Social Instability Stress Research Articles

Lasting effects of adolescent social instability stress on dendritic morphology in the nucleus accumbens in female and male Long Evans rats

Social instability stress (SS) in adolescence in rats leads to long-lasting changes in social behaviour and reward-related behaviour relative to control rats. Given the role of the nucleus accumbens (NAc) in such behaviours, we investigated the morphology of medium spiny neurons (MSNs), which are most neurons in the NAc, in adult female and male rats exposed to SS in adolescence. Irrespective of sex, SS rats had increased number of dendritic spines in both the core and shell regions of the NAc (2.3 % and 18.1 % increase, respectively). In the core, SS rats had a 16 % reduction in the total dendritic lengths of MSNs, whereas in the shell, SS rats had a greater dendritic length closer to the soma, and particularly in SS female rats, whereas the opposite was found farther from the soma (SS 10.6 % > CTL overall). Although the extent to which such structural changes may underlie the enduring effects of SS in adolescence requires investigation, the results add to evidence that changes to the social environment in adolescence can determine adult neuronal structural.

Astrocyte-Derived Exosomes Regulate Sperm miR-34c Levels to Mediate the Transgenerational Effects of Paternal Chronic Social Instability Stress.

The effects of chronically stressing male mice can be transmitted across generations by stress-specific changes in their sperm miRNA content that induce stress-specific phenotypes in their offspring. But how each stress paradigm alters the levels of distinct sets of sperm miRNAs is not known. We showed previously that exposure of male mice to chronic social instability (CSI) stress results in elevated anxiety and reduced sociability specifically in their female offspring across multiple generations because it reduces miR-34c levels in sperm of stressed males and their unstressed male offspring. Here we describe evidence that a strocyte-derived exos omes ( A-Exos ) carrying miR-34c mediate how CSI stress has this transgenerational effect on sperm. We found that CSI stress decreases miR-34c carried by A-Exos in the prefrontal cortex and amygdala, as well as in the blood of males. Importantly, miR-34c A-Exos levels are also reduced in these tissues in their F1 male offspring, who despite not being exposed to stress exhibit reduced sperm miR-34c levels and transmit the same stress-associated traits to their male and female offspring. Furthermore, restoring A-Exos miR-34c content in the blood of CSI-stressed males by intravenous injection of miR-34c-containing A-Exos restores miR-34c levels in their sperm. These findings reveal an unexpected role for A-Exos in maintaining sperm miR-34c levels by a process that when suppressed by CSI stress mediates this example of transgenerational epigenetic inheritance.

High fat diet consumption and social instability stress impair stress adaptation and maternal care in C57Bl/6 dams

Poor maternal diet and psychosocial stress represent two environmental factors that can significantly impact maternal health during pregnancy. While various mouse models have been developed to study the relationship between maternal and offspring health and behaviour, few incorporate multiple sources of stress that mirror the complexity of human experiences. Maternal high-fat diet (HF) models in rodents are well-established, whereas use of psychosocial stress interventions in female mice are still emerging. The social instability stress (SIS) paradigm, serves as a chronic and unpredictable form of social stress. To evaluate the combined effects of a poor maternal diet and intermittent social stress on maternal health and behaviour, we developed a novel maternal stress model using adult female C57Bl/6 mice. We observed that all HF+ mice demonstrated rapid weight gain, elevated fasting blood glucose levels and impaired glucose tolerance independent of the presence (+) or absence (-) of SIS. Behavioural testing output revealed anxiety-like behaviours remained similar across all groups prior to pregnancy. However, integrated anxiety z-scores revealed a mixed anxious profile amongst HF+/SIS+ females prior to pregnancy. HF+/SIS+ females also did not show reduced plasma ACTH and corticosterone levels that were observed in our other HF+ and HF- stress groups after SIS exposure. Further, HF+/SIS+ females demonstrated significant postpartum maternal neglect, resulting in fewer numbers of live offspring. These findings suggest that prolonged maternal HF diet consumption, coupled with previous exposure to SIS, places a significant burden on the maternal stress response system, resulting in reduced parental investment and negative postpartum behaviour towards offspring.

