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Psychological stress affects the neuroendocrine regulation, which modulates mental status and behaviors. Melatonin, a hormone synthesized primarily by the pineal gland, regulates many brain functions, including circadian rhythms, pain, sleep, and mood. Selective pharmacological melatonin agonist ramelteon has been clinically used to treat mood and sleep disorders. Posttraumatic stress disorder (PTSD) is a psychiatric condition associated with severe trauma; it is generally triggered by traumatic events, which lead to severe anxiety and uncontrollable trauma recall. We recently reported that repeated social defeat stress (RSDS) may induce robust anxiety-like behaviors and social avoidance in mice. In the present study, we investigated whether melatonin receptor activation by melatonin and ramelteon regulates RSDS-induced behavioral changes. Melatonin treatment improved social avoidance and anxiety-like behaviors in RSDS mice. Moreover, treatment of the non-selective MT 1 /MT 2 receptor agonist, ramelteon, markedly ameliorated RSDS-induced social avoidance and anxiety-like behaviors. Moreover, activating melatonin receptors also balanced the expression of monoamine oxidases, glucocorticoid receptors, and endogenous antioxidants in the hippocampus. Taken together, our findings indicate that the activation of both melatonin and ramelteon regulates RSDS-induced anxiety-like behaviors and PTSD symptoms. The current study also showed that the regulatory effects of neuroendocrine mechanisms and cognitive behaviors on melatonin receptor activation in repeated social defeat stress., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

Humans and animals live in social relationships shaped by actions of approach and avoidance. Both are crucial for normal physical and mental development, survival, and well-being. Active withdrawal from social interaction is often induced by the perception of threat or unpleasant social experience and relies on adaptive mechanisms within neuronal networks associated with social behavior. In case of confrontation with overly strong or persistent stressors and/or dispositions of the affected individual, maladaptive processes in the neuronal circuitries and its associated transmitters and modulators lead to pathological social avoidance. This review focuses on active, fear-driven social avoidance, affected circuits within the mesocorticolimbic system and associated regions and a selection of molecular modulators that promise translational potential. A comprehensive review of human research in this field is followed by a reflection on animal studies that offer a broader and often more detailed range of analytical methodologies. Finally, we take a critical look at challenges that could be addressed in future translational research on fear-driven social avoidance.

The use of animal models for behavioral and pharmaceutical testing is employed in many different fields of research but often relies solely on male animals. When females are included, the existing literature frequently offers inconsistent results regarding the effects of sex and/or estrous cycle on anxiety-like behaviors. Our current study sought to establish baseline or normative behaviors in three commonly employed tests of anxiety-like behavior, and determine any sex or cycle differences. Anxiety-like behaviors in male and naturally-cycling female Sprague-Dawley rats were assessed using elevated plus maze, open field, and a social interaction/avoidance paradigm. Female rats were examined once daily to determine their stage of estrous. Results from the elevated plus maze but not the open field showed that female rats spent significantly more time in open areas than did male rats; however, there was no effect of estrous cycle stage. The social avoidance test revealed that female rats spent significantly more time in the interaction zone with an empty wire mesh cage (novel object), but there was no sex difference in time spent with an age- and sex- matched target rat. Females often exhibited greater locomotion as compared to males in social and non-social tests, but this was not related to primary anxiety measures in these tests. Overall, our findings indicate that outcomes differ in tests of anxiety-like behaviors, highlighting sex differences in the expression of anxiety-like behaviors that depend on the test employed. Importantly, the lack of estrous cycle effects suggest that for these anxiety-based tests, female Sprague-Dawley rats could be collapsed across the cycle phases to facilitate the inclusion of females in future behavioral experiments., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The goal of the present study was to empirically examine different conceptual mechanisms previously postulated to underlie the development of social avoidance in childhood. Participants were N = 601 children (321 boys, 280 girls) attending elementary schools (M age  = 10.21 years) and middle schools (M age  = 12.77 years) in Shanghai, P.R. China. Measures of motivations for social withdrawal (shyness, unsociability, social avoidance) and socio-emotional adjustment were collected using self-reports and peer nominations at two time-points separated by 9 months. Results from cross-lagged panel analyses indicated that: (1) social avoidance and symptoms of social anxiety were not reciprocally related over time; (2) Time 1 social avoidance predicted incremental change in Time 2 peer problems (whereas Time 1 peer problems did not predict incremental change in Time 2 social avoidance); and (3) Time 1 symptoms of depression significantly predicted incremental change in Time 2 social avoidance (whereas Time 1 social avoidance did not predict incremental change in Time 2 symptoms of depression). These results provide evidence in support of depressive symptoms (but not symptoms of social anxiety or peer problems) as a salient predictor of social avoidance. Results are discussed in terms of the development and implications of social avoidance in Chinese culture.

