Protocol for a systematic review of the association between chronic stress during the life course and telomere length

Systematic review of the association between chronic social stress and telomere length: A life course perspective

It has been suggested that there are causal relationships between alterations in brain glia and major depression. In order to investigate whether a depressive-like state induces changes in brain astrocytes, we analyzed the modulation of astroglia-specific gene expression in the hippocampus of male rats using two models of chronic stress: chronic social stress (5 weeks, daily confrontations with a dominant male) and chronic restraint stress (3 weeks, immobilization 6h/day). Furthermore, the effects of chronic citalopram administration on hippocampal as well as prefrontal cortex (PFC) gene expression were assessed in the chronic social stress experiment. The expression of six astroglial genes was determined: N-myc-downregulated gene 2 (Ndrg2), glial fibrillary acidic protein (GFAP), glutamate transporter 1 (GLT-1), glutamate and aspartate transporter (GLAST), aquaporin 4 (AQP4) and the inward rectifying potassium channel 4.1 (Kir4.1). Furthermore, protein analyses in the hippocampus were performed by means of quantitative Western blots. Since so far, there was no reference gene validated for the PFC in experiments where animals were subjected to chronic social stress, the first step was to test several commonly used reference genes for expression stability in this part of the brain. In order to study hemispheric effects of stress in the PFC, the left and right hemispheres were analyzed separately. The results of astroglial gene expression after chronic stress suggest differential regulation depending of the experimental stress paradigm. Chronic restraint stress altered expression of astroglial genes which have a direct effect on neuronal activity: GLT-1 plays an essential role in glutamate clearance from the synaptic cleft, and Kir4.1 is fundamental in keeping low K+ concentrations in the interstitial space. The upregulation of GLT-1 at the mRNA level and the downregulation of Kir4.1 at the protein level, suggest altered glutamate and potassium ion homeostasis after chronic restraint stress. Also chronic social stress induced profound changes in astroglia. It downregulated GFAP, which might indicate the presence of resting astrocytes. Whether this represents a pathological process or is an adaptive mechanism that protects the system from overshooting remains to be elucidated. Chronic social stress also upregulated NDRG2 expression which was not due to alterations in the number of astrocytes, but to changes in the amount of NDRG2 expressed per cell. Altered NDRG2 expression might have an impact on cell proliferation. The observed changes in gene expression in the hippocampus after chronic social stress were not reversed by a 4-weeks treatment with citalopram, in contrast to previous findings in the dorsal raphe nucleus. However, in the hippocampal formation, citalopram reversed the stress-induced changes in two neuronal genes involved in synaptic transmission, the synaptosomal-associated protein 25 (SNAP-25) and syntaxin-1A. Taken together, these results might indicate that citalopram's therapeutic effects depend on the brain region with its specific neurochemical environment as well as features of the target cells. Also, it appears that restoration of normal astroglial gene expression in the hippocampus is not a prerequisite for the therapeutic effects of citalopram. These findings are in concordance with the hypothesis that chronic antidepressant treatments stimulate plasticity of brain cells; however, glial changes may show a different time course in comparison to neuronal alterations. In regard to the quantification of gene expression in the PFC, it is not possible to draw clear conclusions because expression of several presumptive reference genes was also affected by the chronic stress, at least in the left PFC. Nonetheless, analysis of reference gene stability revealed that cyclophilin was stably expressed in the right PFC. Furthermore, in an attempt to gain insight into the potential role of Ndrg2, astrocyte cultures were generated. Since NDRG2 has been previously related to processes of cell proliferation and stabilization of cell morphology, the astrocyte cultures were transduced with AAV vectors expressing two isoforms of Ndrg2 (Ndrg2S and Ndrg2L). EGFP-transduced cultures as well as buffer treated ones were used as controls. Subsequently, morphological measurements, proliferation studies and analysis of gene expression were performed on the astrocytes. The results suggest that the EGFP-transduced cultures were not an appropriate control for transduction, as these cultures showed differences compared to the buffer control in terms of morphological parameters and proliferation. Therefore, it was not possible to conclude if the changes in cell proliferation observed after NDRG2 transduction were related to NDRG2 expression or to the transduction procedure per se. No significant changes were observed in the morphological parameters measured, and GFAP quantification did not show significant alterations after NDRG2 transduction while there was a high variability in the results from the different experiments