Transmission of reduced levels of miR-34/449 from sperm to preimplantation embryos is a key step in the transgenerational epigenetic inheritance of the effects of paternal chronic social instability stress

ABSTRACT The transgenerational effects of exposing male mice to chronic social instability (CSI) stress are associated with decreased sperm levels of multiple members of the miR-34/449 family that persist after their mating through preimplantation embryo (PIE) development. Here we demonstrate the importance of these miRNA changes by showing that restoring miR-34c levels in PIEs derived from CSI stressed males prevents elevated anxiety and defective sociability normally found specifically in their adult female offspring. It also restores, at least partially, levels of sperm miR-34/449 normally reduced in their male offspring who transmit these sex-specific traits to their offspring. Strikingly, these experiments also revealed that inducing miR-34c levels in PIEs enhances the expression of its own gene and that of miR-449 in these cells. The same induction of embryo miR-34/449 gene expression likely occurs after sperm-derived miR-34c is introduced into oocytes upon fertilization. Thus, suppression of this miRNA amplification system when sperm miR-34c levels are reduced in CSI stressed mice can explain how a comparable fold-suppression of miR-34/449 levels can be found in PIEs derived from them, despite sperm containing ~50-fold lower levels of these miRNAs than those already present in PIEs. We previously found that men exposed to early life trauma also display reduced sperm levels of miR-34/449. And here we show that miR-34c can also increase the expression of its own gene, and that of miR-449 in human embryonic stem cells, suggesting that human PIEs derived from men with low sperm miR-34/449 levels may also contain this potentially harmful defect.

468. Sex-Dependent Differences in Intra-Hippocampal and Hippocampal-Prefrontal Coherence, Microglial Activation, and Perineuronal Nets Following Chronic Social Instability Stress in Mice

468. Sex-Dependent Differences in Intra-Hippocampal and Hippocampal-Prefrontal Coherence, Microglial Activation, and Perineuronal Nets Following Chronic Social Instability Stress in Mice

The role of sociability in social instability stress: Behavioral, neuroendocrine and monoaminergic effects

Extensive literature has reported a link between social stress and mental health. In this complex relationship, individual strategies for coping with social stress are thought to have a possible modulating effect, with sociability being a key factor. Despite the higher incidence of affective disorders in females and sex-related neurochemical differences, female populations have been understudied. The aim of the present study was, therefore, to analyze the behavioral, neuroendocrine, and neurochemical effects of stress in female OF1 mice, paying special attention to social connectedness (female mice with high vs low sociability). To this end, subjects were exposed to the Chronic Social Instability Stress (CSIS) model for four weeks. Although female mice exposed to CSIS had increased arousal, there was no evidence of depressive-like behavior. Neither did exposure to CSIS affect corticosterone levels, although it did increase the MR/GR ratio by decreasing GR expression. Female mice exposed to CSIS had higher noradrenaline and dopamine levels in the hippocampus and striatum respectively, with a lower monoaminergic turnover, resulting in an increased arousal. CSIS increased serotonin levels in both the hippocampus and striatum. Similarly, CSIS was found to reduce kynurenic acid, 3-HK, and IDO and iNOS enzyme levels in the hippocampus. Interestingly, the observed decrease in IDO synthesis and the increased serotonin and dopamine levels in the striatum were only found in subjects with high sociability. These highly sociable female mice also had significantly lower levels of noradrenaline in the striatum after CSIS application. Overall, our model has produced neuroendocrine and neurochemical but not behavioral changes, so it has not allowed us to study sociability in depth. Therefore, a model that induces both molecular and behavioral phenotypes should be applied to determine the role of sociability.

Wistar-Kyoto rats and chronically stressed Wistar rats present similar depression- and anxiety-like behaviors but different corticosterone and endocannabinoid system modulation

The interplay of social, psychological, and biological stresses can trigger mental health conditions such as major depressive disorder (MDD), adjustment disorder, and posttraumatic stress disorder (PTSD). The endocannabinoid system (ECS), comprising endocannabinoids and cannabinoid receptors, is the critical pathway that mediates responses to stress stimuli. This study aimed to investigate the ECS's impact on responding to chronic social instability stress (SIS). Wistar (WIS) rats and an endogenously depressed rat model, Wistar-Kyoto (WKY), were used to evaluate depression- and anxiety-like behavioral responses, cognitive function, hormone levels, and ECS function. The animals in the stress group (WIS-STS and WKY-STS) were exposed to TMT (predator odor) for 10 mins (two exposures in total: one in light cycle and one in dark cycle) and daily roommate changes (30 days in total), while the control group (CTL) rats were exposed to a sham odor stimulus (distilled water) and did not undergo roommate changes.The results in the open field test suggest that WKY rats had significantly lower locomotor activity than WIS rats. In contrast, WKY rats and chronically stressed WIS rats presented similar depression- and anxiety-like behaviors and impaired cognitive function in the elevated plus maze, forced swimming test, and novel objective recognition test. However, chronic SIS did not exacerbate these behavioral changes in WKY rats. ELISA and Western blot analysis indicated that chronic SIS did not induce further upregulation of endocannabinoids and CB1R downregulation in WKY rats compared to WIS rats. In addition, the Luminex assay revealed that WKY rats showed a higher resilience on the HPA-axis modulation towards chronic SIS, distinguished by the hyperactivity of the HPA-axis modulation in WIS rats.Overall, the study revealed that the chronic SIS animal model (stressed WIS rats) and an animal model of endogenous depression (WKY rats) can generate similar behavioral changes in anxious behavior, behavioral despair, and cognitive impairment. Both animal models present hyperactivity of the ACTH modulation and ECS activity, while WKY rats are more resilient on CORT modulation towards chronic SIS.

