Social Avoidance Behavior Research Articles

Effect of the dietary intake of fish oil on psycho-social behavioral disorder caused by social-defeat stress

Exposure to psychosocial stress is a risk factor for human diseases such as depression. Social defeat stress (SDS) is a well-known rodent model of human psychosocial stress, and animals exposed to SDS show social avoidance behavior. Fish oil, which is rich in docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), is expected to decrease the risk of depressive disorders. In this study, we determined whether fish oil affects the social behavior of SDS-exposed mice and measured serotonin levels and expression of genes related to tryptophan (TRP) metabolism in the hippocampus. The experimental animals were fed a diet containing fish oil during SDS exposure. For the fish oil treatment, experimental mice were fed a diet containing fish oil at low (L-FO), middle (M-FO), and high (H-FO) concentrations. The control group was supplemented with an equivalent amount of canola oil (no fish oil: N-FO). After the SDS protocol, we performed a social interaction test and assessed the sociality of experimental mice. In the N-FO group, SDS-exposed mice showed negative social interactions compared with non-stressed mice. The L-FO and H-FO groups showed negative social interactions after SDS exposure; however, the M-FO group did not exhibit negative social behavior. The serotonin levels of SDS-exposed mice were lower than those of non-stressed mice in the N-FO group. In contrast with these results in the N-FO group, there was no difference in serotonin levels between SDS-exposed and non-stressed mice in the FO groups. In addition, the expression of genes related to TRP metabolism in SDS-exposed mice increased in the N-FO group, but not in the FO group. These results suggest that fish oil improves the psychosocial behavioral disorders caused by SDS. This improvement could be explained by the increase in serotonin synthesis in the hippocampus.

Personal socio-cultural preferences modulate neural correlates of decisions to socialize with powerful persons.

Social power differences fundamentally shape the behavioral interaction dynamics of groups and societies. While it has long been recognized that individual socio‐cultural preferences mitigate social interactions involving persons of power, there is limited empirical data on the underlying neural correlates. To bridge this gap, we asked university student participants to decide whether they were willing to engage in social activities involving their teachers (higher power status), classmates (equal power status), or themselves (control) while functional brain images were acquired. Questionnaires assessed participants' preferences for power distance, uncertainty avoidance, and cultural intelligence. As expected, participants generally accepted more social interactions with classmates than teachers. Also, left inferior frontal activity was higher when accepting than when rejecting social interactions with teachers. Critically, power distance preferences further modulated right lateral frontoparietal activity contrasting approach relative to avoidance decisions towards teachers. In addition, uncertainty avoidance modulated activity in medial frontal, precuneus, and left supramarginal areas distinguishing approach decisions towards teachers relative to classmates. Cultural intelligence modulated neural responses to classmate approach/avoidance decisions in anterior cingulate and left parietal areas. Overall, functional activities in distinct brain networks reflected different personal socio‐cultural preferences despite observed social decisions to interact with others of differential power status. Such findings highlight that social approach or avoidance behaviors towards powerful persons involves differential subjective neural processes possibly involved in computing implicit social utility.

The BDNF-TrkB Pathway Acts Through Nucleus Accumbens D2 Expressing Neurons to Mediate Stress Susceptible Outcomes.

Brain-derived neurotrophic factor (BDNF) has a critical role in stress response including neuropsychiatric disorders that are precipitated by stress, such as major depressive disorder (MDD). BDNF acts through its full-length BDNF receptor tyrosine kinase B (TrkB) to trigger a pro-plasticity effect. In contrast, the truncated isoform of the BDNF receptor (TrkB.t1) triggers an anti-plasticity effect. In stress outcomes, BDNF acting in the hippocampus has a stress resilience effect, and, inversely, in the nucleus accumbens (NAc), BDNF acts as a stress susceptible molecule. It is unknown if BDNF-TrkB acts on a specific NAc projection neuron, i.e., medium spiny neuron (MSN or spiny projection neuron), a subtype in stress outcomes. To determine this, we performed chronic social or vicarious witness defeat stress (CSDS or CWDS) in mice expressing TrkB.t1 in dopamine receptor 1 or 2 containing MSNs (D1- or D2-MSNs). Our results showed that TrkB.t1 overexpression in NAc D2-MSNs prevented the CSDS-induced social avoidance or other stress susceptible behaviors in male and female mice. We further showed that this overexpression in D2-MSNs blocked stress susceptible behavior induced by intra-NAc BDNF infusion. In contrast, our results demonstrate that overexpression of TrkB.t1 on NAc D1-MSNs facilitates the SDS susceptible behaviors. Our study provides enhanced details into the NAc cell subtype role of BDNF-TrkB signaling in stress outcomes.