Chronic stress creates an allostatic overload that may lead to mood disorders such as anxiety and depression. Modern causes of chronic stress in humans are mostly social in nature, relating to work and relationship stress. Research into neural and molecular mechanisms of vulnerability and resilience following chronic social stress (CSS) is ongoing and uses animal models to discover efficient prevention strategies and treatments. To date, most CSS studies have neglected the female sex and used male-focused aggression-based animal models such as chronic social defeat stress (CSDS). Accumulating evidence on sex differences suggests differences in the stress response, the prevalence of stress-related illness and in response to treatment, indicating that researchers should expand CSS investigation to include female-focused protocols alongside the popular CSDS protocols. Here, we describe a novel female mouse model of CSS and a parallel modified male mouse model of CSDS in C57BL/6 mice. These new models enable the investigation of vulnerability, coping and downstream effectors mediating short-term and long-term consequences of CSS in both sexes. Our data demonstrate differential effects on male and female mice during, soon after, and many weeks after CSS. Female mice are more prone to body weight loss during CSS and hyperactive anxious behaviour following CSS. Both sexes show reduced social interaction, but only stressed male mice show long-term changes in emotional memory and neuroendocrine function. We further discuss future avenues of research using these models to investigate mechanisms pertaining to sensitivity to CSS and treatment response profiles, in a sex-appropriate manner.

Background:Chronic stress has been found to suppress adult neurogenesis, but it remains unclear whether it may affect the maturation process of adult-born neurons. Here, we examined the influence of chronic social defeat stress on the morphological and electrophysiological properties of adult-born dentate granule cells at different developmental stages.Methods:Adult C57BL/6 mice were subjected to 10 days of chronic social defeat stress followed by a social interaction test 24 hours after the last defeat. Defeated mice were segregated into susceptible and unsusceptible subpopulations based on a measure of social interaction test. Combining electrophysiology with retrovirus-mediated birth-dating and labeling, we examined the impact of chronic social defeat stress on temporal regulation of synaptic plasticity of adult-born dentate granule cells along their maturation.Results:Chronic social defeat stress decreases the survival and dendritic complexity of adult-born dentate granule cells. While chronic social defeat stress doesn’t alter the intrinsic electrophysiological properties and synaptic transmission of surviving adult-born dentate granule cells, it promotes the developmental switch in synaptic N-methyl-D-aspartate receptors from predominant GluN2B- to GluN2A-containing receptors, which transform the immature synapse of adult-born dentate granule cells from one that exhibits enhanced long-term potentiation to one that has normal levels of long-term potentiation. Furthermore, chronic social defeat stress increases the level of endogenous repressor element-1 silencing transcription factor mRNA in adult-born dentate granule cells, and knockdown of the repressor element-1 silencing transcription factor in adult-born dentate granule cells rescues chronic social defeat stress-induced morphological deficits and accelerated developmental switch in synaptic N-methyl-D-aspartate receptor subunit composition.Conclusions:These results uncover a previously unsuspected role of chronic social defeat stress in regulating adult neurogenesis and suggest that chronic social defeat stress can affect synaptic maturation process of adult-born dentate granule cells.