Postmenopausal Status Exacerbates Stress-Related Neurological Disorders in Rats

Aims: This study was aimed at assessing the effects of social instability stress (SIS) and immobilization stress (IS) in postmenopausal (PM) conditions. Postmenopause is a physiological state often associated with mild neuronal disorders (NDs) such as anxiety and irritability. The aging of the worldwide population, coupled with multiple stressors, can lead to significant public health concerns, including severe NDs.
 Place and Duration of Study: Tests and analyses were carried out within the confines of the Laboratory of Animal Physiology of the University of Yaoundé I (Cameroon) for 3 months. 
 Study Design: To induce PM syndrome, an 84-day ovariectomized Wistar rat model was used.
 Methodology: Random sampling of 4 groups of 6 rats, each aged between 8 and 10 weeks, was used. SIS and IS were induced during PM installation. Behavioral status, biochemical, and histopathological analyses were carried out.
 Results: SIS combined with IS exacerbates NDs induced by low estrogen levels. Furthermore, ovariectomized stressed rats are more depressed and anxious than the control. They presented severe hippocampal inflammation, oxidative stress, and memory impairment owing to low levels of ACh and reduced neuronal expression in the hippocampus. Overall, PM status makes NDs linked to stress worse in rats.
 Conclusion: Stress promotes oxidative stress, neuroinflammation, and neuronal death, leading to greater affective and cognition disorders when estrogen levels are low. Thus, there is a need to focus on the management of stress during menopausal life.

Female dominance hierarchies influence responses to psychosocial stressors

Social species form dominance hierarchies to ensure survival and promote reproductive success. Traditionally studied in males, rodent hierarchies are considered despotic, and dominant social rank results from a history of winning agonistic encounters. By contrast, female hierarchies are thought to be less despotic, and rank is conferred by intrinsic traits. Both social buffering and elevated social status confer resilience to depression, anxiety, and other consequences of chronic stress. Here, we investigate whether female social hierarchies and individual traits related to social rank likewise influence stress resilience. We observe the formation of dyadic female hierarchies under varying conditions of ambient light and circadian phase and subject mice to two forms of chronic psychosocial stress: social isolation or social instability. We find that stable female hierarchies emerge rapidly in dyads. Individual behavioral and endocrinological traits are characteristic of rank, some of which are circadian phase dependent. Further, female social rank is predicted by behavior and stress status prior to social introduction. Other behavioral characteristics suggest that rank is motivation-based, indicating that female rank identity serves an evolutionarily relevant purpose. Rank is associated with alterations in behavior in response to social instability stress and prolonged social isolation, but the different forms of stress produce disparate rank responses in endocrine status. Histological examination of c-Fos protein expression identified brain regions that respond to social novelty or social reunion following chronic isolation in a rank-specific manner. Collectively, female rank is linked to neurobiology, and hierarchies exert context-specific influence upon stress outcomes.

Chronic social instability stress increases the arousal and alters the inflammatory response in OF1 female mice

Chronic social instability stress increases the arousal and alters the inflammatory response in OF1 female mice

Chronic Social Instability Stress in female mice inoculated with melanoma tumor cells: neurochemical and behavioral effects

Chronic Social Instability Stress in female mice inoculated with melanoma tumor cells: neurochemical and behavioral effects

Acute and long-term sex-dependent effects of social instability stress on anxiety-like and social behaviours in Wistar rats

