Effect of combined chronic predictable and unpredictable stress on depression-like symptoms in mice

Abstract

Background: Mental stress mainly induces depression, and predictable stress, as well as a constant bombardment of chronic unpredictable micro-stressors, always coexist in daily life. However, the combined effect of predictable and unpredictable stress on depression is still not fully understood. Methods:The chronic restraint stress (CRS) is to restrain the mice for 6 h per day for 3 weeks, and the chronic unpredictable mild stress (CUMS) is to stimulate the mice with 7 different stressors for 3 weeks. We evaluated the combined effect of CRS and CUMS on depression-like symptoms using behavioral tests and investigated the action mechanism through analysis of neurotransmitters, brain-derived factors, inflammatory factors, antioxidants, and intestinal microorganisms.Results: Our data suggested the combined stress of CRS and CUMS caused significant weight loss, food intake reduction, depression-like behaviors-including anhedonia, learned helplessness, and reduction in spontaneous activity-and even atrophy and severe structural damage to the hippocampus in mice. Our pathogenesis study showed that combined stress-induced the reduction of glucocorticoid receptor (GR) levels, loss of oligodendrocytes (NG2 and Olig2 cells), and inhibition of neuron proliferation in the CA1, CA3, and DG regions of the hippocampus, decreased the contents of monoamine neurotransmitters (5-HT and NE) and BDNF in the cerebral cortex, caused hyperactivity of the HPA system, led to immune dysfunction, aggravated oxidative stress, and weakened the capacity of antioxidants in mice. Compared with single stress, combined stress gave rise to a more significant diversity change of the gut microbiota.Conclusions: Combined stress caused significant depression-like behaviors, atrophy, and severe structural damage to the hippocampus in mice via monoamine neurotransmitter, BDNF, HPA axis, neurogenesis, and neurodegenerative, immune, oxidative stress and gut-brain axis action pathways.

Obeticholic Acid Inhibits Anxiety via Alleviating Gut Microbiota-Mediated Microglia Accumulation in the Brain of High-Fat High-Sugar Diet Mice

“…The animal experiments revealed that LPS activated microglia promoted the production of proinflammatory cytokines in the brain and induced anxiety-like behavior [ 55 ], while cotreatment with antibiotic doxycycline could attenuate LPS-induced microglial activation and anxiety in mice [ 58 ]. In this study, OCA significantly reduced neuropsychiatric disorders-related bacteria in the HFHS-fed MDs mice, such as Marinifilaceae, Rikenellaceae and its genus Alistipes , and these microbes have been reported in the previous model and clinical studies [ 59 , 60 , 61 ]. For example, the indole-positive Alistipes could influence the tryptophan metabolism and disrupt the balance of the serotonergic system [ 61 ], which was known to modulate neuronal signals related to anxiety [ 62 ].…”

Expression of Brain-Derived Neurotrophic Factor in the Brain of Depressed Mice: Systematic Literature Review

“…This can represent a picture of stressors that occur both mild, moderate, and severe (Weisbrod et al, 2019). Mental stress can lead to depression (Qiao et al, 2020).…”

Juvenile exposure to acute traumatic stress leads to long-lasting alterations in grey matter myelination in adult female but not male rats

“…OPCs persist throughout the postnatal period and continue to divide and generate myelinating OLs throughout their lifespan ( Bergles and Richardson, 2016 ). While our study focused on immature and mature myelinating OLs, stress can also affect the progenitor pool in these limbic regions ( Qiao et al, 2020 ; Saul et al, 2015 ; Teissier et al, 2020 ). For example, repeated variable stress selectively reduced the number of proliferating OPCs in the AMY in juvenile male mice, while leaving proliferating neurons unchanged ( Saul et al, 2015 ).…”