Chronic social stress causes various psychopathologies and is frequently associated with alterations in the HPA axis function. The heightened glucocorticoid hormone levels in the bloodstream instigate an acute bodily response, which fades over time, even with continued glucocorticoid stimulation. It is known that the resistance to elevated hormone levels can affect the effectiveness of therapy in the treatment of stress-induced psychopathologies. Resistance to elevated hormone levels can impact the effectiveness of therapy for stress-induced psychopathologies. To understand the molecular basis of glucocorticoid resistance, we examined the effect of chronic social defeat stress on the transcriptome of two brain regions — the prefrontal cortex and the dorsal raphe nuclei — using an experimental model of depression. We assessed gene expression levels in C57BL/6 control mice and mice subjected to 30 days of stress, both under basal conditions and following additional stimulation with dexamethasone. The administration of dexamethasone (2 mg/kg) allowed for simulation of the upregulation of glucocorticoids and activation of the glucocorticoid receptor. The results indicate that chronic stress induces gene resistance to glucocorticoid hormones in only 15% of prefrontal cortex genes and 25% of raphe nuclei genes. In stressed animals, there was no response to dexamethasone stimulation, whereas controls showed a reaction. For 66% of the genes in the prefrontal cortex and 40% of the genes in the dorsal raphe nuclei, the response to dexamethasone exhibited a greater intensity in the stressed group as compared to the control group. This set of genes comprises genes linked to immune responses, monoamine conveyance, and synapse establishment. Under stress conditions, as opposed to controls, anti-inflammatory cytokine genes, as well as genes connected to the growth of B- and T-lymphocytes, are downregulated in response to dexamethasone treatment. Furthermore, chronic stress exposure heightens the sensitivity of serotonergic receptor genes Htr1a and Htr5a to dexamethasone. The Htr1a gene exhibited a region-specific response to dexamethasone in stressed animals. Specifically, the expression of the gene increased in response to dexamethasone in the prefrontal cortex, while it decreased in the dorsal raphe nuclei. Additionally, the sensitivity of genes involved in the differentiation of oligodendrocytes changed in the dorsal raphe nuclei of stressed animals. Thus, our data demonstrate that chronic social defeat stress induces resistance and heightened sensitivity to to glucocorticoid activation, resulting in the development of depression.

Introduction: Chronic stress causes a variety of physiological and behavioral alterations, including social impairments, altered endocrine function, and an increased risk for psychiatric disorders. Thereby, social stress is one of the most effective stressful stimuli among mammals and considered to be one of the major risk factors for the onset and progression of neuropsychiatric diseases. For analyzing the effects of social stress in mice, the resident/intruder paradigm of social defeat is a widely used model. Although the chronic social defeat stress model has been extensively studied, little is known about the effects of repeated or chronic social defeat stress on the endocannabinoid system (ECS). The present study aimed to understand the effects of chronic social stress on anxiety behavior and the levels of endocannabinoids (ECs) and two N-acylethanolamines (NAEs) in different brain regions of mice. Materials and Methods: Two-month-old, male C57Bl/6J mice were exposed to chronic psychosocial stress for 3 weeks. The effects of stress on anxiety behavior were measured using the light-dark box and hole board test. The EC levels of 2-arachidonoyl glycerol (2-AG) and anandamide (N-arachidonoylethanolamine [AEA]), as well as the levels of two NAEs (oleoylethanolamide [OEA] and palmitoylethanolamide), were analyzed by liquid chromatography-tandem mass spectrometry in the hippocampus, cerebellum, and cortex. Results: In comparison with control mice (n=12), mice exposed to social defeat stress (n=11) showed increased anxiety behaviors in the light-dark box and hole board test and gained significantly more weight during the experimental period. Additionally, chronic social stress induced differential alterations in the brain levels of 2-AG and AEA. More precisely, 2-AG levels were higher in the cortex and cerebellum, whereas reduced AEA levels were found in the hippocampus. Furthermore, we observed lower OEA levels in the hippocampus. Conclusion: The current study confirms that the ECS plays an essential role in stress responses, whereby its modulation seems to be brain region dependent.