Background: Interleukin-6 (IL-6) is elevated in circulation with chronic stress and may contribute to neurobehavioral complications. We have reported that repeated social defeat stress in mice caused recruitment of proinflammatory monocytes to the brain and triggered the onset of anxiety-like behavior. Therefore, the purpose of this study was to determine the role of IL-6 signaling in the peripheral immune response, neuroinflammation, and anxiety following stress., Methods: Wild-type and IL-6 knockout mice were subjected to repeated social defeat, and immune and behavioral parameters were determined 14 hours later., Results: Although monocyte release and recruitment to the brain during stress were maintained in the IL-6 knockout mice, anxiety and social avoidance were prevented. NanoString analysis of fluorescence-activated cell-sorted blood monocytes (CD11b + /Ly6C hi ) and brain monocytes (CD11b + /CD45 hi ) revealed a unique pattern of immune-related gene expression that was dependent on stress and IL-6. For instance, blood monocytes after stress had a transcriptional signature and immune profile consistent with priming, which was attenuated in monocytes from IL-6 knockout stress mice. Moreover, the monocytes recruited to the brain and associated with the development of anxiety had a transcriptional signature (enhanced IL-1β, CD14, Mmp9, Myd88, Ager, and Stat3) that was dependent on IL-6., Conclusions: Here, we show the effects of IL-6 on the transcriptional signature of monocytes in circulation and brain after stress. Overall, robust increases in IL-6 after stress induced a primed profile in monocytes that were recruited to the brain and propagated IL-1-mediated inflammation and anxiety., (Copyright © 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

