Name: Assessment of Post-Chronic Social Defeat Treatment in Mice: Social Threat-Safety Test, Scoring, and Analysis
Uploaded: 2023-12-15T13:20:00
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assessment of post-chronic social defeat treatment in mice: social threat-safety test, scoring, and analysis

Hot-säkerhetstest för stresskänslighet eller motståndskraft i musmodeller

Stress is defined as the disruption of homeostasis caused by physical or psychological stimuli1. Stress is a well-known major risk factor for the development of mental disorders such as post-traumatic stress disorder, depression, and anxiety2,3. In particular, social stress is considered a major risk factor for the development of stress-related mental disorders4. One type of social stress that has gained particular importance in research is social subordination stress5. Mice, like humans, are capable of a rich set of social behavior6, rendering them suitable for investigations involving social stress. In the laboratory setting, when adult mice are group housed, they establish a social structure involving the formation of ranks7. Accordingly, the colony model was designed to study the effects of naturally established social hierarchies in mixed-sex groups of mice8. Over the years, variations of the colony model have been developed to utilize social subordination stress, including same-sex group models, the social instability model, and the intruder-colony model. In recent years, however, one particular variant known as the male resident-intruder model has been popularized in literature, simplifying the social complexity to two mice: a resident and an intruder. The animal of interest, known as the intruder, is placed into the cage of a larger, older, and retired breeder, known as the resident or aggressor. The resident then physically attacks the intruder as a method of confrontation, establishing a social hierarchy wherein the resident is dominant and the intruder is subordinate. When confrontations are one-time events, they classify as &#34;acute&#34; (the &#34;acute social defeat model&#34;), whereas repeated confrontations lasting over several days (usually 10) are known as &#34;chronic&#34; (the &#34;chronic social defeat model&#34;). In the chronic social defeat (CSD) model, attacks are intermittent and typically confined to a period of 5-10 min9, termed the physical phase. Following the physical phase, the intruder and resident are kept overnight in the same cage, separated in half with a mesh wall, allowing for all forms of interaction except physical contact. This configuration, known as the sensory phase, induces stress through the continuous appearance of threat instead of direct physical confrontation. In 2018, van der Kooji and colleagues introduced a modified chronic social defeat treatment to focus on the psychosocial component of the model by standardizing and strictly limiting the physical phase10. The modified model limits physical attacks to three 10 s episodes with different residents, occurring in 15 min inter-episode intervals of the sensory phase. Following the third physical episode, the sensory phase lasts overnight. This cycle repeats for 10 consecutive days with new residents per episode. The modified treatment enhances the translational validity of the chronic social defeat model as physical harm of the intruder is minimized, and outcome variability from differential durations of physical attacks is reduced.
Since the CSD model is utilized to study stress-related illness (e.g., depression, anxiety, post-traumatic stress disorder), post-behavioral assays are chosen, including, but not limited to, behavioral assays of aggression, memory, and anhedonia. In recent years, post-CSD behavioral assays in mice often evaluate how and to what extent sociability is affected9. Sociability is defined as the innate preference of mice to socially interact rather than socially avoid a conspecific. Since sociability is subject to stress effects, assays that solely assess social avoidance development were established. Stress-induced social avoidance has a translational relevance as it represents one of the main behavioral symptoms of social anxiety and depression in humans11. Similar to humans, not all mice develop social avoidance following CSD treatment, suggesting the presence of individuality in stress responsiveness. Cohen and colleagues have proposed cut-off behavioral criteria to be a promising approach for studying the neurobiology of individuality12. Selection of animals based on behavior results in group division, underlining the basis for gene-environment studies. Subsequently, different subgroups often show distinct enrichment of specific genetic variants/modifications, which in turn can be investigated under different environmental conditions13. Accordingly, individuality in the development of social avoidance was utilized to divide the single group of chronically socially defeated male mice into two subgroups: stress susceptible (socially avoidant) and stress resilient (socially non-avoidant9,14). However, the interpretation of the social avoidance phenotype in mice as a maladaptive or adaptive behavior should be considered in the overall context of both the treatment (here CSD) and post-treatment behavioral assay. Additionally, the post-treatment behavioral assay of choice would ideally assess other facets of sociability and not solely social avoidance development. Our recent work revealed the involvement of conditioned learning in CSD-induced social avoidance15. Specifically, CSD-induced social avoidance is an aversive conditioned response towards the characterizing traits of the residents&#39; strain serving as the conditioned stimulus to the unconditioned stimulus, namely the attacks by the residents. Moreover, within the socially avoidant subgroup, some individuals can discriminate between the traits of the aversive residents&#39; strain and those of other safe novel strains, while other individuals show generalized social avoidance to both strains. We propose here a refined behavioral post-CSD assay: the Social Threat-Safety Test (STST)15. Unlike other social interaction tests9, the STST enables a simultaneous assessment of social avoidance development as a measurement of the correct aversive conditioned response (i.e., successful conditioned learning) and social threat-safety discrimination ability, both of which are utilized to identify stress-susceptible and stress-resilient individuals within a single group of chronically socially defeated male mice. The assessment of social threat-safety discrimination versus aversive response generalization extends the translational criteria used to classify the single group of chronically socially defeated animals into resilient and susceptible subgroups.

