Social Defeat Experience Research Articles

Psychotic Experiences Questionnaire. Part 1

BACKGROUND: The rationale for the concept of psychotic and psychotic-like experiences, delusions and auditory hallucinations, on the basis of which the Psychotic Experiences Questionnaire was developed.
 AIM: The purpose of this study is to present the results of testing and validating of a questionnaire that assesses the severity of psychotic experiences. The study aims to determine the content of the experience at different phases of manifestation, including the phase of psychotic-like experiences, as well as metacognitive appraisals of the experience and its relationship to social anxiety.
 MATERIAL AND METHODS: The sample of 122 respondents includes non-clinical and two clinical groups — with symptoms of the affective spectrum and with symptoms of the psychotic spectrum. To assess the convergent validity of the Questionnaire, the Russian-language Symptom Check List-90-Revised was used. Metacognitive appraisals of psychotic experience and the overall severity of social anxiety (“Social Anxiety and Social Anxiety Disorder Questionnaire”) were measured.
 RESULTS: The structure of the Questionnaire obtained by cluster analysis was verified by confirmatory factor analysis, and optimal agreement between theoretical and empirical models was demonstrated (CFI=0.998; TLI=0.998; SRMR=0.102; RMSEA=0.02; RMSEA p-value=0.986). Three scales and corresponding subscales (six categories) defining the phases of unfolding of psychotic experience were identified. The high reliability and item consistency of the Questionnaire was determined using Cronbach's alpha coefficient. Convergent validity was assessed using Pearson correlation analysis of the questionnaire scales with the SCL scales — psychoticism, paranoid ideation and obsessive-compulsive symptoms; reliable and adequate statistical relationships were obtained. The role of social anxiety and metacognitive appraisals of psychotic experiences in their actualisation and maintenance is shown. The conceptualisation of thought the emergence of intrusions, “voices” as a dialogical embodiment of the internalised experience of social defeat in re-expanded inner speech is presented.
 CONCLUSION: The results of approbation and validation of the questionnaire are presented, and the relationships of the psychotic experiences component with its metacognitive appraisals and social anxiety are described. The concept of psychotic experiences is considered a continuum in which disruptions in the usual controllability of mental processes vary range from mild (objectification of thinking) — to moderate (disturbance of self-perception, intrusive phenomena, including “voices”) — to severe (disturbance of the sense of agency, including command “voices”).

Behavioural traits related with resilience or vulnerability to the development of cocaine-induced conditioned place preference after exposure of female mice to vicarious social defeat

Exposure to stress induced by intermittent repeated social defeat (IRSD) increases vulnerability to the development of cocaine-induced conditioned place preference (CPP) among male mice; however, some defeated mice are resilient to these effects of stress. In the present study we evaluated the effects of vicarious IRSD (VIRSD) in female mice and explored behavioural traits that are potentially predictive of resilience. C57BL/6 female mice (n = 28) were exposed to VIRSD, which consisted of the animals witnessing a short experience of social defeat by a male mouse on postnatal day (PND) 47, 50, 53 and 56. The control group (n = 10) was not exposed to stress. Blood samples were collected on PND 47 and 56 for corticosterone and interleukin-6 determinations. On PND 57–58, female mice performed several behavioural tests (elevated plus maze, hole-board, object recognition, social interaction, TST and splash tests). Three weeks later, the effects of cocaine (1.5 mg/kg) on the CPP paradigm were assessed. VIRSD decreased corticosterone levels (on PND 56), increased interleukin-6 levels, enhanced novelty-seeking, improved recognition memory and induced anxiety- and depression-like symptoms. Control and VIRSD female mice did not acquire CPP, although some stressed individuals with certain behavioural traits - including a high novelty-seeking profile or the development of depression-like behaviour in the splash test shortly after VIRSD - acquired cocaine CPP. Our results confirm that some behavioural traits of female mice are associated with vulnerability or resilience to the long-term effects of social stress on cocaine reward, as previously observed in males.