In order to relieve anxiety and depression accompanying stress, physicians resort to tricyclic antidepressants, such as imipramine. We had previously shown that imipramine reversed stress-induced social avoidance behavior, and down-regulated microglial activation 24days after stress cessation. To further characterize the effects of imipramine on stress induced neuroimmune dysregulation and associated changes in behavior, the aims of this study were to determine if imipramine 1) ameliorated stress-induced inflammation in the periphery and central nervous system, and 2) prevented stress related anxiety- and depressive-like behaviors. C57BL/6 mice were treated with imipramine (15mg/kg) in their drinking water, and exposed to repeated social defeat (RSD). Imipramine attenuated stress-induced corticosterone and IL-6 responses in plasma. Imipramine decreased the percentage of monocytes and granulocytes in the bone marrow and circulation. However, imipramine did not prevent splenomegaly, stress-related increased percentage of granulocytes in this organ, and the production of pro-inflammatory cytokines in the spleen, following RSD. Moreover, imipramine abrogated the accumulation of macrophages in the brain in mice exposed to RSD. Imipramine blocked neuroinflammatory signaling and prevented stress-related anxiety- and depressive-like behaviors. These data support the notion that pharmacomodulation of the monoaminergic system, besides exerting anxiolytic and antidepressant effects, may have therapeutic effects as a neuroimmunomodulator during stress., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: Psychosocial stress is associated with altered immunity, anxiety, and depression. Repeated social defeat (RSD), a model of social stress, triggers egress of inflammatory myeloid progenitor cells (MPCs; CD11b(+)/Ly6C(hi)) that traffic to the brain, promoting anxiety-like behavior. In parallel, RSD enhances neuroinflammatory signaling and long-lasting social avoidant behavior. Lorazepam and clonazepam are routinely prescribed anxiolytics that act by enhancing GABAergic activity in the brain. Besides binding to the central benzodiazepine binding site (CBBS) in the central nervous system (CNS), lorazepam binds to the translocator protein (TSPO) with high affinity causing immunomodulation. Clonazepam targets the CBBS and has low affinity for the TSPO. Here the aims were to determine if lorazepam and clonazepam would: (1) prevent stress-induced peripheral and central inflammatory responses, and (2) block anxiety and social avoidance behavior in mice subjected to RSD., Methods: C57/BL6 mice were divided into experimental groups, and treated with either lorazepam (0.10mg/kg), clonazepam (0.25mg/kg) or vehicle (0.9% NaCl). Behavioral data and tissues were collected the morning after the last cycle of RSD., Results: Lorazepam and clonazepam were effective in attenuating mRNA expression of CRH in the hypothalamus and corticosterone in plasma in mice subjected to RSD. Both drugs blocked stress-induced levels of IL-6 in plasma. Lorazepam and clonazepam had different effects on stress-induced enhancement of myelopoiesis and inhibited trafficking of monocytes and granulocytes in circulation. Furthermore, lorazepam, but not clonazepam, inhibited splenomegaly and the production of pro-inflammatory cytokines in the spleen following RSD. Additionally, lorazepam and clonazepam, blocked stress-induced accumulation of macrophages (CD11b(+)/CD45(high)) in the CNS. In a similar manner, both lorazepam and clonazepam prevented neuroinflammatory signaling and reversed anxiety-like and depressive-like behavior in mice exposed to RSD., Conclusion: These data support the notion that lorazepam and clonazepam, aside from exerting anxiolytic and antidepressant effects, may have therapeutic potential as neuroimmunomodulators during psychosocial stress. The reversal of RSD-induced behavioral outcomes may be due to the enhancement of GABAergic neurotransmission, or some other off-target effect. The peripheral actions of lorazepam, but not clonazepam, seem to be mediated by TSPO activation., (Copyright © 2015 Elsevier Inc. All rights reserved.)

In the present study, we examined the profile of psychiatric symptoms in boys with fragile X syndrome (FXS) using a parent report instrument. In addition, by comparing boys with FXS to boys with nonsyndromic autism spectrum disorder (ASD) utilizing multiple matching strategies, we examined between-group differences in the types of psychiatric symptoms observed and in the strength of their concurrent associations. Across all matching strategies, symptoms of manic/hyperactive behaviors and general anxiety were more frequently reported for boys with FXS than for boys with nonsyndromic ASD. Results also indicated a positive association between social avoidance and general anxiety in FXS that was stronger than that observed in nonsyndromic ASD across all matching strategies. Theoretical and treatment implications are discussed., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Psoriasis is an autoimmune skin disease that often co‐occurs with psychological morbidities such as anxiety and depression, and psychosocial issues also lead psoriasis patients to avoid other people. However, the precise mechanism underlying the comorbidity of psoriasis and anxiety is unknown. Also, whether the social avoidance phenomenon seen in human patients also exists in psoriasis‐like animal models remains unknown. In the present study, anxiety‐like behaviours and social avoidance‐like behaviours were observed in an imiquimod‐induced psoriasis‐like C57‐BL6 mouse model along with typical psoriasis‐like dermatitis and itch‐like behaviours. The 11.7T resting‐state functional magnetic resonance imaging showed differences in brain regions between the model and control group, and voxel‐based morphometry showed that the grey matter volume changed in the basal forebrain region, anterior commissure intrabulbar and striatum in the psoriasis‐like mice. Seed‐based resting state functional connectivity analysis revealed connectivity changes in the amygdala, periaqueductal gray, raphe nuclei and lateral septum. We conclude that the imiquimod‐induced psoriasis‐like C57‐BL6 mouse model is well suited for mechanistic studies and for performing preclinical therapeutic trials for treating anxiety and pathological social avoidance in psoriasis patients. [ABSTRACT FROM AUTHOR]