Fear of illness & virus evaluation (FIVE) COVID-19 scales for children-parent/caregiver-report development and validation

ObjectiveCommonly-used youth anxiety measures may not comprehensively capture fears, worries, and experiences related to the pervasive impact of the COVID-19 pandemic. This study described the development of the Fear of Illness and Virus Evaluation (FIVE) scales and validated the caregiver-report version. MethodAfter initial development, feedback was obtained from clinicians and researchers, who provided suggestions on item content/wording, reviewed edits, and provided support for the updated FIVE’s content and face validity. Factor structure, measurement invariance, and psychometric properties were analyzed using data from a multi-site, longitudinal study of COVID-19-related effects on family functioning with 1599 caregivers from the United States and Canada. ResultsConfirmatory factor analyses indicated a hierarchical five-factor structure best fit the data, resulting in a 31-item measure with four lower-order subscales: (1) Fears about Contamination and Illness; (2) Fears about Social Distancing, (3) Avoidance Behaviors, and (4) Mitigation Behaviors, and a higher-order factor, (5) Total Fears, indicated by the two fear-related lower-order subscales. Measurement invariance by country of residence, child age, and child sex was found. All subscales demonstrated strong internal consistency, appropriate item-scale discrimination, and no floor or ceiling effects. The Total Fears subscale demonstrated appropriate test-retest reliability. Concurrent validity supported by strong correlation with a youth anxiety measure. DiscussionThe FIVE provides a psychometrically-sound measure of COVID-19-related fears and behaviors in youth in a caregiver-report format. Future research is necessary to evaluate correlates and longitudinal symptom patterns captured by the FIVE caregiver-report, as well as the validity and reliability of a youth self-report version of the FIVE.

Prefrontal-amygdalar oscillations related to social behavior in mice

The medial prefrontal cortex and amygdala are involved in the regulation of social behavior and associated with psychiatric diseases but their detailed neurophysiological mechanisms at a network level remain unclear. We recorded local field potentials (LFPs) from the dorsal medial prefrontal cortex (dmPFC) and basolateral amygdala (BLA) while male mice engaged on social behavior. We found that in wild-type mice, both the dmPFC and BLA increased 4-7 Hz oscillation power and decreased 30-60 Hz power when they needed to attend to another target mouse. In mouse models with reduced social interactions, dmPFC 4-7 Hz power further increased especially when they exhibited social avoidance behavior. In contrast, dmPFC and BLA decreased 4-7 Hz power when wild-type mice socially approached a target mouse. Frequency-specific optogenetic manipulations replicating social approach-related LFP patterns restored social interaction behavior in socially deficient mice. These results demonstrate a neurophysiological substrate of the prefrontal cortex and amygdala related to social behavior and provide a unified pathophysiological understanding of neuronal population dynamics underlying social behavioral deficits.