Chronic social defeat alters behaviors and neuronal activation in the brain of female Mongolian gerbils

Chronic social defeat has been found to be stressful and to affect many aspects of the brain and behaviors in males. However, relatively little is known about its effects on females. In the present study, we examined the effects of repeated social defeat on social approach and anxiety-like behaviors as well as the neuronal activation in the brain of sexually naïve female Mongolian gerbils (Meriones unguiculatus). Our data indicate that repeated social defeats for 20 days reduced social approach and social investigation, but increased risk assessment or vigilance to an unfamiliar conspecific. Such social defeat experience also increased anxiety-like behavior and reduced locomotor activity. Using ΔFosB-immunoreactive (ΔFosB-ir) staining as a marker of neuronal activation in the brain, we found significant elevations by social defeat experience in the density of ΔFosB-ir stained neurons in several brain regions, including the prelimbic (PL) and infralimbic (IL) subnuclei of the prefrontal cortex (PFC), CA1 subfields (CA1) of the hippocampus, central subnuclei of the amygdala (CeA), the paraventricular nucleus (PVN), dorsomedial nucleus (DMH), and ventrolateral subdivision of the ventromedial nucleus (VMHvl) of the hypothalamus. As these brain regions have been implicated in social behaviors and stress responses, our data suggest that the specific patterns of neuronal activation in the brain may relate to the altered social and anxiety-like behaviors following chronic social defeat in female Mongolian gerbils.

The Role of Social Defeat in Neurological differences in Psychotic Patients

IntroductionThe social defeat hypothesis (SDH) suggests that a chronic experience of social defeat increases the likelihood of the development of psychosis. The SDH indicates that a negative experience of exclusion leads to an increase in the baseline activity of the mesolimbic dopamine system (MDS), which in turn leads to the onset of psychosis. Social defeat models have previously been produced using animal models and preclinical literature; however, these theories have not fully been tested in human clinical samples. There have been studies implying changes in brain structure due to social defeat interactions; however, research evidence is varied.ObjectivesThis study aims to uncover whether exposure to SoDe has an impact on brain structure. Furthermore, we hope to understand if these changes are relevant to other mental health disorders.Methods698 (506 no SoDe, 191 SoDe) participants between the ages of 15-41 were recruited from the PRONIA-FP7 study. SoDe was measured from the self-reported questionnaires’ Bullying Scale’ and ‘The Everyday Discrimination Scale’. T1-weighted structural MRI data were processed; five 2 sample t-test analyses were carried out to compare the GMV differences in the entire sample and between the four groups.ResultsThe VBM analysis showed significant group interactions in the right thalamus proper when comparing participants who had experience SoDe to participants who had not experienced SoDe including all 4 groups along with left cerebral white matter differences. In the ROP subgroup, significant group interactions in the left cerebellum white matter were found along with right cerebral white matter, left cerebral white matter and right Thalamus proper.ConclusionsThe findings suggest that there are significant group interactions in thalamus and cerebral white matter. This is in keeping with some previous research suggesting volumetric changes in the thalamus due to stress and psychosis. Similarly for white matter there is some evidence suggesting differences due to SoDe and psychosis. However, there is a scarcity of research in this area with different research suggesting distinctive findings and therefore the evidence is inconclusive. In the ROP group analysis significant group interactions were present in the cerebellum due to SoDe experience. There is research suggesting the cerebellum’s role in multiple different aspects like social interaction, higher-order cognition, working memory, cognitive flexibility, and psychotic symptoms, with every research suggesting multiple different things the role of the cerebellum in SoDe in the ROP population is in question. Nonetheless this large-scale research presents some interesting novel finding and leads the way to a new area of research. Further analysis will explore the relationship between groups on markers of stress (CRP) and neuroinflammation as potential mediation of the environmental effects of SoDe.Disclosure of InterestNone Declared