Adolescence is a critical time of social learning in which both the quantity and quality of social interactions shape adult behavior and social function. During adolescence, social instability such as disrupting or limiting social interactions can lead to negative life-long effects on mental health and well-being in humans. Animal models on social instability are critically important in understanding those underlying neurobiological mechanisms. However, studies in rats using these models have produced partly inconsistent results and can be difficult to generalize. Here we assessed in a sex and age consistent manner the long-term behavioural consequences of social instability stress (SIS - 1-hr daily isolation and change in cage mate between postnatal day (PD30–45)) in Wistar rats. Female and male rats underwent a battery of tests for anxiety-like, exploratory, and social behaviour over five days beginning either in adolescence (PD46) or in adulthood (PD70). Social instability led to reduced anxiety-like behaviour in the elevated plus maze in both sexes in adolescence and in adulthood. Social interactions were also reduced in rats that underwent SIS – an effect that was independent of sex and age when tested. SIS improved social recognition memory in both sexes whereas a sex-dependent effect was seen in the social novelty preference test where male rats that underwent SIS spent more time in social approach toward a novel peer than toward their cage mate. In comparison, control male and female groups did not differ in this test, in time spent with novel versus the cage mate. Thus, overall, social instability stress in Wistar rats altered the behavioural repertoire, with enduring alterations in social behaviour, enhanced exploratory behaviour, and reduced anxiety-like behaviour. In conclusion, the social instability stress paradigm may better be interpreted as a form of enrichment in Wistar rats than as a stressor.

Chronic social instability stress down-regulates IL-10 and up-regulates CX3CR1 in tumor-bearing and non-tumor-bearing female mice

Extensive literature has reported a link between stress and tumor progression, and between both of these factors and mental health. Despite the higher incidence of affective disorders in females and the neurochemical differences according to sex, female populations have been understudied. The aim of this study was therefore to analyze the effect of stress on tumor development in female OF1 mice. For this purpose, subjects were inoculated with B16F10 melanoma cells and exposed to the Chronic Social Instability Stress (CSIS) model. Behavioral, neurochemical and neuroendocrine parameters were analyzed. Female mice exposed to CSIS exhibited reduced body weight and increased arousal, but there was no evidence of depressive behavior or anxiety. Exposure to CSIS did not affect either corticosterone levels or tumor development, although it did provoke an imbalance in cerebral inflammatory cytokines, decreasing IL-10 expression (IL-6/IL-10 and TNF-α/IL-10); chemokines, increasing CX3CR1 expression (CX3CL1/CX3CR1); and glucocorticoid receptors, decreasing GR expression (MR/GR). In contrast, tumor development did not alter body weight and, although it did alter behavior, it did so to a much lesser extent. Tumor inoculation did not affect corticosterone levels, but increased the MR/GR ratio in the hippocampus and provoked an imbalance in cerebral inflammatory cytokines and chemokines, although differently from stress. These results underscore the need for experimental approaches that allow us to take sex differences into account when exploring this issue, since these results appear to indicate that the female response to stress is mediated by mechanisms different from those often proposed in relation to male mice.

Effect of social instability stress in adolescence or adulthood on sensitivity to sucrose concentration in a social context in male and female Long-Evans rats.

Although there is evidence of sex differences in responding to social stress, and that age when stressed matters, females are understudied and adult-stress comparisons are few. Here, we investigated stress effects on reward sensitivity by examining rats' choice of social versus sucrose reward in a continuous spatial allocation design. We predicted social instability stress (SS) in adolescence would result in greater social discounting (spend less time near a novel peer when provided access to sucrose) relative to nonstressed controls (CTLs) and relative to SS in adulthood. All increased sucrose intake as the concentration increased, with no evidence of social discounting. SS males tested soon after the stress had a decrease in intake, whereas those tested long after had an increase in both time near the peer and in intake. CTL and SS females did not differ in intake, although their dose-response curves differed when tested soon after the SS. We also tested whether SS changed the stimulus value of the rat as a social peer; when tested in triads, CTL rats spent similar time in interaction with SS versus CTL rats. In sum, effects of SS on reward sensitivity were greater for males irrespective of administered in adolescence versus adulthood.

Early life social instability stress causes lasting cognitive decrement and elevated hippocampal stress-related gene expression

BackgroundEarly life stress may have profound effects on brain health, yielding both short- and long-term cognitive or psychiatric impairment. Early life Social Instability Stress (SIS) in rodents has been used to model the effects of early chronic human stress. While many studies have assessed acute and short-term responses to this stressor, less attention has been paid to the lasting effects of early life stress in rodents. MethodsThe current study utilized SIS in young mice to assess the impact of early life adversity over the lifespan. Mice were assessed in adulthood between the ages of 18 to 66 weeks for changes in behaviors associated with anxiety, affect, sociability, aggression, motivation, and recognition memory. Additionally, mice were assessed for changes in glucocorticoid level and hippocampal mRNA expression in a subset of genes that display alterations in humans following exposure to stress (CRHR1, CRHR2, FKBP5, SLC6A4). ResultsMice exposed to early SIS showed disrupted memory and increased hippocampal expression of FKBP5, CRHR2 and SLC6A4 mRNA compared to non-stressed mice. Importantly, there was a significant association between increased FKBP5 and CRHR2 with reduced recognition memory. Additionally, mice exposed to SIS showed increased responding on a progressive ratio schedule of reinforcement, indicating that reduction in memory performance was not mediated by decreased effort. ConclusionsEcologically-relevant social stress in mice causes long-term decrements in recognition memory, possibly mediated by persistent changes in moderators of the stress cascade. Additionally, animals exposed to early life stress showed increased motivation for reward, which may contribute to a host of hedonic seeking behaviors throughout life. These data suggest that SIS can be used to evaluate therapeutic interventions to attenuate or reverse lasting effects of early life adversity.

