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

בדיקת בטיחות איומים לרגישות או עמידות ללחץ במודלים של עכברים

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.

מחבר זרקור: חשיפת מנגנונים של עמידות ללחץ - ממצאים משמעותיים, התקדמות ומחקר עתידי

מבחן בטיחות איום חברתי חושף פנוטיפים הקשורים ללחץ פסיכו-סוציאלי

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.

Watch this Scientific Journal Video about Assessment of Post-Chronic Social Defeat Treatment in Mice: Social Threat-Safety Test, Scoring, and Analysis at JoVE.com

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

הערכת טיפול בתבוסה חברתית פוסט-כרונית בעכברים: מבחן איום חברתי-בטיחות, ניקוד וניתוח

התחילו בהעברת כל העכברים הכרוניים, המובסים חברתית או שטופלו ב-CSD ועברו ביקורת לכלובים חדשים, שישקפו את התנאים אליהם הגיעו לראשונה ותנו להם לנוח למשך הלילה. למחרת בבוקר, יש לחטא את הזירה בעלת שלושת התאים באמצעות תמיסת אתנול 5% ולהציב אותה מתחת למצלמה, מה שמבטיח מצב אור של 37 לוקס וראות מלאה של הזירה כולה. באופן דומה, נקו את מארזי הרשת עם אתנול 5% ומקמו אותם בפינות המיועדות.הגדירו אזור אינטראקציה של שני סנטימטרים סביב גבולות מארזי רשת השינוי. בשלב ההרגלה, הביאו את בעל החיים הנושא למרכז הזירה ואפשרו חקירה של שש דקות לפני החזרתו לכלוב הביתי שלו. ציון משך הזמן שהחיה מבלה בחקירה ספציפית כאשר אפו של בעל החיים נמצא בתוך אזור האינטראקציה.לאחר מכן, מקם את היעד החברתי CD-1 ביעד החברתי החדש 129/Sv תחת מארזי רשת נפרדים. כדי להתחיל את שלב הניסויים, החזירו מיד את בעל החיים הנבדק למרכז הזירה, ואפשרו חקירה למשך שש דקות. שימו לב למשך הזמן שבו בעל החיים מקיים אינטראקציה עם המטרות החברתיות.שוב, התמקדות בטווח כאשר האף של החיה נמצא בתוך אזור האינטראקציה. לאחר מכן, להחזיר את כל בעלי החיים לבית הגידול האישי שלהם. הקפידו לנקות את מארזי הזירה והרשת בתמיסת אתנול 5% לאחר הערכת כל חיה.החלף את המיקום של רשת הסגירה בין בעלי חיים שונים כדי לאזן כל הטיית מיקום פוטנציאלית. חשב את מדד האינטראקציה החברתית כפי שמוצג. בהתבסס על מדד האינטראקציה החברתית, חלקו את העכברים ללא-נמנעים, לנמנעים-חסרי הבחנה ולנמנעים-מפלים.נצפה הבדל משמעותי במדד האינטראקציה החברתית עם היעד החברתי CD-1 בין שתי הקבוצות. לקבוצות המשנה של הנמנעים מפלים ונמנעים ללא הבחנה היה מדד אינטראקציה חברתית של פחות מ-1 עם היעד החברתי CD-1. בשיקוף התפתחות הימנעות חברתית כלפי גירוי התנאים, לתת-הקבוצה הלא-נמנעת היה מדד אינטראקציה חברתית יותר או שווה ערך ל-1 עם אותו יעד חברתי, המשקף למידה מותנית מרתיעה לקויה עם מטרה זו.תת-הקבוצה של הנמנעים מפלים הראתה רמות חברותיות שלמות כלפי גירוי בטוח או ניטרלי, בעוד שתת-הקבוצה של נמנעים ללא הבחנה הראתה הכללת תגובה מרתיעה. היעדר הטיה מועדפת חברתית בא לידי ביטוי במדדי אינטראקציה חברתית של יותר או שווה ערך ל-1, כאשר שני היעדים החברתיים נמצאים בתוך קבוצת הביקורת.

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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 ...