Migration, perceived discrimination and the development of psychosis

IntroductionMigration is a rapidly growing phenomenon in European countries and its association with psychotic disorders is a public health concern. Psychosis is more prevalent among migrants, which suggests that adverse social experiences play an important role in its pathogenesis. Throughout the migration process, migrants are exposed to several social disadvantages, including in the post-immigration context, where perceived discrimination appears to be an important stressor. In fact, the highest incidence rates of psychosis occur in the most discriminated populations, namely migrants with darker skin complexion, particularly when living in low-ethnic-density neighborhoods, where both discrimination and social isolation are more prominent.ObjectivesTo conduct an updated review about the association between migration, perceived discrimination and psychosis, aiming to better understand the mechanisms involved.MethodsNarrative literature review using the keywords “migration”; “psychosis”; “discrimination”; “racism” on PubMed database, in conjunction with presentation of a clinical case concerning a patient from Guinea-Bissau, admitted to our hospital in the context of first-episode psychosis (FEP), with onset months after completing the Mediterranean migration route to Europe.ResultsLiterature suggests that experiences of racism and social exclusion contribute to feelings of imminent danger, fear and general anxiety, which may develop into paranoid ideas of ubiquitous persecution. Furthermore, intense social defeat experiences, common in migrants, are associated with more distressing forms of delusional content, with delusions of psychological persecution being more common. However, there is also evidence that migrants with FEP have better occupational and social functioning profiles compared to natives, suggesting that, in these patients, there is a higher burden of social-environmental risk factors, with the onset of psychosis occurring only when this burden overcomes a higher threshold. Our patient fits this description. After completing his migratory route and while living in an Italian refugee camp, he described suffering experiences of severe discrimination. Real or not, these experiences escalated to become delusional ideas of persecution involving European governments, thought to seek for his humiliation. Despite the presence of psychotic symptoms, this patient was able to maintain a reasonable level of functioning during years, up to his psychiatric admission.ConclusionsGiven the notorious effect of perceived discrimination and racism on the increased risk of psychosis in immigrants, it is urgent to adopt policies that promote the social protection of these vulnerable groups, namely through enhancing their integration in the host countries.Disclosure of InterestNone Declared

Exploring the associations between dimensions of schizotypy and social defeat

ABSTRACT Background This study investigated relationships between self-reported experiences of social defeat and individual dimensions of self-reported schizotypy. Methods 1632 adults aged between 18 and 79 participated across two non-clinical samples (n = 920, n = 712). Multiple regression analyses tested the relationships between dimensions of schizotypy and social defeat. Results The analyses demonstrated evidence of relationships between increased overall schizotypy and increased social defeat, with schizotypal suspiciousness and disorganised or constrained thought and speech consistently emerging as the two most important individual predictors. Conclusion These results suggest that increased schizotypy is associated with increased social defeat, although the specific relationships may depend on the specific aspects of social defeat and schizotypy being measured. Future research should investigate whether social defeat plays a role in the manifestation of specific schizotypy traits.

Increased rates of social defeat and schizotypy in racial minorities

This study examines the extent to which a measure of multidimensional schizotypy is associated with experiences of social defeat. Based on the social defeat hypothesis of psychosis, which suggests that chronic stressful experiences leading to social defeat increase risk for psychotic-like experiences, we expect that individual differences on a schizotypy measure would be explained by differences in social defeat. We hypothesized that racial and ethnic minorities would report higher rates of schizotypy relative to non-minorities and that social defeat would explain those differences. Participants included a community sample of English-speaking adults ages 18 and older, recruited from online social media platforms (N = 501; M age = 28.06). Demographic information was collected, as well as the Multidimensional Schizotypy Scale–Brief (Kwapil et al., 2018) and the Defeat Scale (Gilbert & Allan, 1998). Analyses revealed that social defeat and schizotypy scores are highly correlated. Examination of group differences revealed that racial and ethnic minorities reported higher rates of schizotypy and higher rates of social defeat than non-minorities. ANCOVA analyses revealed that, after controlling for social defeat scores, racial and ethnic status was no longer significantly associated with schizotypy scores.