Background: A chronic social defeat stress (CSDS) model has been proposed as relevant to stress-induced behavioral change in humans. In this study, we examined the effect of Korean Red Ginseng (KRG) on CSDS-induced mood disorders and protein expression in an animal model. Methods: To evaluate the effect of KRG on social defeat stress, test mice were exposed in the resident aggressor's home cage compartment for 14 days beginning 1 h after KRG treatment (10, 20, and 40 mg/kg, per oral (p.o.)). After the exposure, behavioral tests to measure anxiety, social interaction, and depression-like behavior were performed. To investigate the underlying mechanism, N-methyl-D-aspartate receptor expression levels in CSDS-induced mice were evaluated using Western blot analysis. Results: CSDS induced anxiety-like behaviors by decreasing central activity in the open-field test and open-arm approach in the elevated plus maze test and led to social avoidance behavior in the social interaction test. CSDS mice showed upregulated NR1, NR2A, and NR2B expression in the hippocampus. KRG 20 and 40 mg/kg ameliorated anxiety-like activities and KRG 20 mg/kg alleviated social avoidance by decreasing time in the corner zone. KRG treatment recovered CSDS-induced NR1, NR2A, and NR2B protein levels in the hippocampus. Conclusion: These results indicate that KRG has a therapeutic effect on CSDS-induced mood disorder by alleviating N-methyl-D-aspartate receptor overexpression in the hippocampus.

• The relationship between intergroup contact experiences and social distancing of migrant people from majority group. • The poisoning effect of negative on the beneficial effect of positive contact of migrant people. • The stronger mediating role of anxiety compared to symbolic and stereotype threat on the effects of intergroup contact. • Positive and negative intergroup contact effects were consistent across two different countries, Italy and Turkey. This research investigates the relationship between different valence contact of migrants with native people and their motivation to avoid further interactions with the majority group, as a preventing factor of adaptation by either side. Specifically, the joint and differential effects of positive and negative contact of migrants with natives on outgroup avoidance were addressed by examining also the mediating role of affective variables such as stereotype threat, symbolic threat and anxiety. Hypotheses were tested on two samples of African immigrants in Italy and Syrian immigrants in Turkey. Positive contact was not associated with outgroup avoidance and anxiety among African respondents who reported higher negative contact with natives. This evidence was not found among Syrian immigrants. In both samples, however, the moderating role of negative contact was found on stereotype threat. Across the two samples, anxiety was the strongest mediator of the relationship between negative contact of migrants on their avoidance of the majority group. Overall, the evidence we gathered furthers knowledge of the impact of negative intergroup contact on preventing migrant social integration. [ABSTRACT FROM AUTHOR]

Objective: Individuals who experience heightened rejection sensitivity (RS) are at greater risk of increased internalizing symptoms over time. This is especially so for adolescents and young adults, as this is a time of many social transitions and an average increase in such symptoms. Yet, little longitudinal research has explored specific mechanisms that may help explain how RS lends itself to increased symptomology during adolescence and young adulthood. In this study, we tested the summative effect of emotion dysregulation, expressive suppression, and social avoidance (i.e., ER-deficits) as mechanisms. Moreover, we estimated bidirectional temporal associations between ER-deficits and symptoms.Method: Participants included 402 adolescents and young adults aged 17 to 27 years (M = 19.9 years, 66% female) who completed two assessments over a 1-year period.Results: In a path model, participants who reported more RS increased in anxious symptoms, and RS was indirectly associated with increased anxious and depressive symptoms via the three ER-deficits. Additionally, cross-lagged panel analyses showed that dysregulation and suppression predicted increased symptoms over time, while anxious symptoms predicted increased social avoidance over time.Conclusion: These findings expand understanding of the role of RS in young people's increasing internalizing symptoms, implicating ER-deficits in these processes. [ABSTRACT FROM AUTHOR]