Motivations for the Practice of Self-Care Measures Applicable to Mitigate COVID-19 Pandemic

Objective: To identify relevant factors influencing the practice of self-care measures for prevention of the ongoing COVID-19 preventions based on prior evidence-based experiences. Method: We conducted a literature review of empirical studies conducted between the years 2000 and 2020 focusing on self-care measures in a pandemic situation. Result: Of the 250 studies identified, 19 studies met inclusion criteria. Sixty-three percent of the eligible studies reported handwashing, 21% reported social distancing, facemask wearing, 11% reported social avoidance and information-seeking behaviour. The identified factors motivating these practices include risk perception, health education and social trust. Conclusion: We found that public health agencies commonly recommend self-care measures during pandemics. The adherence to them depends on individuals' perception of risk, knowledge about the situation, trust in the government agencies providing the recommendations and empathy that can motivate adherence. Practice Implication: The public, researchers, and policymakers could learn from the past and present situation to understand what measures are proven relevant and what factors could motivate adherence. More emphasis could be placed on the role of individuals in health promotion and disease prevention as they have been proven to be helpful.

Molecular and neural basis of pleasant touch sensation

Pleasant touch provides emotional and psychological support that helps mitigate social isolation and stress. However, the underlying mechanisms remain poorly understood. Using a pleasant touch-conditioned place preference (PT-CPP) test, we show that genetic ablation of spinal excitatory interneurons expressing prokineticin receptor 2 (PROKR2), or its ligand PROK2 in sensory neurons, abolishes PT-CPP without impairing pain and itch behaviors in mice. Mutant mice display profound impairments in stress response and prosocial behaviors. Moreover, PROKR2 neurons respond most vigorously to gentle stroking and encode reward value. Collectively, we identify PROK2 as a long-sought neuropeptide that encodes and transmits pleasant touch to spinal PROKR2 neurons. These findings may have important implications for elucidating mechanisms by which pleasant touch deprivation contributes to social avoidance behavior and mental disorders.

Taurine Alleviates Chronic Social Defeat Stress-Induced Depression by Protecting Cortical Neurons from Dendritic Spine Loss

Abnormal amino acid metabolism in neural cells is involved in the occurrence and development of major depressive disorder. Taurine is an important amino acid required for brain development. Here, microdialysis combined with metabonomic analysis revealed that the level of taurine in the extracellular fluid of the cerebral medial prefrontal cortex (mPFC) was significantly reduced in mice with chronic social defeat stress (CSDS)-induced depression. Therefore, taurine supplementation may be usable an intervention for depression. We found that taurine supplementation effectively rescued immobility time during a tail suspension assay and improved social avoidance behaviors in CSDS mice. Moreover, taurine treatment protected CSDS mice from impairments in dendritic complexity, spine density, and the proportions of different types of spines. The expression of N-methyl d-aspartate receptor subunit 2A, an important synaptic receptor, was largely restored in the mPFC of these mice after taurine supplementation. These results demonstrated that taurine exerted an antidepressive effect by protecting cortical neurons from dendritic spine loss and synaptic protein deficits.

Sağlık Çalışanlarının Covid-19 Bilgi Düzeyinin Pandemi Sırasında Sosyal Yakınlık ve Riskten Kaçınma Davranışlarına Etkisi

Healthcare professionals struggle with disease on the front lines by risking their lives in all pandemics. The main purpose of this study is to determine the effect of the COVID-19 knowledge level of employees on social closeness and risk avoidance behaviors during the pandemic. A hospital-based cross-sectional research design was used in the study. The research universe consisted of all healthcare professionals of two public hospitals providing secondary care in Ankara. The convenience sampling method was preferred in the survey. The total number of questionnaires evaluated and used to analyze the data is 521. It has been determined that the direct causal effect of the COVID-19 knowledge level of health professionals on risk avoidance behaviors is positive and 0.29 units. In comparison, the direct causal effect on the social closeness behaviors is positive and 0.17 units. In addition, a significant relationship was found between female gender and risk avoidance behavior. The level of knowledge experienced among healthcare professionals during the COVID-19 epidemic increases their tendency to show risk avoidance and social closeness behaviors.

Low-intensity focused ultrasound stimulation reverses social avoidance behavior in mice experiencing social defeat stress.

