to CON levels, and we therefore infer that CSD increases IDO1 activity by increasing its post-translational activation. Furthermore, repeated oral IDOInh reversed excessive fear memory in CSD mice to CON levels. IDOInh reversal of CSD-induced hyper-activity in the kynurenine pathway and fear system contributes significantly to the evidence for a causal pathway between psychosocial stress, immune-inflammation and the excessive fearfulness that is a major psychopathology in stress-related neuropsychiatric disorders. ABSTRACTPsychosocial stress is a major risk factor for mood and anxiety disorders, in which excessive reactivity to aversive events/stimuli is a major psychopathology. In terms of pathophysiology, immune-inflammation is an important candidate, including high blood and brain levels of metabolites belonging to the kynurenine pathway. Animal models are needed to study causality between psychosocial stress, immune-inflammation and hyper-reactivity 3-HK in CSD mice to CON levels, and we therefore infer that CSD increases IDO1 activity by increasing its post-translational activation. Furthermore, repeated oral IDOInh reversed excessive fear memory in CSD mice to CON levels. IDOInh reversal of CSD-induced hyperactivity in the kynurenine pathway and fear system contributes significantly to the evidence for a causal pathway between psychosocial stress, immune-inflammation and the excessive fearfulness that is a major psychopathology in stress-related neuropsychiatric disorders.3

Human depression, for which chronic psychosocial stress is a major risk factor, is characterized by consistent alterations in neurocircuitry. For example, there is increased functional connectivity (FC) within and between regions comprising the default mode network (DMN) including prefrontal cortex and cingulate cortex. Alterations in network FC are associated with specific aspects of psychopathology. In mice, chronic psychosocial stress (CPS) leads to depression-relevant behavior, including increased fear learning, learned helplessness, fatigue and decreased motivation for reward. Using multimodal in vivo magnetic resonance imaging (MRI) and spectroscopy (MRS), we investigated CPS effects on function and structure in the mouse brain under light anesthesia. Mice underwent a baseline MRI/MRS session, followed by 15-day CPS (n=26) or control handling (n=27), and a post-treatment MRI/MRS session. In BOLD fMRI, relative to controls, CPS mice exhibited robust, reproducible increases in FC within 8 of 9 identified cortical networks, including the prefrontal and cingulate cortices that contribute to the "mouse DMN". CPS mice exhibited increases in between-network FC, including amygdala -prefrontal cortex and amygdala -cingulate cortex. MRS identified metabolic alterations in CPS mice as increased inositol levels in amygdala and increased glycerophosphorylcholine levels in prefrontal cortex. Diffusion-weighted MRI detected increased fractional anisotropic values in the cingulum. This study demonstrates that chronic psychosocial stress induces FC states in the mouse brain analogous to those observed in depression, as well as cerebral metabolism and white matter pathway alterations that contribute to understanding of pathological processes. It also demonstrates the importance of brain imaging to the establishment of valid animal models in translational psychiatry. AbstractHuman depression, for which chronic psychosocial stress is a major risk factor, is characterized by consistent alterations in neurocircuitry. For example, there is increased functional connectivity (FC) within and between regions comprising the default mode network (DMN) including prefrontal cortex and cingulate cortex. Alterations in network FC are associated with specific aspects of psychopathology. In mice, chronic psychosocial stress (CPS) leads to depression-relevant behavior, including increased fear learning, learned helplessness, fatigue and decreased motivation for reward.Using multimodal in vivo magnetic resonance imaging (MRI) and spectroscopy (MRS), we investigated CPS effects on function and structure in the mouse brain under light anesthesia. Mice underwent a baseline MRI/MRS session, followed by 15-day CPS (n=26) or control handling (n=27), and a posttreatment MRI/MRS session. In BOLD fMRI, relative to controls, CPS mice exhibited robust, reproducible increases in FC within 8 of 9 identified cortical networks, including the prefrontal and cingulate cortices that contribute to the "mouse DMN". CPS mice exhibited increases in b...