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Changes in Behaviour and Body Weight Following a Single or Double Social Defeat in Rats
Stress
Abstract and Figures
In a series of experiments, the consequences of a single and double social conflict on various behaviours and body weight in rats were studied. Animals were subjected to social defeat by placing them into the territory of an aggressive male conspecific for one hour, either once, or twice at the same time on two consecutive days. To assess the consequences of social defeat, three experiments were performed with independent groups of rats. In the first experiment, an open field test was performed two days after the last conflict. Locomotor activity was strongly reduced after social defeat. There were no differences between the single and double defeat group. To assess the effects of social defeat on subsequent social behaviour, a second experiment was performed in which experimental animals were confronted with an unfamiliar non-aggressive rat two days after a single or double conflict. Social defeat resulted in a reduction of social contact with the unfamiliar conspecific. There was no difference between the single and double conflict group. In the third experiment, the effects of social conflict on food intake, body weight and saccharine preference were measured. Food intake was not affected after a single conflict, but in the double conflict group food intake was decreased for several days. Body weight gain was decreased after both single and double social defeat. The decrease was stronger in the double conflict group. Water intake and saccharine preference were not significantly affected. This study revealed that social defeat in rats causes pronounced changes in various behaviours and body weight. Different aspects of behaviour are differentially affected by defeat with respect to the magnitude and time course of the changes induced. Moreover, different behavioural parameters are differentially sensitive to repetition of the stressor.
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... A number of studies have demonstrated that besides acute and short-lasting responses, a social conflict may result in various behavioral and physiological changes that last long after termination of the stressful encounter. For instance, previous studies reported disturbances in the daily rhythms of body temperature (Meerlo, De Boer, Daan, Koolhaas, & Van den Hoofdakker, 1996;Meerlo, Overkamp, & Koolhaas, 1997) and heart rate (Tornatzky & Miczek, 1993), decreases in food intake and body weight (Meerlo, Overkamp, Daan, Van den Hoofdakker, & Koolhaas, 1996;, a suppression of social activity (Meerlo, Overkamp, Daan, et al., 1996;Scholtens & Van de Poll, 1987), and a suppression of explorative activity (Koolhaas et al., 1990;Meerlo, Overkamp, Benning, Koolhaas, & Van den Hoofdakker, 1996). All of these changes last from several days to weeks after the actual encounter and are often interpreted in terms of stress-related maladaptations. ...
... A number of studies have demonstrated that besides acute and short-lasting responses, a social conflict may result in various behavioral and physiological changes that last long after termination of the stressful encounter. For instance, previous studies reported disturbances in the daily rhythms of body temperature (Meerlo, De Boer, Daan, Koolhaas, & Van den Hoofdakker, 1996;Meerlo, Overkamp, & Koolhaas, 1997) and heart rate (Tornatzky & Miczek, 1993), decreases in food intake and body weight (Meerlo, Overkamp, Daan, Van den Hoofdakker, & Koolhaas, 1996;, a suppression of social activity (Meerlo, Overkamp, Daan, et al., 1996;Scholtens & Van de Poll, 1987), and a suppression of explorative activity (Koolhaas et al., 1990;Meerlo, Overkamp, Benning, Koolhaas, & Van den Hoofdakker, 1996). All of these changes last from several days to weeks after the actual encounter and are often interpreted in terms of stress-related maladaptations. ...
This study shows that the long-term consequences of a social conflict in rats do not depend on the physical intensity of the fight in terms of aggression received but, especially, on how the subjects deal with it. Experimental rats were introduced into the cage of an aggressive conspecific for 1 hr, and the effects on daily rhythms of heart rate, body temperature, and activity thereafter were measured by means of telemetry. In some rats, the confrontation caused a strong decrease in the daily rhythm amplitude that lasted up to 3 weeks, whereas other subjects showed only minor changes. The changes in rhythm amplitude did not correlate with the number of attacks received from the territory owner. Contrary to this, the changes showed a clear negative correlation with the aggression of the experimental rats themselves. Subjects fighting back and counterattacking the cage owner subsequently had a smaller reduction in rhythm amplitude.
... Persistent exposure to stress is associated with decreased body weight or reduced weight gain (Meerlo et al., 1996;Nasu et al., 2024;Tanaka et al., 2003). Therefore, we measured the body weight of rats daily during the 6-day stress exposure. ...
