Stress, a matter of balance

Modern society is a dynamic plot pervaded by cultural, social, emotional, and biological experiences, some of which ultimately endanger our lifestyle and affect our physiology and behaviour. For health and survival, adequate regulatory control of the HPA stress axis is required. Over the years, chronic stress has been frequently implicated in altered brain function. Current evidence shows that the habituation of HPA axis response is more complex than previously thought. The adaptive reduction of repeated stress-induced responses seems to involve complex crosstalk between negative feedback mechanisms induced by the release of GCs under repeated stress, response habituation processes produced by repetitive exposure to the stress stimulus, and likely more complex learning and memory encoding information regarding previous stressful events. We directed our research towards two major problems that currently impede advances in modeling HPA habituation in mice and mechanisms leading to it. By doing so, we contribute to a better understanding of normal behavior and mechanisms. Here, we show that glucocorticoid receptors in the hypothalamic paraventricular nucleus in CRF neurons are essential for HPA axis habituation. When re-exposed to the same stressor, glucocorticoid receptors led to essential cellular modulation and dampened HPA axis activation by increasing inhibitory tone onto CRF neurons. The current research study provides a new set of data that confidently positions the GR-CRF system as a crucial player in the executive function following repeated stress exposure, thus offering a molecular mechanism through which this effect occurs. Hence, it shows a possible pharmacological target that could support the production of active measures to mitigate the deleterious effects of repeated stress exposure

Expression and glucocorticoid-dependent regulation of the stressinducible protein DRR1 in the mouse adult brain

Identifying molecular targets that are able to buffer the consequences of stress and therefore restore brain homeostasis is essential to develop treatments for stress-related disorders. Down-regulated in renal cell carcinoma 1 (DRR1) is a unique stress-induced protein in the brain and has been recently proposed to modulate stress resilience. Interestingly, DRR1 shows a prominent expression in the limbic system of the adult mouse. Here, we analyzed the neuroanatomical and cellular expression patterns of DRR1 in the adult mouse brain using in situ hybridization, immunofluorescence and Western blot. Abundant expression of DRR1 mRNA and protein was confirmed in the adult mouse brain with pronounced differences between distinct brain regions. The strongest DRR1 signal was detected in the neocortex, the CA3 region of the hippocampus, the lateral septum and the cerebellum. DRR1 was also present in circumventricular organs and its connecting regions. Additionally, DRR1 was present in non-neuronal tissues like the choroid plexus and ependyma. Within cells, DRR1 protein was distributed in a punctate pattern in several subcellular compartments including cytosol, nucleus as well as some pre- and postsynaptic specializations. Glucocorticoid receptor activation (dexamethasone 10 mg/kg s.c.) induced DRR1 expression throughout the brain, with particularly strong induction in white matter and fiber tracts and in membrane-rich structures. This specific expression pattern and stress modulation of DRR1 point to a role of DRR1 in regulating how cells sense and integrate signals from the environment and thus in restoring brain homeostasis after stressful challenges

Purine and pyrimidine metabolism: Convergent evidence on chronic antidepressant treatment response in mice and humans

Selective Serotonin Reuptake Inhibitors (SSRIs) are commonly used drugs for the treatment of psychiatric diseases including major depressive disorder (MDD). For unknown reasons a substantial number of patients do not show any improvement during or after SSRI treatment. We treated DBA/2J mice for 28 days with paroxetine and assessed their behavioral response with the forced swim test (FST). Paroxetine-treated long-time floating (PLF) and paroxetine-treated short-time floating (PSF) groups were stratified as proxies for drug non-responder and responder mice, respectively. Proteomics and metabolomics profiles of PLF and PSF groups were acquired for the hippocampus and plasma to identify molecular pathways and biosignatures that stratify paroxetine-treated mouse sub-groups. The critical role of purine and pyrimidine metabolisms for chronic paroxetine treatment response in the mouse was further corroborated by pathway protein expression differences in both mice and patients that underwent chronic antidepressant treatment. The integrated -omics data indicate purine and pyrimidine metabolism pathway activity differences between PLF and PSF mice. Furthermore, the pathway protein levels in peripheral specimens strongly correlated with the antidepressant treatment response in patients. Our results suggest that chronic SSRI treatment differentially affects purine and pyrimidine metabolisms, which may explain the heterogeneous antidepressant treatment response and represents a potential biosignature