Особенности социального поведения мышей после длительного действия психоэмоционального и инфекционного факторов

The behavior of male mice of the inbred C57B/6 strain was investigated after prolonged exposure to two factors ‒ social stress and helminth infection, the combination of which is often observed in humans. Four experimental groups of mice were compared: 1) with a long-lasting experience of social defeats in intermale confrontations (30 days) (SS); 2) infected with O. felineus helminths (6 months) (OF); 3) exposed to both factors (SS + OF); 4) intact mice without influence of any factors (CON). The behavior of all animals was assessed in the open field test with a box placed in it, which was empty for the first 3 min of the test and kept an unfamiliar male of the inbred BALB/c strain for the second 3 min. Social stress had a more pronounced effect on the assessed behavioral parameters of mice in this test than infection. Mice SS were the most active in exploring of the box with an unfamiliar male inside than other animals: they climbed on it much more often and had a longer average time spent near the box. In addition, they had increased exploratory (number of wall rearings) and grooming (the number and duration) activities. Behavior of infected OF mice did not differ from CON one in both the first and the second 3 min of the test. In mice with a combined effect of factors (SS + OF), non-social forms of behavior also did not differ from the control indices, and the reaction to an unfamiliar male in the box was weaker than in mice SS. It was concluded that long-lasting experience of social defeats in intermale confrontations has a more pronounced effect on the social and non-social behavior in mice, compared with chronic infection of animals with O. felineus helminths. Moreover, the combination of two influencing factors promotes to the decreasing of social interest in mice.

Co-expression of glutamatergic and autism-related genes in the hippocampus of male mice with disturbances of social behavior

В настоящее время существует представление о вовлеченности глутаматергической системы (ГГ) в механизмы развития аутизма. В предыдущих исследованиях нами было показано, что негативный социальный опыт, приобретенный в ежедневных межсамцовых конфронтациях, приводит к нарушениям в социальном поведении: снижению коммуникативности, нарушению социализации, появлению стереотипных форм поведения, которые могут рассматриваться как симптомы аутистического спектра. В связи с этим целью нашей работы было изучение с помощью транскриптомного анализа изменений экспрессии генов, кодирующих белки, вовлеченные в функционирование глутаматергической системы, и генов, связанных с патологией аутизма (ГА), в гиппокампе. В эксперименте использовали животных с нарушениями социального поведения, вызванными повторным опытом социальных побед или поражений в ежедневных агонистических взаимодействиях. Для формирования групп животных с контрастными типами поведения использовали модель сенсорного контакта (хронического социального стресса). Полученные образцы мозга были секвенированы в ЗАО «Геноаналитика» (http://genoanalytica.ru/, Россия, Москва). Транскриптомный анализ показал, что у агрессивных животных снижается экспрессия генов Shank3, Auts2, Ctnnd2, Nrxn2, для которых показано участие в развитии аутизма, а также глутаматергического гена Grm4. В то же время у животных с негативным социальным опытом экспрессия ГА Shank2, Nlgn2, Ptcdh10, Reln, Arx возрастает. При этом ГГ (Grik3, Grm2, Grm4, Slc17a7, Slc1a4, Slc25a22), за исключением гена Grin2a, повышают свою экспрессию. Корреляционный анализ выявил статистически значимую взаимосвязь из- мененной экспрессии ГГ и ГА. Полученные результаты, с одной стороны, могут служить подтверждением участия ГГ в патофизиологии развития симптомов аутистического спектра, с другой – свидетельствовать о коэкспрессии ГГ и ГА в гиппокампе, развивающейся под влиянием социальной среды. Так как большинство ГА, изменивших экспрессию в настоящем исследовании, являются генами, связанными с клеточным скелетом и внеклеточным матриксом, в частности участвующими в формировании синапсов, а ГГ, изменившие свою экспрессию, – генами, кодирующими субъединицы рецепторов, то можно предположить, что вовлечение ГГ в патофизиологию аутизма происходит на уровне рецепторов.

Social defeat stress: Mechanisms underlying the increase in rewarding effects of drugs of abuse.