... Although social defeat stress mimics typical features of human bullying, which is particularly common among adolescents (Menesini and Salmivalli, 2017;Rettew and Pawlowski, 2016), for many years preclinical studies were only focused on the effects of this type of social stress experienced in adulthood. These studies demonstrated that exposure to social defeat in adult rats profoundly affects behavior by inducing depression-and anxiety-like profiles, decreased social interactions, cognitive dysfunction, rapid acquisition of psychostimulant selfadministration, and hyperlocomotion induced by psychostimulants (Blanchard et al., 2001;Miczek, 2005, 2001;Haney et al., 1995;Meerlo et al., 1996;Patki et al., 2014Patki et al., , 2013Riga et al., 2015;Rygula et al., 2005;Tidey and Miczek, 1997). ...
The two-hit stress model predicts that exposure to stress at two different time-points in life may increase or decrease the risk of developing stress-related disorders later in life. Most studies based on the two-hit stress model have investigated early postnatal stress as the first hit with adult stress as the second hit. Adolescence, however, represents another highly sensitive developmental window during which exposure to stressful events may affect programming outcomes following exposure to stress in adulthood. Here, we discuss the programming effects of different types of stressors (social and nonsocial) occurring during adolescence (first hit) and how such stressors affect the responsiveness toward an additional stressor occurring during adulthood (second hit) in rodents. We then provide a comprehensive overview of the potential mechanisms underlying interindividual and sex differences in the resilience/susceptibility to developing stress-related disorders later in life when stress is experienced in two different life stages.
... Thus, considering that the risk of victimization was not linked to prior social status, our results strongly suggest that the trigger for aggression was the unknown phenotype and not the existence of a mark. The impact of social stressors has been reported to have varied effects on food intake, depending on the type of stressor and the species 28 , but social stress by social defeat has been associated with less eating in defeated individuals 29,30 . It could be speculated that victimized individuals might be prevented from accessing feeders. ...
Phenotype alterations can occur naturally during the life span of the domestic fowl. These alterations increase the risk to become a target of aggression and may cause a severe impact on the welfare of affected birds. We analysed the behavioural consequences of sequential phenotype alterations and their long-term effects within stable social groups of adult birds differing in group size. Phenotypically homogeneous groups, with 100% or 0% marked individuals, and heterogeneous groups, with 70%, 50% or 30% marked birds, were housed at constant density in groups of 10, 20 or 40. We applied sequential phenotype alterations to homogeneous groups (by marking or unmarking birds) and compared their behavioural response to heterogeneous groups considered controls. Results show that aggression was greatly affected by phenotype alteration but, unexpectedly, group size did not play any relevant role modulating social responses. Aggression was directed towards the first altered birds and was significantly higher than in control groups. Long term effects were detected, as victimized individuals failed to engage in aggression at any time and adapted their behaviour to minimize aggressive encounters (e.g. high perch use). Therefore, we provide evidence of long-lasting submissive strategies in stable groups of adult domestic fowl, highlighting the relevance of phenotype alteration on the social dynamics of affected birds. Phenotype alterations could help explain much of the targeted aggression observed in producing flocks which severely affects animal welfare.
... Experiments on avoidance behaviour following chronic social defeat have reported depressionlike behaviours (i.e., decreased preference for attractants like sucrose (anhedonia), and reduced locomotion and exploratory activity in a novel environment) in a subset of animals, as well as social avoidance behaviour towards unknown conspecifics 204,[237][238][239][240][241] . Currently, mounting evidence suggests that generalised social avoidance may not be so indiscriminate as initially thought, with reports that chronic social avoidance-induced social avoidance behaviour in mice does not generalise to other phenotypic characteristics than those expressed by the aggressor. ...