The excitatory neurons of the medial prefrontal cortex (mPFC) respond to social stimuli. However, little is known about how the neural activity is altered during social avoidance, and whether it could act as a target of low-intensity focused ultrasound stimulation (LIFUS) to rescue social deficits. The present study aimed to investigate the mechanisms of neuronal activities and inflammatory responses underlying the effect of LIFUS on social avoidance. We found that chronic LIFUS stimulation can effectively improve social avoidance in the defeated mice. Calcium imaging recordings by fiber photometry in the defeated mice showed inhibited ensemble activity during social behaviors. LIFUS instantaneously triggered the mPFC neuronal activities, and chronic LIFUS significantly enhanced their neuronal excitation related to social interactions. We further found that the excessive activation of microglial cells and the overexpression of the inflammation signaling, i.e. Toll-like receptors(TLR4)/nuclear factor-kappaB(NF-КB), in mPFC were significantly inhibited by LIFUS. These results suggest that the LIFUS may inhibit social avoidance behavior by reducing activation of the inflammatory response, increasing neuronal excitation, and protecting the integrity of the neuronal structure in the mPFC. Our findings raised the possibility of LIFUS being applied as novel neuromodulation for social avoidance treatment in neuropsychiatric diseases.

Acute administration of fluoxetine increases social avoidance and risk assessment behaviors in a sex- and social stress-dependent manner in Syrian hamsters (Mesocricetus auratus)

Most studies investigating the effects of acute administration of selective serotonin reuptake inhibitors (SSRI) on responses to social stress have been conducted with males. This is despite the fact that SSRIs remain the primary pharmacotherapy for social stress-related disorders for both sexes and that the prevalence of these disorders is twofold higher in women than in men. To determine whether acute treatment with the SSRI, fluoxetine, alters behavioral responses to social defeat stress in a sex- or social stress-dependent manner, male and female Syrian hamsters were subjected to one of three social defeat conditions: no defeat (placed into an empty resident aggressor (RA) cage), a single defeat by one RA for 15 min, or three consecutive defeats using different RAs for 5 min each. The day following social defeat, subjects were infused with either vehicle or fluoxetine (20 mg/kg, I.P.) 2 h prior to a 5 min social avoidance test. Overall, we found that fluoxetine increased social vigilance regardless of sex or defeat condition. We also found that fluoxetine affected social avoidance in a sex by stress intensity interaction, such that fluoxetine increased avoidance in no defeat males and in males defeated once but significantly increased avoidance in females only after three defeats. These data suggest that treatment with an SSRI could initially exacerbate the effects of social stress in both sexes. These data also emphasize the importance of including sex as a biological variable when investigating the efficacy of pharmacotherapy for stress-related disorders.

Inactivation of Zona Incerta Blocks Social Conditioned Place Aversion and Modulates Post-traumatic Stress Disorder-Like Behaviors in Mice.

Zona incerta (ZI), a largely inhibitory subthalamic region connected with many brain areas, has been suggested to serve as an integrative node for modulation of behaviors and physiological states, such as fear memory conditioning and aversion responses. It is, however, unclear whether ZI regulated the repeated social defeat stress (RSDS)-induced social conditioned place aversion (CPA) and post-traumatic stress disorder (PTSD)-like behaviors. In this study, the function of ZI was silenced via bilateral injection of tetanus toxin light chain (Tet-tox), a neurotoxin that completely blocks the evoked synaptic transmissions, expressing adeno-associated viruses (AAVs). We found ZI silencing: (1) significantly blocked the expression of RSDS-induced social CPA with no effect on the innate preference; (2) significantly enhanced the anxiety level in mice experienced RSDS with no effect on the locomotion activity; (3) altered the PTSD-associated behaviors, including the promotion of spatial cognitive impairment and the preventions of PPI deficit and social avoidance behavior. These effects were not observed on non-stressed mice. In summary, our results suggest the important role of ZI in modulating RSDS-induced social CPA and PTSD-like behaviors.

Chronic Social Defeat During Adolescence Induces Short- and Long-Term Behavioral and Neuroendocrine Effects in Male Swiss-Webster Mice.