Social interaction is known to be the main source of stress in human beings, which explains the translational importance of this research in animals. Evidence reported over the last decade has revealed that, when exposed to social defeat experiences (brief episodes of social confrontations during adolescence and adulthood), the rodent brain undergoes remodeling and functional modifications, which in turn lead to an increase in the rewarding and reinstating effects of different drugs of abuse. The mechanisms by which social stress cause changes in the brain and behavior are unknown, and so the objective of this review is to contemplate how social defeat stress induces long-lasting consequences that modify the reward system. First of all, we will describe the most characteristic results of the short- and long-term consequences of social defeat stress on the rewarding effects of drugs of abuse such as psychostimulants and alcohol. Secondly, and throughout the review, we will carefully assess the neurobiological mechanisms underlying these effects, including changes in the dopaminergic system, corticotrophin releasing factor signaling, epigenetic modifications and the neuroinflammatory response. To conclude, we will consider the advantages and disadvantages and the translational value of the social defeat stress model, and will discuss challenges and future directions.

Dominance relationships in Syrian hamsters modulate neuroendocrine and behavioral responses to social stress

Stress is a well-known risk factor for psychopathology and rodent models of social defeat have strong face, etiological, construct and predictive validity for these conditions. Syrian hamsters are highly aggressive and territorial, but after an acute social defeat experience they become submissive and no longer defend their home territory, even from a smaller, non-aggressive intruder. This defeat-induced change in social behavior is called conditioned defeat (CD). We have shown that dominant hamsters show increased neural activity in the ventromedial prefrontal cortex (vmPFC) following social defeat stress and exhibit a reduced CD response at social interaction testing compared to subordinates. Although the vmPFC can inhibit the neuroendocrine stress response, it is unknown whether dominants and subordinates differ in stress-induced activity of the extended hypothalamic-pituitary-adrenal (HPA) axis. Here, we show that, following acute social defeat, dominants exhibit decreased submissive and defensive behavior compared to subordinates but do not differ from subordinates or social status controls (SSCs) in defeat-induced cortisol concentrations. Furthermore, both dominants and SSCs show greater corticotropin-releasing hormone (CRH) mRNA expression in the basolateral/central amygdala compared to subordinates, while there was no effect of social status on CRH mRNA expression in the paraventricular nucleus of the hypothalamus or bed nucleus of the stria terminalis. Overall, status-dependent differences in the CD response do not appear linked to changes in stress-induced cortisol concentrations or CRH gene expression, which is consistent with the view that stress resilience is not a lack of a physiological stress response but the addition of stress coping mechanisms.Lay summaryDominant hamsters show resistance to the behavioral effects of acute social defeat compared to subordinates, but it is unclear whether social status modulates the neuroendocrine stress response in Syrian hamsters. This study indicates that dominant social status does not alter stress-induced activity of the extended hypothalamic-pituitary-adrenal (HPA) axis, which suggests that the ability of dominants to cope with social defeat stress is not associated with changes in their neuroendocrine stress response.

Voluntary exercise increases resilience to social defeat stress in Syrian hamsters

Exposure to social stressors can cause profound changes in an individual's well-being and can be an underlying factor in the etiology of a variety of psychopathologies, such as post-traumatic stress disorder (PTSD). In Syrian hamsters, a single social defeat experience results in behavioral changes collectively known as conditioned defeat (CD), and includes an abolishment of territorial aggression and the emergence of high levels of defensive behaviors. In contrast, voluntary exercise has been shown to promote stress resilience and can also have anxiolytic-like effects. Although several studies have investigated the resilience-inducing effects of voluntary exercise after exposure to physical stressors, such as restraint and electric shock, few studies have examined whether exercise can impart resilience in response to ethologically-based stressors, such as social defeat. In Experiment 1, we tested the hypothesis that voluntary exercise can have anxiolytic-like effects in socially defeated hamsters. In the elevated plus maze, the exercise group exhibited a significant reduction in risk assessment, a commonly used index of anxiety, compared to the no-exercise group. In the open-field test, animals in the exercise group exhibited a significant reduction in locomotor behavior and rearing, also an indication of an anxiolytic-like effect of exercise. In Experiment 2, we examined whether exercise can reverse the defeat-induced potentiation of defensive behaviors using the CD model. Socially defeated hamsters in the exercise group exhibited significantly lower levels of defensive/submissive behaviors compared to the no-exercise group upon exposure to the resident aggressor. Taken together, these results are among the first to suggest that voluntary exercise may promote resilience to social defeat stress in Syrian hamsters.

