Effects Of Chronic Social Defeat Stress Research Articles

Resilience to the effects of social stress on vulnerability to developing drug addiction

We review the still scarce but growing literature on resilience to the effects of social stress on the rewarding properties of drugs of abuse. We define the concept of resilience and how it is applied to the field of drug addiction research. We also describe the internal and external protective factors associated with resilience, such as individual behavioral traits and social support. We then explain the physiological response to stress and how it is modulated by resilience factors. In the subsequent section, we describe the animal models commonly used in the study of resilience to social stress, and we focus on the effects of chronic social defeat (SD), a kind of stress induced by repeated experience of defeat in an agonistic encounter, on different animal behaviors (depression- and anxiety-like behavior, cognitive impairment and addiction-like symptoms). We then summarize the current knowledge on the neurobiological substrates of resilience derived from studies of resilience to the effects of chronic SD stress on depression- and anxiety-related behaviors in rodents. Finally, we focus on the limited studies carried out to explore resilience to the effects of SD stress on the rewarding properties of drugs of abuse, describing the current state of knowledge and suggesting future research directions.

The involvement of oxytocin in the effects of chronic social defeat stress on emotional behaviours in adult female mandarin voles.

Chronic social defeat stress (CSDS) can induce anxiety and depression in male rodents, but the prevalence of anxiety and depression is much higher in females, and effects of CSDS on adult females and its underlying mechanism remain unclear. Oxytocin is a stress-buffering hormone in the brain that modulates the physiological effects of stress. Strikingly, research regarding the effect of oxytocin on emotional changes caused by CSDS is still lacking in females. Thus, we focused on the involvement of the oxytocin system in changes in emotional regulation induced by CSDS in female voles. Seventy-day-old female mandarin voles (Microtus mandarinus) were exposed to aggressive adult females for 14days, and the effects of CSDS on emotion and regulation of oxytocin system were characterized. In addition, we injected vehicle, oxytocin and oxytocin receptor antagonist into the nucleus accumbens (Nacc) of female voles to investigate the involvement of Nacc oxytocin in the effect of CSDS on emotion. Herein, we reported that CSDS increased anxiety and depression-like behaviour and the circulating level of corticosterone, but decreased the number of oxytocin projections and the protein and mRNA expression levels of oxytocin receptor in the Nacc. Injection of oxytocin into the Nacc reversed the effects of CSDS on anxiety-like and depressive-like behaviour, whereas combined injections of oxytocin and oxytocin receptor antagonist eliminated these effects. In conclusion, CSDS increases the levels of anxiety and depression possibly via a reduction in oxytocin projections and the oxytocin receptor level in the Nacc. Nacc oxytocin may be involved in the effects of CSDS on emotional behaviours.

Different effects of chronic social defeat on social behavior and the brain CRF system in adult male C57 mice with different susceptibilities

Chronic social defeat stress (CSDS) has been found to produce different impacts on anxiety-like behaviors, spatial cognitive function and memory in rodents with different susceptibilities. However, the impacts of chronic social defeat on social behaviors in adult male mice with different susceptibilities to social defeat and the underlying mechanisms in the brain remain unclear. In the present study, we found that ten days of social defeat reduced the tendency of susceptible adult male C57 mice to approach an unfamiliar individual and increased their avoidance of an unfamiliar CD-1 mouse but had no effects on resilient individuals. In addition, CSDS enhanced anxiety-like behavior in susceptible animals, but produced no effects in the resilient group. Meanwhile, CSDS increased the number of corticotropin-releasing factor (CRF)-positive neurons in the paraventricular nucleus of the hypothalamus and CRF-R2-positive neurons in the accumbens nucleus shell in both resilient and susceptible animals. CSDS increased the number of CRF-R1-positive neurons and CRF-R1 mRNA expression in the prelimbic cortex (PrL) and the number of CRF-R2-positive neurons in the basolateral amygdala, but reduced the number of CRF-R2-positive neurons and mRNA expression in the PrL in susceptible animals. Therefore, the different effects of CSDS on sociability and anxiety-like behavior in mice with different susceptibilities may be associated with region- and type-specific alterations in CRF receptor levels. These findings help us understand the underlying mechanism by which social stress affects emotion and social behavior and provides an important basis for the treatment of disorders of social and emotional behavior caused by social stress.