Chronic stress exposure during adolescence is a significant risk factor for the development of depression. Chronic social defeat (CSD) in rodents is an animal model of depression with excellent ethological, predictive, discriminative, and face validity. Because the CSD model has not been thoroughly examined as a model of stress-induced depression within the adolescence stage, the present study analyzed the short- and long-term behavioral and neuroendocrine effects of CSD during early adolescence. Therefore, adolescent male Swiss-Webster (SW) mice were exposed to the CSD model from postnatal day (PND) 28 to PND37. Twenty-four hours (mid-adolescence) or 4 weeks (early adulthood) later, mice were tested in two models of depression; the social interaction test (SIT) and forced swimming test (FST); cognitive deficits were evaluated in the Barnes maze (BM). Finally, corticosterone and testosterone content was measured before, during, and after CSD exposure, and serotonin transporter (SERT) autoradiography was studied after CSD in adolescent and adult mice. CSD during early adolescence induced enduring depression-like behaviors as inferred from increased social avoidance and immobility behavior in the SIT and FST, respectively, which correlated in an age-dependent manner with SERT binding in the hippocampus; CSD during early adolescence also induced long-lasting learning and memory impairments in the Barnes maze (BM). Finally, CSD during early adolescence increased serum corticosterone levels in mid-adolescence and early adulthood and delayed the expected increase in serum testosterone levels observed at this age. In conclusion: (1) CSD during early adolescence induced long-lasting depression-like behaviors, (2) sensitivity of SERT density during normal brain development was revealed, (3) CSD during early adolescence induced enduring cognitive deficits, and (4) results highlight the vulnerability of the adolescent brain to social stressors on the adrenal and gonadal axes, which emphasizes the importance of an adequate interaction between both axes during adolescence for normal development of brain and behavior.

Ginsenoside Rb1 Produces Antidepressant-Like Effects in a Chronic Social Defeat Stress Model of Depression Through the BDNF–Trkb Signaling Pathway

Ginsenoside Rb1 (Rb1), an important bioactive ingredient of Panax ginseng, has potent neuroprotective effects. The objective of the study is to elucidate the impact of Rb1 treatment on chronic social defeat stress (CSDS)–induced depressive-like behaviors and its related mechanism. According to the obtained results, the daily oral administration of Rb1 (35 and 70 mg/kg) and imipramine (15 mg/kg) for 28 days significantly reversed the social avoidance behavior, anhedonia, and behavioral despair via CSDS exposure, as demonstrated by the considerable elevation in the time in the zone in the social interaction test, consumption of sucrose solution in the sucrose preference test, and decrease in immobility time in the forced swim test. Moreover, Rb1 obviously restored the CSDS-induced decrease in the BDNF signaling pathway and hippocampal neurogenesis. Rb1 significantly increased the hippocampal levels of ERK, AKT, and CREB phosphorylation and increased the number of DCX+ cells in DG. Importantly, the antidepressant effects of Rb1 were completely blocked in mice by using K252a (the nonselective tyrosine kinase B inhibitor). In conclusion, our results indicated that Rb1 exerts promising antidepressant-like effects in mice with CSDS-induced depression, and its effects were facilitated by enhancing the BDNF signaling cascade and upregulation of hippocampal neurogenesis.

Electroacupuncture improves repeated social defeat stress-elicited social avoidance and anxiety-like behaviors by reducing Lipocalin-2 in the hippocampus