Författare Spotlight: Avslöja mekanismer för stresstålighet - viktiga resultat, framsteg och framtida forskning

Test av social hotsäkerhet avslöjar psykosociala stressrelaterade fenotyper

Our research seeks to uncover the underlying mechanisms of stress resilience. By understanding those mechanisms, we can employ them to develop better treatment strategies for stress related mental disorders and prevention. Our research has developed a new mouse model with high face validity that allows stratifying a single group of stressed mice into resilience and susceptibility associated phenotypes that are based on the fear circuitry.Also, we provide evidence for the presence of global resilience mechanisms. Our study on stressed mice revealed that they exhibited characteristics that are indicative of both resilience and susceptibility in humans. Specifically, they show different abilities in threat safety discrimination and responsiveness to extinction, which are key features associated with resilience.The resilience and susceptibility associated phenotypes that we identified in mice have face validity and are based on the fear circuitry. This circuitry is highly conserved across species and is arguably one of the best studied circuits. In turn, this allows mechanistic investigations that have the potential to contribute to treatment, development and prevention measures.We'll use our new model to dig deeper into neurobiological mechanisms of resilience and understand how we can actively promote resilience. In addition, we will employ longitudinal analysis to decifer how individual resilience develops over time.

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Assessment of Post-Chronic Social Defeat Treatment in Mice: Social Threat-Safety Test, Scoring, and Analysis  

Bedömning av postkronisk behandling av socialt nederlag hos möss: socialt hot-säkerhetstest, poängsättning och analys

Börja med att flytta alla kroniska, socialt besegrade eller CSD-behandlade och kontrollera möss till nya burar, spegla de förhållanden de först anlände i och låt dem vila över natten. Följande morgon desinficerar du arenan med tre kammare med en 5 % etanollösning och ställer upp den under kameran, vilket säkerställer ett ljustillstånd på 37 lux och full synlighet av hela arenan. På samma sätt, rengör näthöljena med 5 % etanol och placera dem i de avsedda hörnen.Definiera en två centimeter lång interaktionszon runt näthägnadernas gränser. För tillvänjningsfasen, ta med djuret till mitten av arenan och låt det utforskas i sex minuter innan du sätter tillbaka det i sin hembur. Poängsätt hur lång tid djuret spenderar på att utforska specifikt när djurets nos är inne i interaktionszonen.Placera sedan det sociala målet CD-1 i det nya sociala målet 129/Sv under separata näthöljen. För att initiera testfasen, placera omedelbart tillbaka försöksdjuret i mitten av arenan och tillåt utforskning under en period av sex minuter. Notera hur länge djuret interagerar med de sociala målen.Återigen, fokusera på spännvidden när djurets nos är inom interaktionszonen. Efteråt återför du alla djuren till deras individuella livsmiljö. Se till att rengöra arenan och nätinhägnaderna med 5 % etanollösning efter att ha bedömt varje djur.Byt position för nätförslutningarna mellan olika djur för att balansera eventuell platsbias. Beräkna indexet för social interaktion enligt bilden. Baserat på indexet för social interaktion delar du in mössen i icke-undvikare, urskillningslösa undvikare och diskriminerande-undvikare.En signifikant skillnad i indexet för social interaktion med det sociala målet CD-1 mellan de båda grupperna observerades. Undergrupperna diskriminerande-undvikare och urskillningslösa-undvikare hade ett socialt interaktionsindex på mindre än 1 med CD-1 socialt mål. Som en återspegling av utvecklingen av socialt undvikande mot betingelserna stimulus, hade undergruppen icke-undvikande ett socialt interaktionsindex som var mer än eller motsvarande 1 med samma sociala mål, vilket återspeglar nedsatt aversiv betingad inlärning med det målet.Undergruppen diskriminerande-undvikare uppvisade intakta nivåer av sällskaplighet mot ett säkert eller neutralt stimulus, medan undergruppen urskillningslösa-undvikare uppvisade aversiv responsgeneralisering. Frånvaron av social preferens återspeglades i sociala interaktionsindex på mer än eller motsvarande 1, med båda sociala målen inom kontrollgruppen.

Research

JoVE Journal

Behavior

Assessment of Post-Chronic Social Defeat Treatment in Mice: Social Threat-Safety Test, Scoring, and Analysis

Social Threat-Safety Test Uncovers Psychosocial Stress-Related Phenotypes

Social stress is a major cause of the development of mental disorders. To enhance the translational value of preclinical studies, social stress experience ...