P406. Chronic Adolescent Social Instability Stress Leads to Impaired Recognition Memory and Increased Hippocampal FKBP5 and CRHR2 Expression in Adulthood

Recently published studies indicate that the Covid-19 pandemic has dramatically increased rates of anxiety, depression, and suicide in adolescents and young adults. Human and animal studies strongly indicate that early life stress leads to lasting changes to cognition and psychiatric outcomes, but less is known about how chronic adolescent stress may alter brain function across the lifespan.

Chronic Social Instability Stress in Tumor-Bearing and Non-Tumor-Bearing Female Mice: Protective Effects of Reduced IL-10 and Increased CX3CR1 Expression

Chronic Social Instability Stress in Tumor-Bearing and Non-Tumor-Bearing Female Mice: Protective Effects of Reduced IL-10 and Increased CX3CR1 Expression

Social instability stress in female mice inoculated with melanoma tumor cells: corticosterone levels and anxious-like behavior

Social instability stress in female mice inoculated with melanoma tumor cells: corticosterone levels and anxious-like behavior

Social Instability Stress in Adolescence and Social Interaction in Female Rats

Adolescence is a critical time of brain development for regions governing social behaviour and social learning. Social experiences influence the ongoing maturation of the neural structures and ultimately modify the social behaviour of adults in response to social cues. Social instability stress in adolescence (SS; daily 1-hour isolation + change of cage partner in postnatal days [PND] 30–45) leads to a long-lasting reduction in social interaction in SS rats compared with non-stressed (CTL) rats in males; here we investigate females. In a first experiment, we found that female rats exposed to adolescent SS also showed the decrement in social interaction irrespective of age at which tested, and replicated the effects previously found in males. In experiment 2, which involved females only, SS and CTL rats did not differ in anxiety-like behaviour in the elevated plus maze (EPM) and the reduction in social interaction was not significant. Nevertheless, when tested in adolescence at P47 (and not at P71), SS female rats had higher corticosterone release during the social interaction test than did CTL rats, and they exhibited a different pattern of neural activation as measured by immunoreactivity to the protein products of zif268 and c-fos (SS < CTL in medial prefrontal cortex and SS > CTL in hippocampus), and reduced oxytocin immunoreactivity in the paraventricular nucleus of the hypothalamus than did CTL rats. These results extend our previous findings of effects of SS in adolescent female rats on behavioural responses to psychostimulants to social behaviour, and point to directions for investigations of the neural mechanisms involved.

Venlafaxine reduces the striatal il6/il10 ratio and increases hippocampal GR expression in female mice subjected to chronic social instability stress

Women are twice as likely as men to develop depression and antidepressant treatment is more frequent in females. Moreover, neuroinflammatory changes related to affective disorders differ in accordance with sex. Despite this evidence, female populations have been largely omitted from preclinical experiments studying antidepressants. The aim of this work is to analyze the potential restorative effect of venlafaxine on an animal model of depression. Female CD1 mice were subjected to chronic social instability (CSI) stress for 7 weeks, and were administered venlafaxine during the last 3 weeks of the stress period. Behavioral and physiological parameters were then analyzed. Stressed mice showed a decreased sucrose preference and increased whisking behavior, and had a lower body weight, higher plasma corticosterone levels and increased hypothalamic GR expression. They also had lower levels of 5-HT, 5-HIAA and NA and a higher KYN/TRYP ratio in the hippocampus. Moreover, CSI increased striatal IL-6 mRNA expression levels. Venlafaxine treatment reduced the striatal IL-6/IL-10 ratio and increased hippocampal GR expression, although it did not reverse stress-induced behavioral changes. In conclusion, seven weeks of exposure to CSI produced depressive-like alterations in female mice. The venlafaxine treatment regimen was found to have a modest anti-inflammatory effect in the striatum and increased hippocampal GR mRNA, although it failed to redress stress-induced behavioral disturbances.