Social behaviours are essential for the survival and reproduction of many species, including our own. A fundamental feature of all social behaviour is social preference, which is an individual’s propensity to interact with members of their species (termed conspecifics). In an average population, various social preference behaviours are readily observed, ranging from uninterested (not engaging with conspecifics) to very social (engaging with conspecifics). Individuals expressing these behaviours are typically labelled as having an asocial or prosocial, respectively. Little is known about how the underlying social circuitry gives rise to such distinct social behaviours in the population. It is well established that adverse social experiences can impact social behaviour, including isolation during early development. Undesired social isolation (loneliness) alters behavioural patterns, neuroanatomy (e.g., brain volume) and neurochemistry in ways that resemble developmental neuropsychiatric disorders, including autism and schizophrenia. However, few studies have investigated the impact of early life isolation on social circuitry, and how this results in dysfunctional social behaviour commonly associated with these and other disorders. In this thesis, juvenile zebrafish was used to model social preference behaviour, as it is an excellent translational model for human developmental and behavioural disorders. Population-level analysis revealed that several features of social preference behaviour could be summarised via Visual Preference Index (VPI) scores representing sociality. Using multiple behavioural parameters, comprehensive investigations of asocial and prosocial fish identified via VPIs revealed distinct responses towards conspecifics between the two phenotypes. These initial results served as a baseline for facilitating the identification of atypical social behaviour following periods of social isolation. The impact of isolation on social preference was assessed by applying either the full isolation over the initial three weeks of development or partial isolation, 48 hours or 24 hours, before testing. Following periods of social isolation, juvenile zebrafish displayed anxiety-like behaviours. Furthermore, full and partial isolation of 48 hours, but not 24 hours, altered responses to conspecifics. To assess the impact of social isolation on the social circuitry, the brain activities of fish were analysed and compared between different rearing conditions using high-resolution two-photon imaging. Whole-brain functional maps of isolated social phenotypes were distinct from those in the average population. Isolation-induced activity changes were found mainly in brain regions linked to social behaviour, social cue processing, and anxiety/stress (e.g., the caudal hypothalamus and preoptic area). Since some of these affected regions are modulated by serotonin, the reversibility of the adverse effects of social isolation on preference behaviour was investigated by using pharmacological manipulation of the monoaminergic system. The administration of an anxiolytic the drug buspirone demonstrated that altered social preference behaviour in isolated fish could be rescued by acutely reducing serotonin levels. By investigating social preference at the behavioural and functional level in wild-type juvenile zebrafish, this work contributes to our understanding of how the social brain circuity produces diverse social preferences. Furthermore, it provides important information on how early-life environmental adversity gives rise to atypical social behaviour and the neurotransmitters modulating the circuit, offering new opportunities for effective intervention.
... Thus, it does not affect circadian locomotor activity throughout the day and night. An environment in which the animal is placed in the territory of a male rat of the same species for an hour, which is social defeat stress, also rapidly suppresses nocturnal locomotor activity, but does not increase daytime activity (Meerlo et al., 1996). ...
The circadian system, which is essential for the alignment of sleep/wake cycles, modulates adult neurogenesis. The olfactory epithelium (OE) has the ability to generate new neurons throughout life. Loss of olfactory sensory neurons (OSNs) as a result of injury to the OE triggers the generation of new OSNs, which are incorporated into olfactory circuits to restore olfactory sensory perception. This regenerative potential means that it is likely that the OE is substantially affected by sleep deprivation (SD), although how this may occur remains unclear. The aim of this study is to address how SD affects the process of OSN regeneration following OE injury. Mice were subjected to SD for 2 weeks, which induced changes in circadian activity. This condition resulted in decreased activity during the night-time and increased activity during the daytime, and induced no histological changes in the OE. However, when subjected to SD during the regeneration process after OE injury, a significant decrease in the number of mature OSNs in the dorsomedial area of the OE, which is the only area containing neurons expressing NQO1 (quinone dehydrogenase 1), was observed compared to the NQO1-negative OE. Furthermore, a significant decrease in proliferating basal cells was observed in the NQO1-positive OE compared to the NQO1-negative OE, but no increase in apoptotic OSNs was observed. These results indicate that SD accompanied by disturbed circadian activity could induce structurally negative effects on OSN regeneration, preferentially in the dorsomedial area of the OE, and that this area-specific regeneration delay might involve the biological activity of NQO1.
Social recognition is an essential part of social function and often promotes specific social behaviors based on prior experience. Social and defensive behaviors in particular often emerge with prior experiences of familiarity or novelty/stress, respectively. This is also commonly seen in rodents toward same-strain and interstrain conspecifics. Medial amygdala (MeA) activity guides social choice based on age and sex recognition and is sensitive to social experiences. However, little is known about whether the MeA exhibits differential responses based on strain or how this is impacted by experience. Social stress impacts posterior MeA (MeAp) function and can shift measures of social engagement. However, it is unclear how stress impacts MeAp activity and contributes to altered social behavior. The primary goal of this study in adult male Sprague Dawley rats was to determine whether prior stress experience with a different-strain (Long–Evans) rat impacts MeAp responses to same-strain and different-strain conspecifics in parallel with a change in behavior using in vivo fiber photometry. We found that MeAp activity was uniformly activated during social contact with a novel same-strain rat during a three-chamber social preference test following control handling but became biased toward a novel different-strain rat following social stress. Socially stressed rats also showed initially heightened social interaction with novel same-strain rats but showed social avoidance and fragmented social behavior with novel different-strain rats relative to controls. These results indicate that heightened MeAp activity may guide social responses to novel, threatening, rather than non-threatening, social stimuli after stress.