Cognitive behavioural therapy (CBT) is considered to be an effective treatment for internet gaming disorder (IGD). This study examined the effectiveness of CBT in treating impulsivity, anxiety, avoidance, and family and environmental problems in patients. A total of 101 patients completed the CBT programme, and 104 completed the supportive therapy. The CBT programme consisted of fourteen 90‐min sessions with one therapist and four to five patients, once or twice a week. The supportive therapy group visited a psychiatric outpatient department once or twice a week until they completed 14 visits. Outcomes were measured in terms of improvement in IGD, psychological symptoms, and social interaction. The CBT group (improvement: 67 [66.3%] versus non‐improvement: 34 [33.7%]) showed more improvement in IGD compared with the supportive therapy group. The CBT group also showed a greater decrease in internet addiction, anxiety, impulsivity, and social avoidance. In the CBT group, among patients who improved, the greatest improvements were in internet addiction, attention, depression, anxiety, impulsivity, social avoidance, and family cohesion. Our CBT programme may be more effective than supportive therapy with regard to improvement in IGD symptoms by controlling anxiety, impulsivity, and social avoidance. In addition, CBT‐related improvements in patients with IGD could be enhanced by controlling anxiety, social avoidance, and family cohesion. [ABSTRACT FROM AUTHOR]

Objective: Autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and anxiety are three of the most common childhood psychiatric disorders. Early trajectories of social avoidance have been linked with these psychiatric disorders in previous studies, but it remains unclear how social avoidance differentially predicts comorbid disorders in a high-risk genetic subgroup. Here, we delineate the association between trajectories of social avoidance from infancy and subsequent ASD, ADHD, and anxiety outcomes at preschool in children with fragile X syndrome (FXS), a well-characterized single-gene disorder highly associated with social avoidance as well as elevated rates of ASD, ADHD, and anxiety.Method: Males with FXS (n = 78) aged 4–62 months participated in a longitudinal study resulting in 201 assessments. The Social Avoidance Scale (SAS) documented socially avoidant behaviors from infancy in three domains—physical movement, facial expression, and eye contact during both the first minute and the last hour of an interaction. ASD, ADHD, and anxiety symptom outcomes at preschool were measured via parent-report questionnaires.Results: Increased social avoidance across infancy and preschool predicted elevated ASD symptom severity but reduced ADHD and anxiety symptom severity in males with FXS.Conclusion: ASD, ADHD, and anxiety symptoms relate inconsistently to social avoidance behaviors, providing new insight toward the debate of independence or overlap among these disorders in FXS and other disorders (i.e., ASD). The results suggest that the nuanced profile of the developmental and temporal aspects of social avoidance may inform more the accuracy of differential diagnoses of comorbid psychiatric disorders in FXS.

Objective: Autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and anxiety are three of the most common childhood psychiatric disorders. Early trajectories of social avoidance have been linked with these psychiatric disorders in previous studies, but it remains unclear how social avoidance differentially predicts comorbid disorders in a high-risk genetic subgroup. Here, we delineate the association between trajectories of social avoidance from infancy and subsequent ASD, ADHD, and anxiety outcomes at preschool in children with fragile X syndrome (FXS), a well-characterized single-gene disorder highly associated with social avoidance as well as elevated rates of ASD, ADHD, and anxiety. Method: Males with FXS (n = 78) aged 4–62 months participated in a longitudinal study resulting in 201 assessments. The Social Avoidance Scale (SAS) documented socially avoidant behaviors from infancy in three domains—physical movement, facial expression, and eye contact during both the first minute and the last hour of an interaction. ASD, ADHD, and anxiety symptom outcomes at preschool were measured via parent-report questionnaires. Results: Increased social avoidance across infancy and preschool predicted elevated ASD symptom severity but reduced ADHD and anxiety symptom severity in males with FXS. Conclusion: ASD, ADHD, and anxiety symptoms relate inconsistently to social avoidance behaviors, providing new insight toward the debate of independence or overlap among these disorders in FXS and other disorders (i.e., ASD). The results suggest that the nuanced profile of the developmental and temporal aspects of social avoidance may inform more the accuracy of differential diagnoses of comorbid psychiatric disorders in FXS. [ABSTRACT FROM AUTHOR]

