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Depression is a debilitating mental disease, characterized by persistent low mood and anhedonia. Stress represents a major environmental risk factor for depression; the complex interaction of stress with genetic factors results in different individual vulnerability or resilience to the disorder. Dysfunctions of the glutamate system have a primary role in depression. Clinical neuroimaging studies have consistently reported alterations in volume and connectivity of cortico-limbic areas, where glutamate neurons and synapses predominate. This is confirmed by preclinical studies in rodents, showing that repeated stress induces morphological and functional maladaptive changes in the same brain regions altered in humans. Confirming the key role of glutamatergic transmission in depression, compelling evidence has shown that the non-competitive NMDA receptor antagonist, ketamine, induces, at sub-anesthetic dose, rapid and sustained antidepressant response in both humans and rodents.We show here that the Chronic Mild Stress model of depression induces, only in stress-vulnerable rats, depressed-like anhedonic behavior, together with impairment of glutamate/GABA presynaptic release, BDNF mRNA trafficking in dendrites and dendritic morphology in hippocampus. Moreover, we show that a single administration of ketamine restores, in 24 h, normal behavior and most of the cellular/molecular maladaptive changes in vulnerable rats. Interestingly, ketamine treatment did not restore BDNF mRNA levels reduced by chronic stress but rescued dendritic trafficking of BDNF mRNA.The present results are consistent with a mechanism of ketamine involving rapid restoration of synaptic homeostasis, through re-equilibration of glutamate/GABA release and dendritic BDNF for synaptic translation and reversal of synaptic and circuitry impairment. Keywords: Chronic stress, Ketamine, Stress vulnerability, Glutamate release, BDNF, Antidepressant

Chronic psychosocial stress at workplace is an important factor in the development of physical and mental illness. Objective biological measures of chronic stress are still lacking, but inflammatory response and growth factors are increasingly considered as potential stress biomarkers. Therefore, we investigated the relationship between psychophysical strain and serum levels of 48 chemokines, cytokines and growth factors measured using a multiplex immunoassay, and serum brain-derived neurotrophic factor (BDNF) measured by ELISA. Severity of psychophysical strain was scored in 115 healthy hospital workers using specific scales for anxiety, depression-like emotion, gastrointestinal or cardiac disturbances, and ergonomic dysfunction. Multivariate analysis revealed that higher anxiety scale scores were correlated with lower serum chemokine C-C motif ligand-2 (CCL2/MCP-1), chemokine C-C motif ligand-5 (CCL5/RANTES), chemokine C-C motif ligand-27 (CCL27/CTACK), chemokine C-C motif ligand-11 (CCL11/Eotaxin) and interleukin-6 (IL-6); gastrointestinal disturbances correlated with increased levels of interleukin-17 (IL-17) and reduced CCL11/Eotaxin, CCL27/CTACK and CCL2/MCP-1; while cardiac dysfunctions associate only to reduced CCL27/CTACK, and ergonomic dysfunction correlated with increased BDNF and reduced CCL11/Eotaxin and CCL5/RANTES. Thus, these 7 serum factors may provide a distinct signature for each different stress-related psychophysical outcome giving indications on individual vulnerabilities., Graphical abstract Image 1, Highlights • Overall Strain was associated with low serum levels of the chemokines CCL11, CCL27, CCL2, CCL5. • Anxiety was associated with low serum levels of CCL11, CCL27, CCL2, CCL5 and IL-6. • Gastrointestinal complains associated with High levels of the interleukin IL-17, together with low CCL11, CCL27, CCL2. • Ergonomic problems associated with low CCL11 and CCL5 and increased BDNF, and cardiac disturbances associated with reduced CCL2. • These 7 serum markers may help in prevention of developing more severe diseases in these particular psychophysical domains.

The question of how to quantify insufficient coping behavior under chronic stress is of major clinical relevance. In fact, chronic stress increasingly dominates modern work conditions and can affect nearly every system of the human body, as suggested by physical, cognitive, affective and behavioral symptoms. Since freshmen students experience constantly high levels of stress due to tight schedules and frequent examinations, we carried out a 3-center study of 1,303 students from Italy, Spain and Argentina in order to develop socioculturally independent means for quantifying coping behavior. The data analysis relied on 2 self-report questionnaires: the Coping Strategies Inventory (COPE) for the assessment of coping behavior and the Zurich Health Questionnaire which assesses consumption behavior and general health dimensions. A neural network approach was used to determine the structural properties inherent in the COPE instrument. Our analyses revealed 2 highly stable, socioculturally independent scales that reflected basic coping behavior in terms of the personality traits activity-passivity and defeatism-resilience. This replicated previous results based on Swiss and US-American data. The percentage of students exhibiting insufficient coping behavior was very similar across the study sites (11.5-18.0%). Given their stability and validity, the newly developed scales enable the quantification of basic coping behavior in a cost-efficient and reliable way, thus clearing the way for the early detection of subjects with insufficient coping skills under chronic stress who may be at risk of physical or mental health problems. This project was funded in part through the Seventh EU Framework Programme for Research and Technological Development (grant 248544; OPTIMI).

Hair analysis has been proposed as a minimally invasive technique capable of furnishing information regarding the stress response during medium- and long-term periods. Bristle samples were collected from the rump region of sows at three key physiological phases (before delivery - BD; weaning time - WT; pregnancy diagnosis - PD) during consecutive reproductive cycles in order to test swine hair as a reliable matrix of cortisol evaluation. Cortisol was extracted from the bristles and assayed using radioimmunoassay. The highest mean hair cortisol concentrations were demonstrated (p

The exposure to chronic stressors could have deleterious effects on an animal’s health and well-being and could negatively influence the result of an experimental design. The stress situation involves an activation of the hypothalamic–pituitary–adrenocortical (HPA) axis changes in the adrenocortical secretion of glucocorticoids (GC). Short-term and long-term changes are nowadays assessed by measuring GC concentrations in plasma, feces, urine and saliva but there are clear limitations to each of these approaches. Therefore there is no current non-invasive validated procedure for determining long-term activity of this system in laboratory animals rodents. The aim of the present study was, for the first time, to develop and validate a reliable method for measuring hair corticosterone concentrations in rats. Sprague Dawley rats of 10 weeks were shaved in the morning on their back and collected 200 mg of hair samples. The procedure involved: two isopropanol washes of the samples to remove contaminants, powdering of the washed and dried hair, a 21-h methanol extraction followed by evaporation of the solvent, reconstitution of the extract in phosphate buffer and analysis of the extracted corticosterone by radioimmuneassay (RIA). The sensitivity of the assay was 0.6 pg/mg. The measured recovery was: 97.5% +/- 6.1 and the coefficient of variation of the whole process (extraction + analysis): 7.8%. Therefore this new procedure could be useful in many experimental contexts involving the study of stress, endocrinology and neuroscience fields but also for monitoring chronic stress that might be associated with experimental manipulations.