Escalated cocaine "binges" in rats: enduring effects of social defeat stress or intra-VTA CRF.

Exposure to intermittent social defeat stress elicits corticotropin releasing factor (CRF) release into the VTA and induces long-term modulation of mesocorticolimbic dopamine activity in rats. These adaptations are associated with an intense cocaine-taking phenotype, which is prevented by CRF receptor antagonists. The present studies examine whether infusion of CRF into the VTA is sufficient to escalate cocaine-taking behavior, in the absence of social defeat experience. Additionally, we aimed to characterize changes in cocaine valuation that may promote binge-like cocaine intake. Male Long-Evans rats were microinjected into the VTA with CRF (50 or 500ng/side), vehicle, or subjected to social defeat stress, intermittently over 10days. Animals were then trained to self-administer IV cocaine (FR5). Economic demand for cocaine was evaluated using a within-session behavioral-economics threshold procedure, which was followed by a 24-h extended access "binge." Rats that experienced social defeat or received intra-VTA CRF microinfusions (50ng) both took significantly more cocaine than controls over the 24-h binge but showed distinct patterns of intake. Behavioral economic analysis revealed that individual demand for cocaine strongly predicts binge-like consumption, and demand elasticity (i.e. α) is augmented by intra-VTA CRF, but not by social defeat. The effects of CRF on cocaine-taking were also prevented by intra-VTA pretreatment with CP376395, but not Astressin-2B. Repeated infusion of CRF into the VTA persistently alters cocaine valuation and intensifies binge-like drug intake in a CRF-R1-dependent manner. Conversely, the persistent pattern of cocaine bingeing induced by social defeat stress may suggest impaired inhibitory control, independent of reward valuation.

Learning shapes the aversion and reward responses of lateral habenula neurons.

The lateral habenula (LHb) is believed to encode negative motivational values. It remains unknown how LHb neurons respond to various stressors and how learning shapes their responses. Here, we used fiber-photometry and electrophysiology to track LHb neuronal activity in freely-behaving mice. Bitterness, pain, and social attack by aggressors intensively excite LHb neurons. Aversive Pavlovian conditioning induced activation by the aversion-predicting cue in a few trials. The experience of social defeat also conditioned excitatory responses to previously neutral social stimuli. In contrast, fiber photometry and single-unit recordings revealed that sucrose reward inhibited LHb neurons and often produced excitatory rebound. It required prolonged conditioning and high reward probability to induce inhibition by reward-predicting cues. Therefore, LHb neurons can bidirectionally process a diverse array of aversive and reward signals. Importantly, their responses are dynamically shaped by learning, suggesting that the LHb participates in experience-dependent selection of behavioral responses to stressors and rewards.

Prior treadmill exercise promotes resilience to vicarious trauma in rats

BackgroundPost-traumatic stress disorder (PTSD) is a serious psychological condition, which can develop both from physically experiencing and also from witnessing traumatic events. There is evidence that physical exercise can have a positive impact on the symptoms of PTSD. Relevant to this, in our previous pre-clinical work, beneficial effects of treadmill exercise were reported on PTSD-like behaviors in a social defeat paradigm, a rat model of direct physical trauma. However, the role of exercise on vicariously acquired PTSD-like phenotype was not examined. ObjectiveIn this study, we utilized a rodent PTSD model, which mimics both the physical as well as the witness experience of trauma, and examined the impact of moderate treadmill exercise in mitigating vicariously acquired PTSD-like behaviors in rats. MethodsOur PTSD model is a modified social defeat paradigm, which involves aggressive encounters between a large Long-Evans male rat (resident) and a smaller Sprague-Dawley male rat (intruder), resulting in intruder social defeat. The cage mate of the intruder is positioned to witness intruder defeat. Rats were grouped as control (CON), social defeat (SD), exercise (EX), trauma witness (TW), and exercise prior to trauma witness (EX-TW). After acclimatization for 7days, the exercised groups were subjected to a daily 30-min treadmill exercise regimen for 14days. On day 21, the SD group was exposed for 7days of social defeat, while the TW groups witnessed social defeat. On days 28–34, behavioral and cognitive tests including short-term (STM) and long-term (LTM) memory function, anxiety- and depression-like behaviors were conducted. ResultsTW and SD rats demonstrated the highest levels of anxiety- and depression-like behaviors, while EX-TW rats did not exhibit anxiety- and depression-like behaviors. TW and SD rats showed no impairments in STM. However, TW and SD rats showed impairments in LTM, and exercise rescued LTM impairments in EX-TW rats. ConclusionsThis study demonstrates that rats subjected to direct experience or witness of social defeat exhibited PTSD-like behaviors, while moderate treadmill exercise prevented trauma witness-induced behavioral impairments. These studies have important translational value suggesting that prior treadmill exercise might provide resilience to stressful stimuli and perhaps mitigate the witnessing effects of traumatic events.

