Stress-Induced Morphological, Cellular and Molecular Changes in the Brain—Lessons Learned from the Chronic Mild Stress Model of Depression

Abstract

Major depressive disorder (MDD) is a severe illness imposing an increasing social and economic burden worldwide. Numerous rodent models have been developed to investigate the pathophysiology of MDD. One of the best characterized and most widely used models is the chronic mild stress (CMS) model which was developed more than 30 years ago by Paul Willner. More than 2000 published studies used this model, mainly to assess novel compounds with potential antidepressant efficacy. Most of these studies examined the behavioral consequences of stress and concomitant drug intervention. Much fewer studies focused on the CMS-induced neurobiological changes. However, the stress-induced cellular and molecular changes are important as they may serve as potential translational biomarkers and increase our understanding of the pathophysiology of MDD. Here, we summarize current knowledge on the structural and molecular alterations in the brain that have been described using the CMS model. We discuss the latest neuroimaging and postmortem histopathological data as well as molecular changes including recent findings on microRNA levels. Different chronic stress paradigms occasionally deliver dissimilar findings, but the available experimental data provide convincing evidence that the CMS model has a high translational value. Future studies examining the neurobiological changes in the CMS model in combination with clinically effective antidepressant drug intervention will likely deliver further valuable information on the pathophysiology of MDD.

Chronic Stress Alters Astrocyte Morphology in Mouse Prefrontal Cortex

“…Finally, this study focused on identifying chronic stress effects on PFC astrocyte morphology; the mechanisms responsible for chronic stress-induced atrophy or the consequences of these changes on neuronal morphology, activity and function remain to be investigated. Indeed, these astrocytic changes may be linked to the decrease in synapse number and synaptic markers reported in chronic stress models [2, 88] and MDD [18, 19, 89].…”

Adult neurogenic process in the subventricular zone‐olfactory bulb system is regulated by Tau protein under prolonged stress

“…12,13 Although the extent and relevance of adult neurogenesis in humans are currently debated, 14,15 accumulating evidence suggests that neurogenesis persists in the adult brain of both humans and rodent animals during the entire lifespan while it drops in Alzheimer's disease (AD) [16][17][18][19][20] and other pathological conditions causally related to AD, such as depression and stress. [21][22][23] Chronic stress, a major precipitant of depression and AD [24][25][26][27] is known to impair brain plasticity, including suppression of neurogenesis. 23,[28][29][30][31][32] Recent evidence about stress-driven neurogenic deficits highlights the critical role for the cytoskeletal Tau protein 22,33 a prominent stabilizer of microtubules (MT), 34 which promotes co-organization of MT and actin networks.…”

Hippocampal overexpression of NOS1AP promotes endophenotypes related to mental disorders

“…Moreover, chronic mild stress has been shown to induce a broad range of molecular changes in different brain regions (e.g. [80] , [81] , [82] ). Thus, we cannot conclusively confirm that the described effects following hippocampal overexpression of NOS1AP would also be observed as a consequence of pathophysiologically increased NOS1AP.…”