Abstract Aims Psychosocial stress is a form of mental stress associated with human relationships that underlies the pathogenesis of mental disorders such as depression. Previous studies have suggested that intake of energy-dense foods, also known as "palatable foods," can relieve psychosocial stress. However, it remains unclear whether the volume of palatable food affects abnormal behavior induced by psychosocial stress. In the present study, we aimed to determine whether levels of high-fat food intake significantly influence psychosocial stress using the social-defeat stress (SDS) paradigm. Main methods Mice subjected to SDS ate either a high-fat or normal chow diet for 10 days. Behavioral tests were conducted following the completion of the SDS paradigm. The hypothalamus, liver, and blood were examined post-mortem. Key findings Mice with sufficient intake of high-fat chow immediately following exposure to SDS did not exhibit social avoidance behavior, suggesting that a high-fat diet may improve social behavior. However, inadequate intake of high-fat food, which did not alter cholesterol metabolism or hypothalamic-pituitary-adrenal axis activity, was not associated with such benefits, instead increased anxiety-like behavior. Significance The results of the present study demonstrate that eating a high-fat diet may attenuate stress, but that this benefit disappears with insufficient intake of high-fat foods. The benefits of a high-fat diet under SDS may be related to cholesterol metabolism in the liver. [ABSTRACT FROM AUTHOR]

Anxiety disorders and nicotine use are significant contributors to global morbidity and mortality as independent and comorbid diseases. Early-life stress, potentially via stress-induced hypothalamic-pituitary-adrenal axis (HPA) dysregulation, can exacerbate both. However, little is known about the factors that predispose individuals to the development of both anxiety disorders and nicotine use. Here, we examined the relationship between anxiety-like behaviors and nicotine responses following adolescent stress. Adolescent male and female BALB/cJ mice were exposed to either chronic variable social stress (CVSS) or control conditions. CVSS consisted of repeated cycles of social isolation and social reorganization. In adulthood, anxiety-like behavior and social avoidance were measured using the elevated plus-maze (EPM) and social approach-avoidance test, respectively. Nicotine responses were assessed with acute effects on body temperature, corticosterone production, locomotor activity, and voluntary oral nicotine consumption. Adolescent stress had sex-dependent effects on nicotine responses and exploratory behavior, but did not affect anxiety-like behavior or social avoidance in males or females. Adult CVSS males exhibited less exploratory behavior, as indicated by reduced exploratory locomotion in the EPM and social approach-avoidance test, compared to controls. Adolescent stress did not affect nicotine-induced hypothermia in either sex, but CVSS males exhibited augmented nicotine-induced locomotion during late adolescence and voluntarily consumed less nicotine during adulthood. Stress effects on male nicotine-induced locomotion were associated with individual differences in exploratory locomotion in the EPM and social approach-avoidance test. Relative to controls, adult CVSS males and females also exhibited reduced corticosterone levels at baseline and adult male CVSS mice exhibited increased corticosterone levels following an acute nicotine injection. Results suggest that the altered nicotine responses observed in CVSS males may be associated with HPA dysregulation. Taken together, adolescent social stress influences later-life nicotine responses and exploratory behavior. However, there is little evidence of an association between nicotine responses and prototypical anxiety-like behavior or social avoidance in BALB/cJ mice. [ABSTRACT FROM AUTHOR]

Neuropeptide S (NPS) has anxiolytic effects and facilitates extinction of cued fear in rodents. Here, we investigated whether NPS reverses social fear and social avoidance induced by social fear conditioning (SFC) and acute social defeat (SD), respectively, in male CD1 mice. Our results revealed that intracerebroventricular NPS (icv; 10 and 50 nmol/2 μl) reversed fear of unknown con-specifics induced by SFC and dose-dependently reduced avoidance of known aggressive con-specifics induced by SD. While 50 nmol of NPS completely reversed social avoidance and reinstated social preference, 10 nmol of NPS reduced social avoidance, but did not completely reinstate social preference in socially-defeated mice. Further, a lower dose (1 nmol/2 μl) of NPS facilitated the within-session extinction of cued fear, while a higher dose (10 nmol/2 μl) reduced the expression of cued fear. We could also confirm the anxiolytic effects of NPS (1, 10 and 50 nmol/2 μl) on the elevated plus-maze (EPM), which were not accompanied by alterations in locomotor activity either on the EPM or in the home cage. Finally, we could show that icv infusion of the NPS receptor 1 antagonist D-Cys( t Bu) 5 -NPS (10 nmol/2 μl) did not alter SFC-induced social fear, general anxiety and locomotor activity. Taken together, our study extends the potent anxiolytic profile of NPS to a social context by demonstrating the reduction of social fear and social avoidance, thus providing the framework for studies investigating the involvement of the NPS system in the regulation of different types of social behaviour. [ABSTRACT FROM AUTHOR]