The recovery trajectory of adolescent social defeat stress-induced behavioral, (1)H-MRS metabolites and myelin changes in Balb/c mice.

Adolescent exposure to social stress precipitates emotion-related disorders and affects the development and function of medial prefrontal cortex (mPFC). However, this adversity-induced behavioral and neurological changes remain not fully explored. Adolescent Balb/c mice were subjected to intermittent social defeat stress during postnatal days 28 to 42. Proton magnetic resonance spectroscopy (1H-MRS) measurements, behavioral tests and immunohistochemistry were performed one day or 3 weeks after the last stress episode. Defeated mice exhibited hypoactivity and social avoidance with the latter lasting into the early adulthood, while the anxiety level was unchanged. Social defeat experience lead to temporary decreases in the levels of total creatines (Cr + pCr) and Glx (Glu + Gln), but a delayed increase of N- acetylaspartate (NAA) levels. These alternations were accompanied with a persistent reduction of myelin basic protein expression although the number of mature oligodendrocyte did not change. These findings provide evidence that adolescent adverse social experience permanently impairs the emotion-related behavioral performance and induces biochemical and molecular changes in the brain which at least lasts into early adulthood, thus enhancing our understanding of the neurobiology of social defeat stress. Our finding also implicates that NAA signals on MRS may reflect myelin status.

Immediate post-defeat infusions of the noradrenergic receptor antagonist propranolol impair the consolidation of conditioned defeat in male Syrian hamsters

Social defeat occurs when an animal is attacked and subjugated by an aggressive conspecific. Following social defeat, male Syrian hamsters fail to display species-typical territorial aggression and instead exhibit submissive or defensive behaviors even when in the presence of a non-aggressive intruder. We have termed this phenomenon conditioned defeat (CD). The mechanisms underlying CD are not fully understood, but data from our lab suggest that at least some of the mechanisms are similar to those that mediate classical fear conditioning. The goal of the present experiment was to test the hypothesis that noradrenergic signaling promotes the consolidation of CD, as in classical fear conditioning, by determining whether CD is disrupted by post-training blockade of noradrenergic activity. In Experiment 1, we determined whether systemic infusions of the noradrenergic receptor antagonist propranolol (0, 1.0, 10, or 20mg/kg) given immediately after a 15min defeat by a resident aggressor would impair CD tested 48h later. Hamsters that were given immediate post-training infusions of propranolol (1.0, but not 10 or 20mg/kg) showed significantly less submissive behavior than did those given vehicle infusions supporting the hypothesis that there is noradrenergic modulation of the consolidation of a social defeat experience. In Experiment 2, we demonstrated that propranolol (1.0mg/kg) given immediately, but not 4 or 24h, after defeat impaired CD tested 48h after defeat indicating that the window within which the memory for social defeat is susceptible to beta-adrenergic modulation is temporary. In Experiment 3, we examined whether central blockade of noradrenergic receptors could recapitulate the effect of systemic injections by giving an intracerebroventricular infusion of propranolol immediately after defeat and examining the effect on CD 24h later. Centrally administered propranolol (20μg/3μl but not 2μg/3μl) was also effective in dose-dependently reducing consolidation of CD. Collectively, the present results indicate that noradrenergic activity promotes the consolidation of CD and suggest that CD is a valuable model to study the processes by which emotion and stress modulate memory in an ethologically relevant context. These data also suggest that the popular conception in the clinical literature that the anxiolytic effect of propranolol is primarily due to the drug's peripheral effects may need to be reconsidered.