BackgroundPost-traumatic stress disorder (PTSD) is a trauma-related disorder that is associated with pro-inflammatory activation and neurobiological impairments in the brain and leads to a series of affective-like behaviors. Electroacupuncture (EA) has been proposed as a clinically useful therapy for several brain diseases. However, the potential role of EA treatment in PTSD and its molecular and cellular mechanisms has rarely been investigated.MethodsWe used an established preclinical social defeat stress mouse model to study whether EA treatment modulates PTSD-like symptoms and understand its underlying mechanisms. To this end, male C57BL/6 mice were subjected to repeated social defeat stress (RSDS) for 6 consecutive days to induce symptoms of PTSD and treated with EA at Baihui (GV 20) and Dazhui (GV 14) acupoints.ResultsThe stimulation of EA, but not needle insertion at Baihui (GV 20) and Dazhui (GV 14) acupoints effectively improved PTSD-like behaviors such as, social avoidance and anxiety-like behaviors. However, EA stimulation at the bilateral Tianzong (SI11) acupoints did not affect the PTSD-like behaviors obtained by RSDS. EA stimulation also markedly inhibited astrocyte activation in both the dorsal and ventral hippocampi of RSDS-treated mice. Using next-generation sequencing analysis, our results showed that EA stimulation attenuated RSDS-enhanced lipocalin 2 expression in the hippocampus. Importantly, using double-staining immunofluorescence, we observed that the increased lipocalin 2 expression in astrocytes by RSDS was also reduced by EA stimulation. In addition, intracerebroventricular injection of mouse recombinant lipocalin 2 protein in the lateral ventricles provoked social avoidance, anxiety-like behaviors, and the activation of astrocytes in the hippocampus. Interestingly, the overexpression of lipocalin 2 in the brain also altered the expression of stress-related genes, including monoamine oxidase A, monoamine oxidase B, mineralocorticoid receptor, and glucocorticoid receptor in the hippocampus.ConclusionsThis study suggests that the treatment of EA at Baihui (GV 20) and Dazhui (GV 14) acupoints improves RSDS-induced social avoidance, anxiety-like behaviors, astrocyte activation, and lipocalin 2 expression. Furthermore, our findings also indicate that lipocalin 2 expression in the brain may be an important biomarker for the development of PTSD-related symptoms.

Subchronic and mild social defeat stress downregulates peripheral expression of sweet and umami taste receptors in male mice

Depression is associated with taste disorders; however, the mechanisms by which mental stress affects taste perception are not well understood. This study aimed to elucidate the effects of psychosocial stress on peripheral taste-sensing systems using a mouse depression model. Male mice were subjected to subchronic and mild social defeat stress (sCSDS). Results showed that sCSDS significantly increased body weight, food and water intake, and social avoidance behavior and that sCSDS did not change reward-seeking behavior on sucrose preference but tended to decrease pheromonal preference for female urine. Furthermore, sCSDS downregulated the mRNA levels of sweet and umami taste receptor subunits, i.e., sweet taste receptor type 1 members 2 and 3 (T1R2 and T1R3), but not the umami taste receptor subunit, i.e., taste receptor type 1 member 1 (T1R1), in the circumvallate papillae of mice. It is known that sucrose preference is mediated by the gut–brain axis without taste perception; thus, it was considered that sCSDS affected the peripheral taste-sensing systems, rather than the central reward systems, which mediate sucrose preference. This is the first study to report that psychosocial stress affects peripheral sweet and umami taste-sensing systems.

Association of Increased Amygdala Activity with Stress-Induced Anxiety but not Social Avoidance Behavior in Mice.

Chronic stress leads to many psychiatric disorders, including social and anxiety disorders that are associated with over-activation of neurons in the basolateral amygdala (BLA). However, not all individuals develop psychiatric diseases, many showing considerable resilience against stress exposure. Whether BLA neuronal activity is involved in regulating an individual's vulnerability to stress remains elusive. In this study, using a mouse model of chronic social defeat stress (CSDS), we divided the mice into susceptible and resilient subgroups based on their social interaction behavior. Using in vivo fiber photometry and in vitro patch-clamp recording, we showed that CSDS persistently (after 20 days of recovery from stress) increased BLA neuronal activity in all the mice regardless of their susceptible or resilient nature, although impaired social interaction behavior was only observed in susceptible mice. Increased anxiety-like behavior, on the other hand, was evident in both groups. Notably, the CSDS-induced increase of BLA neuronal activity correlated well with the heightened anxiety-like but not the social avoidance behavior in mice. These findings provide new insight to our understanding of the role of neuronal activity in the amygdala in mediating stress-related psychiatric disorders.