Background: Rett syndrome (RTT) is a severe neurodevelopmental disorder characterized by regression of language and motor skills, cognitive impairment, and frequent seizures. Although the diagnostic criteria focus on communication, motor impairments, and hand stereotypies, behavioral abnormalities are a prevalent and disabling component of the RTT phenotype. Among these problematic behaviors, anxiety is a prominent symptom. While the introduction of the Rett Syndrome Behavioral Questionnaire (RSBQ) represented a major advancement in the field, no systematic characterization of anxious behavior using the RSBQ or other standardized measures has been reported. Methods: This study examined the profiles of anxious behavior in a sample of 74 girls with RTT, with a focus on identifying the instrument with the best psychometric properties in this population. The parent-rated RSBQ, Anxiety, Depression, and Mood Scale (ADAMS), and Aberrant Behavior Checklist-Community (ABC-C), two instruments previously employed in children with neurodevelopmental disorders, were analyzed in terms of score profiles, relationship with age and clinical severity, reliability, concurrent validity, and functional implications. The latter were determined by regression analyses with the Vineland Adaptive Behavior Scales-Second Edition (Vineland-II) and the Child Health Questionnaire (CHQ), a quality of life measure validated in RTT. Results: We found that scores on anxiety subscales were intermediate in range with respect to other behavioral constructs measured by the RSBQ, ADAMS, and ABC-C. Age did not affect scores, and severity of general anxiety was inversely correlated with clinical severity. We demonstrated that the internal consistency of the anxiety-related subscales were among the highest. Test-retest and intra-rater reliability was superior for the ADAMS subscales. Convergent and discriminant validity were measured by inter-scale correlations, which showed the best profile for the social anxiety subscales. Of these, only the ADAMS Social Avoidance showed correlation with quality of life. Conclusions: We conclude that anxiety-like behavior is a prominent component of RTT's behavioral phenotype, which affects predominantly children with less severe neurologic impairment and has functional consequences. Based on available data on standardized instruments, the ADAMS and in particular its Social Avoidance subscale has the best psychometric properties and functional correlates that make it suitable for clinical and research applications. [ABSTRACT FROM AUTHOR]

Highlights: [•] Mice can be characterized as susceptible or resilient after social defeat. [•] Paradoxically, resilient mice display enhanced fear expression and poor extinction. [•] These effects are not due to increased anxiety or poor behavioral flexibility. [•] Mechanisms of resilience may leave animals vulnerable to maladaptive fear behavior. [ABSTRACT FROM AUTHOR]

Interest has recently surged in the use of social stress models, especially social defeat. Such interest lies both in the recognition that stressors of social origin play a major role in human psychopathologies and in the acknowledgement that natural and hence ethologically-based stress models have important translational value. The use of the most recent technology has allowed the recognition of the mechanisms through which social defeat might have enduring psychoneuroendocrine effects, especially social avoidance and anhedonia, two behaviours relevant to human depression. In view of the sensitivity of these behavioural outcomes to repeated antidepressant treatments, the social defeat model has been proposed as a possible animal model of depression. The present survey is aimed at examining the limits of such an interpretation and focuses on methodological aspects and on the relevance of social defeat to the study of anxiety-related pathologies. [ABSTRACT FROM AUTHOR]