Disparities in allostatic load, telomere length and chronic stress burden among African American adults: A systematic review

Oxytocin treatments or activation of the paraventricular nucleus-the shell of nucleus accumbens pathway reduce adverse effects of chronic social defeat stress on emotional and social behaviors in Mandarin voles

Chronic social instability stress in female rats: A potential animal model for female depression

Chronic stress is a recognized risk factor for psychiatric and psychological disorders and a potent modulator of adult neurogenesis. Numerous studies have shown that during stress, neurogenesis decreases; however, during the recovery from the stress, neurogenesis increases. Despite the increased number of neurons born after stress, it is unknown if the function and morphology of those neurons are altered. Here we asked whether neurons in adult mice, born during the final 5 days of chronic social stress and matured during recovery from chronic social stress, are similar to neurons born with no stress conditions from a quantitative, functional and morphological perspective, and whether those neurons are uniquely adapted to respond to a subsequent stressful challenge. We observed an increased number of newborn neurons incorporated in the dentate gyrus of the hippocampus during the 10-week post-stress recovery phase. Interestingly, those new neurons were more responsive to subsequent chronic stress, as they showed more of a stress-induced decrease in spine density and branching nodes than in neurons born during a non-stress period. Our results replicate findings that the neuronal survival and incorporation of neurons in the adult dentate gyrus increases after chronic stress and suggest that such neurons are uniquely adapted in the response to future social stressors. This finding provides a potential mechanism for some of the long-term hippocampal effects of stress.

Several psychiatric disorders increase the risk of cardiovascular disease, including posttraumatic stress disorder and major depression. While the precise mechanism for this association has not yet been established, it has been shown that certain disorders promote an unfavorable lipid profile. To study the interaction of stress and lipid dysregulation, we utilized chronic social defeat stress (CSDS), a mouse model of chronic stress with features of posttraumatic stress disorder and major depression. Following exposure to CSDS, mice were given access to either regular chow or a Western-style diet high in fat and cholesterol (HFD). The combination of social stress and HFD resulted in significant perturbations in lipid regulation, including two key features of the metabolic syndrome: increased plasma levels of non-HDL cholesterol and intrahepatic accumulation of triglycerides. These effects were accompanied by a number of changes in the expression of hepatic genes involved in lipid regulation. Transcriptional activity of LXR, SREBP1c, and ChREBP were significantly affected by exposure to HFD and CSDS. We present CSDS as a model of social stress induced lipid dysregulation and propose that social stress alters lipid metabolism by increasing transcriptional activity of genes involved in lipid synthesis.

Women are twice as likely as men to develop major depressive disorder. Exposure to chronic stress can induce depression in some vulnerable individuals, while others are resistant to depressive-like symptoms after equivalent levels of chronic stress. In female rats, individual differences in saccharin intake during chronic social defeat stress may predict subsequent cocaine self-administration, and may be attributed to alterations in mesolimbic dopamine activity. Female rats were exposed to 21 days of chronic social defeat stress, during which they were evaluated for their anhedonia-like responses in the form of saccharin intake. After chronic social defeat stress, the rats were tested for behavioral cross-sensitization to cocaine and escalated cocaine self-administration in a 24-h "binge." A separate group of animals underwent in vivo microdialysis of the nucleus accumbens (NAc) shell to assess dopamine (DA) in response to acute cocaine challenge. Cluster analysis revealed two phenotypes among the stressed female rats based on their saccharin intake while being exposed to stress, termed stress-resistant (SR, 28 %) and stress-sensitive (SS, 72 %). The amount of cocaine self-administered during the 24-h "binge" was positively correlated with preceding saccharin intake. The NAc DA response to a cocaine challenge was significantly lower in SR rats than in the SS and non-stressed control rats. No other significant differences were observed in behavioral cross-sensitization or cocaine self-administration prior to the "binge." Female rats showed individual differences in their anhedonic-like response to chronic social defeat stress, and these differences were reliably associated with subsequent cocaine-taking behavior.

Having your cake and eating it too: A habit of comfort food may link chronic social stress exposure and acute stress-induced cortisol hyporesponsiveness

LPS reduces BDNF and VEGF expression in the structures of the HPA axis of chronic social stressed female rats

A novel chronic social stress paradigm in female mice