Social defeat predicts paranoid appraisals in people at high risk for psychosis

BackgroundThe experience of social defeat may increase the risk of developing psychotic symptoms and psychotic disorders. We studied the relationship between social defeat and paranoid appraisal in people at high risk for psychosis in an experimental social environment created using Virtual Reality (VR). MethodWe recruited UHR (N=64) participants and healthy volunteers (N=43). Regression analysis was used to investigate which baseline measures predicted paranoid appraisals during the VR experience. ResultsAt baseline, UHR subjects reported significantly higher levels of social defeat than controls (OR=.957, (CI) .941–.973, p<.000). Following exposure to the VR social environment, the UHR group reported significantly more paranoid appraisals than the controls (p<.000). Within the UHR sample, paranoid appraisals were predicted by the level of social defeat at baseline, as well as by the severity of positive psychotic and disorganised symptoms. ConclusionIn people who are at high risk of psychosis, a history of social defeat is associated with an increased likelihood of making paranoid appraisals of social interactions. This is consistent with the notion that social defeat increases the risk of developing psychosis.

Phenotypic responses to social defeat are associated with differences in cued and contextual fear discrimination

Conflict among individuals is one of the most common forms of stressors experienced across a variety of species, including humans. Social defeat models in mice produce two phenotypic behavioral responses characterized by prolonged social avoidance (susceptibility) or continued social interaction (resistance). The resistant phenotype has been proposed as a model of resilience to chronic stress-induced depression in humans. Previously, we have found that mice that are resistant to social defeat stress display significant impairments in extinction learning and retention, suggesting that continued social interaction following the experience of social defeat may be associated with maladaptive fear responses. Here, we examined how individual differences in response to social defeat may be related to differences in cued and context fear discrimination. Following defeat, resistant mice showed increased fear to a neutral cued stimulus (CS−) compared to control and susceptible mice, but were still able to significantly discriminate between the CS+ and CS−. Likewise, both phenotypes were generally able to discriminate between the training context and neutral context at all retention intervals tested (1, 5, 14 days). However, susceptible mice displayed significantly better discrimination compared to resistant and non-defeated control mice when assessing the discrimination ratio. Thus, at a time when most animals begin exhibiting generalization to contextual cues, susceptible mice retain the ability to discriminate between fearful and neutral contexts. These data suggest that the differences observed in context and cued discrimination between susceptible and resistant mice may be related to differences in their coping strategies in response to social defeat. In particular, resistance or resilience to social defeat as traditionally characterized may be associated with altered inhibitory learning. Understanding why individual differences arise in response to stress, including social confrontation is important in understanding the development and treatment of stress related pathologies such as PTSD.

Hyperactivity and Abnormal Exploratory Activity Developing in CD-1 Male Mice under Chronic Experience of Aggression and Social Defeats

Chronic social defeat stress induces diverse effects in mice of different strains and even in animals of the same strain. This paper aims to study the effect of repeated social defeats and, for contrast, repeated aggression in daily agonistic interactions on the behaviors of CD-1 male mice. The behavior of animals that have the same winning and losing track record during 3, 10, 21 days is studied in different tests. The level of aggressiveness, as estimated by the number and total time of attacks, decreases; nevertheless, direct and indirect forms of aggression demonstrated by the aggressive mice (winners) remain significantly high. The number of stereotypic behaviors (rotations and jumps) and total time of digging behaviors are significantly increased in the winners after 21 days compared to 3 and 10 days of intermale confrontations. Among the losers, chronic experience of social defeats is accompanied by the development of pronounced anxiety and a depression-like state estimated by the elevated plus-maze and the Porsolt test scores, respectively. Both groups of male mice with alternative social behaviors demonstrate abnormal locomotor and exploratory behaviors in the open-field test. This phenomenon may be viewed as hyperactivity developed under chronic agonistic interactions and specific for the outbred CD-1 mice. We believe that these animals may be potentially used for modeling the key symptoms of bipolar disorder.