Chronic Stress-induced Behaviors Research Articles

Voluntary wheel running promotes resilience to the behavioral effects of unpredictable chronic mild stress in male and female mice

Besides significant benefits to physical health, exercise promotes mental health, reduces symptoms of mental illness, and enhances psychological development. Exercise can offset the impact of chronic stress, which is a major precursor to the development of mental disorders. The effects of exercise on chronic stress-induced behaviors are contradictory in preclinical studies, primarily due to the lack of data and sex-specific investigations. We sought to evaluate the effects of exercise on chronic stress-induced behavioral changes in both male and female mice. Mice were subjected to an Unpredictable Chronic Mild Stress (UCMS) paradigm with accessibility to running wheels for 2 h daily. Physiological and behavioral evaluations were conducted throughout the stress paradigm to determine if exercise blunts the effects of UCMS. Chronic stress induced voluntary wheel running (VWR) and weight loss in male and female mice. Compared to males, increased VWR was reported in females who also regained their weight lost by the end of the UCMS protocol. Exercise promoted resilience to stress-induced hyponeophagia in the novelty-suppressed feeding test and increased sucrose consumption. Exercise induced a sex-specific reduction in immobility and avoidance behavior in the tail suspension and open field tests and increased exploratory behavior in the light-dark test. These results indicate that exercise can promote resilience to the behavioral effects of chronic stress in males and females, and can affect behavior independent of chronic stress.

Intravenous Reelin Treatment Rescues Atrophy of Spleen White Pulp and Correlates to Rescue of Forced Swim Test Immobility and Neurochemical Alterations Induced by Chronic Stress

Reelin, an extracellular matrix protein with putative antidepressant-like properties, becomes dysregulated by chronic stress. Improvement in cognitive dysfunction and depression-like behavior induced by chronic stress has been reported with both intrahippocampal and intravenous Reelin treatment but the mechanisms responsible are not clear. To determine if treatment with Reelin modifies chronic stress-induced dysfunction in immune organs and whether this relates to behavioral and/or neurochemical outcomes, spleens were collected from both male (n = 62) and female (n = 53) rats treated with daily corticosterone injections for three weeks that received Reelin or vehicle. Reelin was intravenously administered once on the final day of chronic stress, or repeatedly, with weekly treatments throughout chronic stress. Behavior was assessed during the forced swim test and the object-in-place test. Chronic corticosterone caused significant atrophy of the spleen white pulp, but treatment with a single shot of Reelin restored white pulp in both males and females. Repeated Reelin injections also resolved atrophy in females. Correlations were observed between recovery of white pulp atrophy and recovery of behavioral deficits and expression of both Reelin and glutamate receptor 1 in the hippocampus, supporting a role of the peripheral immune system in the recovery of chronic stress-induced behaviors following treatment with Reelin. Our data adds to research indicating Reelin could be a valuable therapeutic target for chronic stress-related disorders including major depression.

Indole-3-Carbinol Selectively Prevents Chronic Stress-Induced Depression-but not Anxiety-Like Behaviors via Suppressing Pro-Inflammatory Cytokine Production and Oxido-Nitrosative Stress in the Brain.

Indole-3-carbinol (I3C), a phytochemical enriched in most cruciferous vegetables, has been shown to display various biological activities such as anti-oxidative stress, anti-inflammation, and anti-carcinogenesis. In this study, we investigated the regulatory effect of I3C on chronic stress-induced behavioral abnormalities in mice. Results showed that repeated I3C treatment at the dose of 10, 30, and 60 mg/kg prevented chronic social defeat stress (CSDS)-induced behavioral abnormalities in the tail suspension test, forced swimming test, sucrose preference test, and social interaction test in mice, and did not affect CSDS-induced behavioral abnormalities in the elevated plus maze, light-dark test, and open-field test, suggesting that the I3C treatment selectively prevents the onset of depression- but not anxiety-like behaviors in chronically stressed mice. Further analysis demonstrated that repeated I3C treatment (60 mg/kg, 10 days) prevented CSDS-induced increases in levels of interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α) mRNA and protein, but did not affect CSDS-induced decreases in levels of IL-4, IL-10, and Ym-1 mRNA and/or protein in the hippocampus and prefrontal cortex, suggesting that I3C can selectively prevent chronic stress-induced pro-inflammatory but not anti-inflammatory responses in the brain. Further analysis showed that repeated I3C treatment (60 mg/kg, 10 days) prevented CSDS-induced increases in levels of nitrite and malondialdehyde (MDA), decreases in contents of glutathione (GSH), and decreases in levels of brain derived neurotrophic factor (BDNF) protein in the hippocampus and prefrontal cortex. These results demonstrated that I3C selectively prevents chronic stress-induced depression-like behaviors in mice likely through suppressing neuroinflammation and oxido-nitrosative stress in the brain.