The primary risk factor for the onset of depression is social stress. In a clinical study, experience to daily social stress has been connected to the occurrence of major depressive disorder. To investigate the underlying mechanisms, animal depressive models have been proposed. In this study, we comprehensively summarized the different methodologies used to induce social-related stress in animals, including the most commonly used resident-intruder model, housing condition, social isolation, early life social event as well as social hierarchy model. Meanwhile, we investigated the behavioral readout adopted in this field. Moreover, we systematically summarized the molecular changes that have been associated with behavior observation. We found that most of the studies were performed on male animals. However, in humans, depression happens 2–3 times greater in females than males, thus we discussed the potential model that has been adopted to study social stress in females as well. We hope this study could provide a good summary for the field to have a comprehensive view of the social stress-related depression model as a foundation for the development of corresponding therapeutic approaches.
Historically, animal models have been routinely used in the characterization of novel chemical entities (NCEs) for various psychiatric disorders. Animal models have been essential in the in vivo validation of novel drug targets, establishment of lead compound pharmacokinetic to pharmacodynamic relationships, optimization of lead compounds through preclinical candidate selection, and development of translational measures of target occupancy and functional target engagement. Yet, with decades of multiple NCE failures in Phase II and III efficacy trials for different psychiatric disorders, the utility and value of animal models in the drug discovery process have come under intense scrutiny along with the widespread withdrawal of the pharmaceutical industry from psychiatric drug discovery. More recently, the development and utilization of animal models for the discovery of psychiatric NCEs has undergone a dynamic evolution with the application of the Research Domain Criteria (RDoC) framework for better design of preclinical to clinical translational studies combined with innovative genetic, neural circuitry-based, and automated testing technologies. In this chapter, the authors will discuss this evolving role of animal models for improving the different stages of the discovery and development in the identification of next generation treatments for psychiatric disorders.KeywordsDrug discoveryAnimal modelsRDoCPsychiatry
Exposure of male rats to a single brief period of footshocks induced behavioural changes as measured in the open field test that lasted for at least 3 weeks. Moreover, such rats showed a long-lasting increased responsiveness to a sudden change in environmental stimuli. These effects of footshock exposure are probably useful as an animal model of depression.
Social conflict engenders behavioral and physiological phonemena that are relevant to the concept of stress. Attack and threat by an opponent leads to profound behavioral, physiological and neurochemical reactions, some adaptative, others maladaptative, by animals that exhibit defensive and submissive responses (Miczek et al., 1989 in press). Here, we focus on the short-and long-term submissive reactions at the level of behavior, endocrine and cardiovascular physiology as well as certain neurochemical systems in mice and rats that confront an aggressive opponent.
In the last fifteen to twenty years the range of research activities that could be subsumed under the general heading of “animal modeling research” has expanded enormously. There are many approaches to developing animal models of depression in particular, and it will quickly become apparent that there is quite a variety of studies underway. In order to understand and evaluate the rapidly expanding literature in several areas of animal modeling research, there must first be a fundamental understanding of the basis and justification for having animal models in the first place. It is also important that this understanding be combined with a realization of the limitations of animal models in relation to psychiatric syndromes and their role in a comprehensive program of psychiatric research with affective disorders as well as other forms of psychopathology. If the fundamental philosophy, rationale, and advantages of animal models are not understood along with their limitations, there will remain a significant risk of either an uninformed rejection of animal modeling research or, on the other hand, an overacceptance of its direct clinical relevance.
Our current understanding of the physiological mechanisms underlying depressive disorders is not only based on behavioral, neuroendocrine and pharmacological studies in depressed humans, but also on experimental studies in a wide variety of animal models of depression. Ideally, the two approaches should operate in close interaction, each providing additional information to the other approach. However, in practice the animal model approach seems to be rather independent from the human studies. In a critical evaluation of the available animal models of depression, Willner concluded that none of the models fulfilled the criteria of a sufficient face, construct and predictive validity. Although this evaluation was made ten years ago, we feel that the situation has improved very little since that time. Most animal models fail to sufficiently mimic both the etiology and the symptomatology of human depressive disorders. With respect to the etiology, stress and major life events are generally considered to be an important factor in the development of depression. Most of the animal models however use stressors which bear little or no relationship to the biology of the species, i.e. to the situations an animal may meet in its everyday life in a natural habitat. Moreover, these models do not pay attention to the temporal dynamics of the disease. In humans, the disease is characterized by its gradual onset, which is often preceded by symptoms of anxiety. Moreover, a relatively large number of patients suffers from recurrent episodes of depression, which tend to occur with decreasing intervals and increasing duration and severity. If we want to improve our knowledge of the causal mechanisms of depression, animal models which allow an experimental analysis of the temporal dynamics of the disease are essential.