The enhancing effects of testosterone in exposure treatment for social anxiety disorder: a randomized proof-of-concept trial

Individuals with a social anxiety disorder (SAD) show hypofunctioning of the hypothalamus–pituitary-gonadal (HPG) axis, which is linked to social fear and avoidance behavior. As testosterone administration has been shown to facilitate social-approach behavior in this population, it may enhance the effectiveness of exposure treatment. In this proof-of-concept study, we performed a randomized clinical assay in which 55 women diagnosed with SAD received two exposure therapy sessions. Session 1 was supplemented with either testosterone (0.50 mg) or placebo. Next, transfer effects of testosterone augmentation on within-session subjective fear responses and SAD symptom severity were assessed during a second, unenhanced exposure session (session 2) and at a 1-month follow-up, respectively. The participants having received testosterone showed a more reactive fear pattern, with higher peaks and steeper reductions in fear levels in session 2. Post-hoc exploration of moderating effects of endogenous testosterone levels, revealed that this pattern was specific for women with high basal testosterone, both in the augmented and in the transfer session. In contrast, the participants with low endogenous testosterone showed reduced peak fear levels throughout session 1, again with transfer to the unenhanced session. Testosterone did not significantly affect self-reported anxiety. The effects of testosterone supplementation on fear levels show transfer to non-enhanced exposure, with effects being modulated by endogenous testosterone. These first preliminary results indicate that testosterone may act on important fear mechanisms during exposure, providing the empirical groundwork for further exploration of multi-session testosterone-enhanced exposure treatment for SAD.

Juvenile social defeat stress exposure favors in later onset of irritable bowel syndrome-like symptoms in male mice

Irritable bowel syndrome (IBS) is the most common functional gastrointestinal disorder. Traumatic stress during adolescence increases the risk of IBS in adults. The aim of this study was to characterize the juvenile social defeat stress (SDS)-associated IBS model in mice. Juvenile mice were exposed to an aggressor mouse for 10 min once daily for 10 consecutive days. Behavioral tests, visceral sensitivity, immune responses, and fecal bacteria in the colon were evaluated in 5 weeks after SDS exposure. Social avoidance, anxiety- and depression-like behavior, and visceral hypersensitivity were observed. Juvenile SDS exposure significantly increased the number of 5-HT-containing cells and calcitonin gene-related peptide-positive neurons in the colon. The gut microbiota was largely similar between the control and juvenile SDS groups. The alterations in fecal pellet output, bead expulsion time, plasma corticosterone concentration, and colonic 5-HT content in response to restraint stress were exacerbated in the juvenile SDS group compared with the control group. The combination of juvenile SDS and restraint stress increased the noradrenaline metabolite 3-Methoxy-4-hydroxyphenylglycol (MHPG) content and MHPG/noradrenaline ratio in the amygdala when compared with restraint stress in control mice. These results suggest that juvenile SDS exposure results in later onset of IBS-like symptoms.

Alterations in circulating extracellular vesicles underlie social stress-induced behaviors in mice.

Chronic stress induces peripheral and intracerebral immune changes and inflammation, contributing to neuropathology and behavioral abnormalities relevant to psychiatric disorders such as depression. Although the pathological implication of many peripheral factors such as pro‐inflammatory cytokines, hormones, and macrophages has been demonstrated, the roles of circulating extracellular vesicles (EVs) for chronic stress mechanisms remain poorly investigated. Here, we report that chronic social defeat stress (CSDS)‐induced social avoidance phenotype, assessed by a previously untested three‐chamber social approach test, can be distinguished by multiple pro‐inflammatory cytokines and EV‐associated molecular signatures in the blood. We found that the expression patterns of miRNAs distinguished the CSDS‐susceptible mice from the CSDS‐resilient mice. Social avoidance behavior scores were also estimated with good accuracy by the expression patterns of multiple EV‐associated miRNAs. We also demonstrated that EVs enriched from the CSDS‐susceptible mouse sera upregulated the production of pro‐inflammatory cytokines in the LPS‐stimulated microglia‐like cell lines. Our results indicate the role of circulating EVs and associated miRNAs in CSDS susceptibility, which may be related to pro‐inflammatory mechanisms underlying stress‐induced neurobehavioral outcomes.