Chronic Stress-induced Behaviors Correlate with Exacerbated Acute Stress-induced Cingulate Cortex and Ventral Hippocampus Activation

Altered activity of corticolimbic brain regions is a hallmark of stress-related illnesses, including mood disorders, neurodegenerative diseases, and substance abuse disorders. Acute stress adaptively recruits brain region-specific functions for coping, while sustained activation under chronic stress may overwhelm feedback mechanisms and lead to pathological cellular and behavioral responses. The neural mechanisms underlying dysregulated stress responses and how they contribute to behavioral deficits are poorly characterized. Here, we tested whether prior exposure to chronic restraint stress (CRS) or unpredictable chronic mild stress (UCMS) in mice could alter functional response to acute stress and whether these changes are associated with chronic stress-induced behavioral deficits. More specifically, we assessed acute stress-induced functional activation indexed by c-Fos+ cell counts in 24 stress- and mood-related brain regions, and determined if changes in functional activation were linked to chronic stress-induced behavioral impairments, summarized across dimensions through principal component analysis (PCA). Results indicated that CRS and UCMS led to convergent physiological and anxiety-like deficits, whereas working and short-term memory were impaired only in UCMS mice. CRS and UCMS exposure exacerbated functional activation by acute stress in anterior cingulate cortex (ACC) area 24b and ventral hippocampal (vHPC) CA1, CA3, and subiculum. In dysregulated brain regions, levels of functional activation were positively correlated with principal components reflecting variance across behavioral deficits relevant to stress-related disorders. Our data supports an association between a dysregulated stress response, altered functional corticolimbic excitation/inhibition balance, and the expression of maladaptive behaviors.

Complement component 3a receptor deficiency attenuates chronic stress-induced monocyte infiltration and depressive-like behavior

Major depressive disorder (MDD) is one of the most common and debilitating neuropsychiatric illnesses. Accumulating evidence suggests a potential role of the immune system in the pathophysiology of MDD. The complement system represents one of the major effector mechanisms of the innate immune system, and plays a critical role in inflammation. However, the role of complement components in MDD is not well understood. Here, we found significant increase in component 3 (C3) expression in the prefrontal cortex (PFC) of depressed suicide subjects. We tested the role of altered C3 expression in mouse model of depression and found that increased C3 expression in PFC as a result of chronic stress causes depressive-like behavior. Conversely, mice lacking C3 were resilient to stress-induced depressive-like behavior. Moreover, selective overexpression of C3 in PFC was sufficient to cause depressive-like behavior in mice. We found that C3a (activated product of C3) receptor, C3aR+ monocytes were infiltrated into PFC following chronic stress. However, C3aR knockout mice displayed significantly reduced monocyte recruitment into PFC and reduced levels of the proinflammatory cytokine IL-1β in PFC after chronic stress. In addition, C3aR knockout mice did not exhibit chronic stress-induced behavior despair. Similarly, chronic stress-induced increases in C3aR+ monocytes and IL-1β in PFC, and depressive-like behavior were attenuated by myeloid cell depletion. These postmortem and preclinical studies identify C3aR signaling as a key factor in MDD pathophysiology.

Cav1.2 channels mediate persistent chronic stress-induced behavioral deficits that are associated with prefrontal cortex activation of the p25/Cdk5-glucocorticoid receptor pathway