Summary: Chronic stress, in particular chronic psychosocial stress, is a risk factor in the aetiology of various psychopathologies including anxiety- and depression-related disorders. Therefore, recent studies have focussed on the development of social-stress paradigms, which are believed to be more relevant to the human situation than non-social-stress paradigms. The majority of these paradigms have been reported to increase both anxiety- and depression-related behaviour in rats or mice. However, in order to dissect the mechanisms underlying anxiety or depression, animal models are needed, which specifically induce one, or the other, phenotype. Here, we study both short- (1d after stressor termination) and long-term (4d or 7d after stressor termination) behavioural and physiological consequences of two well-validated chronic psychosocial stress models: social-defeat/overcrowding (SD/OC) and chronic subordinate colony housing (CSC). We demonstrate that SD/OC and CSC result in different physiological alterations: SD/OC more strongly affecting body-weight development, whereas CSC more strongly affects adrenal and pituitary morphology. Both stressors were shown to flatten circadian locomotor activity immediately after stress termination, which normalized 7d later in SD/OC group but reversed to hyperactivity during the dark phase in the CSC group. Importantly, neither stress paradigm resulted in an increase in depression-related behaviour as assessed using the forced swim test, tail suspension test and saccharin preference test at any time-point. However, both stress paradigms lead to an anxiogenic phenotype; albeit with different temporal profiles and not towards a novel con-specific (social anxiety). CSC exposure elevates anxiety-related behaviour immediately after stressor termination, which lasts for at least 1wk. In contrast, the anxiogenic phenotype only develops 1wk after SD/OC termination. In conclusion, both models are unique for uncovering the molecular underpinnings of anxiety-related behaviour without conflicting depression-based alterations. [ABSTRACT FROM AUTHOR]

Previous research has consistently found an association between elevated anxiety and school refusal behaviour (SRB) in children and young people. Kearney (J Child Psychol Psychiatry 48:53-61, ) suggested that this relationship is best understood by exploring motivations underlying SRB. The present study aimed to establish whether motivating factors associated with non-attendance could explain the relationship between trait anxiety and school attendance in a community sample of 162 12-13-year-old young people. We measured motivating factors using the School Refusal Assessment Scale-Revised (SRAS-R; Kearney in J Psychopathol Behav Assess 24:235-245, ). In addition, we assessed the factor structure of the SRAS-R using confirmatory factor analysis. Goodness-of-fit indices supported a three-factor model highlighting motivational factors related to negative affect, social avoidance and attention-seeking. The results showed a negative relationship between trait anxiety and school attendance that was mediated by social avoidance and attention-seeking. We suggested that a consideration of motivating factors is important to understand and address anxiety-related non-attendance in young people. [ABSTRACT FROM AUTHOR]

Abstract: A 3-week chronic mild stress (CMS) protocol decreased sucrose preference of rats and increased immobility in the forced swim test. It also induced social avoidance and increased grooming, but acted as if reducing anxiety in the plus-maze. Sucrose preference and social avoidance, but not other measures of the behaviour, showed significant correlation. We conclude that CMS-induced depression-like behaviour is associated with social avoidance, a seemingly anxiety-related measure, but not with other anxiety-like traits in rats. [Copyright &y& Elsevier]

Abstract: Electric shocks lead to lasting behavioral deficits in rodents, and as such are often used to model post-traumatic stress disorder (PTSD) in the laboratory. Here we show that a single exposure of rats to 3 mA-strong shocks results in a marked social avoidance that lasts at least 28 days; moreover, the response intensifies over time. In an attempt to study the impact of cue reminders on the behavior of shocked rats, we administered shocks in the presence of a highly conspicuous, 10 cm-large object. This object was introduced into the home cage of rats 28 days after shock exposure. Shocked rats manipulated the object considerably less than controls. More importantly, however, the object was buried by shocked rats. This behavior was virtually absent in controls. The response strongly depended on the intensity of shocks, and was robust. Rats shocked with 3 mA currents spent 40% of time burying the object, which was often hardly visible at the end of the 5 min test. Subsequent experiments demonstrated that the response was not cue-specific as unfamiliar objects were also buried. Rats are well known to bury dangerous objects; the shock-prod burying test of anxiety is based on this response. Behavioral similarities with this test and the differences from the marble-burying behavior of mice suggest that traumatized rats bury unfamiliar objects in defense, and the response can be interpreted as a sign of hyper-vigilance. We further suggest that object burying can be used as a sign of hyper-vigilance in models of PTSD. [Copyright &y& Elsevier]