The serotonin system in the hippocampus CA3 involves in effects of CSDS on social recognition in adult female mandarin voles (Microtus mandarinus)

Chronic social defeat stress (CSDS) exacerbated the development of stress-related psychiatric disorders, and the social recognition dysfunction is the core feature of many psychiatric disorders. However, the effects of CSDS on female social recognition and the underlying neural mechanisms remain unclear. Using highly aggressive adult female mandarin voles (Microtus mandarinus) as animal model, the aim of this work is to investigate the effects of CSDS on social recognition in adult female rodents and the neurobiological mechanisms underlying these effects. Our results indicate the CSDS disrupted the normal social recognition in adult female voles. Meanwhile, defeated voles exhibited increased neural activity in the DG, CA1 and CA3 of the hippocampus. Furthermore, CSDS reduced levels of serotonin (5-HT) and serotonin 1A receptors (5-HT1AR) in the CA3. We also discovered that microinjection of 8-OH-DPAT into the CA3 effectively reversed the social recognition deficits induced by CSDS, and an infusion of WAY-100635 into the CA3 of control female voles impaired social recognition. Moreover, targeted activation of the 5-HT neuron projection from the DRN to CA3 by long-term administration of CNO significantly prevented the CSDS induced social recognition deficits. Taken together, our study demonstrated that CSDS induced social recognition deficits in adult female voles, and these effects were mediated by the action of 5-HT on the 5-HT1AR in the hippocampus CA3. The projection from the DRN to CA3 may be involved in social recognition deficits induced by CSDS.

Chronic social defeat stress induces sustained synaptic structural changes in the prefrontal cortex and amygdala

Previous studies show that chronic stress induces synaptic structural alterations in brain regions involved in emotional processing such as the prefrontal cortex (PFC) and the basolateral amygdala (BLA). Yet, these studies are based mainly in animal exposure to unpredictable stressors or to restraint stress. On the other hand, studies using the chronic social defeat stress (CSDS), a relevant model of depression based on social conflict, are lacking. Here we aim to study the acute (24 h after CSDS) and long-term (one month after CSDS) effects of CSDS on dendritic and synaptic structures in the PFC and BLA of C57BL/6 mice. Specifically, BLA and PFC dendritic spine densities as well as BLA arborisation were analysed. Subsequently, we investigate in these regions the synaptic response to a friendly (interaction with a same strain mouse) or a fearful (interaction with a dominant strain mouse) social stimulus.Spine densities of the apical dendrites from the PFC pyramidal neurons were decreased by CSDS in the long-term (one month after CSDS). In addition, CSDS increased BLA stellate neurons spine density in the short-term (24 h after CSDS) and dendritic arborisation in the long-term. Moreover, long-term CSDS mice exposed to a fearful stimulus experienced a marked social avoidance and showed a significant increase in the expression of the immature form of the brain derived neurotrophic factor (proBDNF) in the amygdala.Taken together these results suggest the existence of persistent neuronal adaptations in the PFC and BLA in socially defeated mice. Specifically, spine density retraction in the PFC and increased BLA dendritic arborisation could represent an adaptive structural change allowing rapid expression of synaptic markers in response to fearful experiences.

Antidepressant-like effects of tetrahydroxystilbene glucoside in mice: Involvement of BDNF signaling cascade in the hippocampus.

Current antidepressants in clinic need weeks of administration and always have significant limitations. Tetrahydroxystilbene glucoside (TSG) is one of the major bioactive ingredients of Polygonum multiflorum with neuroprotective effects. This study aimed to evaluate the antidepressant effects of TSG in mice. The antidepressant-like effects of TSG in mice were examined in the forced swim test (FST), tail suspension test (TST), and chronic social defeat stress (CSDS) model of depression. The effects of CSDS and TSG on the hippocampal brain-derived neurotrophic factor (BDNF) signaling pathway and neurogenesis were further investigated. Moreover, the pharmacological inhibitors and lentiviral-shRNA were used to explore the antidepressant mechanisms of TSG. TSG produced antidepressant-like effects in the FST and TST and also reversed the CSDS-induced depressive-like symptoms. Moreover, TSG treatment significantly restored the decreased hippocampal BDNF signaling pathway and neurogenesis in CSDS mice. Importantly, blockade of the hippocampal BDNF system fully abolished the antidepressant-like effects of TSG in mice. In conclusion, TSG produces antidepressant-like effects in mice via enhancement of the hippocampal BDNF system.

Inhibitory avoidance learning in CD1 mice: Effects of chronic social defeat stress

Chronic social defeat stress (CSDS) is an animal model widely used to determine the neurobiological mechanisms of stress and its associated pathologies. In this study, the effects of CSDS on inhibitory avoidance (IA) were evaluated in post-pubertal and adult male CD1 mice, instead of the C57BL/6J strain used in the CSDS standard protocol. CSDS consisted of daily 5-min (experiments 1 and 2) or 10-min (experiment 3) agonistic encounters on 21 consecutive days. Twenty four hours after the last session of CSDS, all the mice were tested for IA. They were also evaluated in an elevated plus-maze, obtaining complementary measures of locomotor activity and emotionality. In experiments 1 and 2, IA learning was confirmed in both non-stressed and stressed groups, showing stressed post-pubertal mice higher test latencies than controls. In experiment 3, IA was confirmed in the non-stressed but not in the stressed group. In conclusion, a moderate degree of CSDS (5-min encounters) enhances memory in post-pubertal but not in adult mice, while a high degree (10-min encounters) prevents the memory formation of IA in mice. These effects of CSDS on memory are not secondary to motor or emotional effects of stress. Furthermore, CD1 has been shown to be a valid strain for the stressed mice in the CSDS model.

Chronic social defeat stress disrupts regulation of lipid synthesis

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.