Chronic stress is known to precipitate and exacerbate neuropsychiatric symptoms, and exposure to stress is particularly pathological in individuals with certain genetic predispositions. Recent genome wide association studies have identified single nucleotide polymorphisms (SNPs) in the gene CACNA1C, which codes for the Cav1.2 subunit of the L-type calcium channel (LTCC), as a common risk variant for multiple neuropsychiatric conditions. Cav1.2 channels mediate experience-dependent changes in gene expression and long-term synaptic plasticity through activation of downstream calcium signaling pathways. Previous studies have found an association between stress and altered Cav1.2 expression in the brain, however the contribution of Cav1.2 channels to chronic stress-induced behaviors, and the precise Cav1.2 signaling mechanisms activated are currently unknown. Here we report that chronic stress leads to a delayed increase in Cav1.2 expression selectively within the prefrontal cortex (PFC), but not in other stress-sensitive brain regions such as the hippocampus or amygdala. Further, we demonstrate that while Cav1.2 heterozygous (Cav1.2+/−) mice show chronic stress-induced depressive-like behavior, anxiety-like behavior, and deficits in working memory 1–2 days following stress, they are resilient to the effects of chronic stress when tested 5–7 days later. Lastly, molecular studies find a delayed upregulation of the p25/Cdk5-glucocorticoid receptor (GR) pathway in the PFC when examined 8 days post-stress that is absent in Cav1.2+/− mice. Our findings reveal a novel Cav1.2-mediated molecular mechanism associated with the persistent behavioral effects of chronic stress and provide new insight into potential Cav1.2 channel mechanisms that may contribute to CACNA1C-linked neuropsychiatric phenotypes.

Effect of trimethylgallic acid esters against chronic stress-induced anxiety-like behavior and oxidative stress in mice

BackgroundMany studies have shown that the levels of oxidative stress (increased lipid peroxidation, decreased glutathione levels and endogenous antioxidant enzyme activities) and proinflammatory cytokines (e.g., TNF-α) are increased in patients with chronic fatigue syndrome. Gallic acid and other phenolic compounds are potent antioxidants and inhibitor of cytokine production. The present study was designed to investigate the effect of newly synthesized conjugated esters of trimethylgallic acid in an experimental model of chronic stress. MethodsThe animals were forced to swim individually for a period of 6min every day for 15 days to induce chronic stress. The locomotor activity, anxiety-like behavior, and memory retention were evaluated in chronically stressed animals, followed by biochemical estimations and neuroinflammatory surge in the brain. ResultsChronic treatment with trimethylgallic acid esters for 15 days significantly reversed the chronic stress-induced behavioral (impaired locomotor activity, anxiety-like behavior, and decreased percentage of memory retention), biochemical (increased lipid peroxidation and nitrite levels; decreased glutathione levels, superoxide dismutase and catalase activities), and inflammation surge (serum TNF-α) in stressed mice. ConclusionsThe study revealed that trimethylgallic acid esters could ameliorate chronic stress-induced various behavioral and biochemical alterations in mice, showing protective effects against chronic stress.

Sirtuin Activity in Dentate Gyrus Contributes to Chronic Stress-Induced Behavior and Extracellular Signal-Regulated Protein Kinases 1 and 2 Cascade Changes in the Hippocampus

Exposure to chronic stress produces negative effects on mood and hippocampus-dependent memory formation. Alterations in signaling cascades and histone acetylation present a mechanism of modulation of transcription that may underlie stress-dependent processes in the hippocampus critical to learning and memory and development of depressive behaviors. The rat model of chronic variable stress (CVS) was used to investigate the role of changes in protein acetylation and other molecular components of hippocampus-dependent memory formation and anhedonic behavior in response to CVS. Chronic variable stress treatment decreased both extracellular signal-regulated protein kinases 1 and 2 activation and Bcl-2 expression in all three regions of the hippocampus that corresponded behaviorally with a decrease in memory for the novel object location task and increased anhedonia. Extracellular signal-regulated protein kinases 1 and 2 activation was not significantly affected in the amygdala and increased in the medial prefrontal cortex by CVS. Chronic variable stress had no significant effect on activation of Akt in the hippocampus. We investigated molecular and behavioral effects of infusion of the sirtuin inhibitor, sirtinol, into the dentate gyrus (DG). Sirtinol infusion into the DG prevented the CVS-mediated decrease in extracellular signal-regulated protein kinases 1 and 2 activity and Bcl-2 expression, as well as histone acetylation in the DG previously observed following CVS. This corresponded to enhanced performance on the novel object location memory task, as well as reduced anhedonic behavior. These results suggest that changes in sirtuin activity contribute to changes in molecular cascades and histone acetylation within the hippocampus observed following CVS and may represent a novel therapeutic target for stress-induced depression.