Abstract
Depression is a recurrent disorder, with about 50% of patients experiencing relapse. Exposure to stressful events may have an adverse impact on the long-term course of the disorder and may alter the response to a subsequent stressor. Indeed, not all the systems impaired by stress may normalize during symptoms remission, facilitating the relapse to the pathology. Hence, we investigated the long-lasting effects of chronic restraint stress (CRS) and its influence on the modifications induced by the exposure to a second hit on brain-derived neurotrophic factor (BDNF) signaling in the prefrontal cortex (PFC). We exposed adult male Sprague Dawley rats to 4 weeks of CRS, we left them undisturbed for the subsequent 3 weeks, and then we exposed animals to one hour of acute restraint stress (ARS). We found that CRS influenced the release of corticosterone induced by ARS and inhibited the ability of ARS to activate mature BDNF, its receptor Tropomyosin receptor kinase B (TRKB), and their associated intracellular cascades: the TRKB-PI3K-AKT), the MEK-MAPK/ERK, and the Phospholipase C γ (PLCγ) pathways, positively modulated by ARS in non-stressed animals. These results suggest that CRS induces protracted and detrimental consequences that interfere with the ability of PFC to cope with a challenging situation.
Highlights
IntroductionDepression is a severe and highly diffuse disease affecting more than 10% of the general population, and by 2030, it is estimated to become the second leading cause of disability and the largest contributor to disease burden [1]
Depression is a severe and highly diffuse disease affecting more than 10% of the general population, and by 2030, it is estimated to become the second leading cause of disability and the largest contributor to disease burden [1].It has been largely characterized as a recurrent disorder, with approximately 50% of patients experiencing relapse [2]
As previously observed [23,24], we found a significant decrease in the novel object recognition (NOR) discrimination index in all the rats exposed to chronic stress (−32%, p < 0.05 vs. No stress, T value = 2.446) in comparison to non-stressed animals (Figure S1)
Summary
Depression is a severe and highly diffuse disease affecting more than 10% of the general population, and by 2030, it is estimated to become the second leading cause of disability and the largest contributor to disease burden [1]. It has been largely characterized as a recurrent disorder, with approximately 50% of patients experiencing relapse [2]. Negative life events occurring early in life may impact brain functioning and are critical for later psychopathologies [7], whereas the effect of stress in adulthood may have persistent consequences but may recover physiologically through the activation of dynamic processes that help the brain to achieve successful adaptation [8]. Limited information is available on the long-lasting impacts of stress exposure during adult life, as well as on the mechanisms that may promote or prevent relapse
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