Social instigation and repeated aggressive confrontations in male Swiss mice: analysis of plasma corticosterone, CRF and BDNF levels in limbic brain areas / Instigação social e confrontos agressivos repetidos em camundongos Swiss machos: análise de corticosterona plasmática e dos níveis de CRF e BDNF em áreas cerebrais límbicas

Abstract Introduction: Agonistic behaviors help to ensure survival, provide advantage in competition, and communicate social status. The resident-intruder paradigm, an animal model based on male intraspecific confrontations, can be an ethologically relevant tool to investigate the neurobiology of aggressive behavior. Objectives: To examine behavioral and neurobiological mechanisms of aggressive behavior in male Swiss mice exposed to repeated confrontations in the resident intruder paradigm. Methods: Behavioral analysis was performed in association with measurements of plasma corticosterone of mice repeatedly exposed to a potential rival nearby, but inaccessible (social instigation), or to 10 sessions of social instigation followed by direct aggressive encounters. Moreover, corticotropin-releasing factor (CRF) and brain-derived neurotrophic factor (BNDF) were measured in the brain of these animals. Control mice were exposed to neither social instigation nor aggressive confrontations. Results: Mice exposed to aggressive confrontations exhibited a similar pattern of species-typical aggressive and non-aggressive behaviors on the first and the last session. Moreover, in contrast to social instigation only, repeated aggressive confrontations promoted an increase in plasma corticosterone. After 10 aggressive confrontation sessions, mice presented a non-significant trend toward reducing hippocampal levels of CRF, which inversely correlated with plasma corticosterone levels. Conversely, repeated sessions of social instigation or aggressive confrontation did not alter BDNF concentrations at the prefrontal cortex and hippocampus. Conclusion: Exposure to repeated episodes of aggressive encounters did not promote habituation over time. Additionally, CRF seems to be involved in physiological responses to social stressors.

Resumo Introdução: Comportamentos agonísticos ajudam a garantir a sobrevivência, oferecem vantagem na competição e comunicam status social. O paradigma residente-intruso, modelo animal baseado em confrontos intraespecíficos entre machos, pode ser uma ferramenta etológica relevante para investigar a neurobiologia do comportamento agressivo. Objetivos: Analisar os mecanismos comportamentais e neurobiológicos do comportamento agressivo em camundongos Swiss machos expostos a confrontos repetidos no paradigma residente-intruso. Métodos: A análise comportamental foi realizada em associação com medidas de corticosterona plasmática em camundongos expostos repetidamente a um rival em potencial próximo, porém inacessível (instigação social), ou a 10 sessões de instigação social seguidas de encontros agressivos diretos. Além disso, o fator de liberação de corticotrofina (CRF) e o fator neurotrófico derivado do cérebro (BNDF) foram medidos no encéfalo desses animais. Camundongos controles não foram expostos à instigação social ou confrontos agressivos. Resultados: Os camundongos expostos a confrontos agressivos exibiram um padrão semelhante de comportamentos agressivos e não agressivos típicos da espécie na primeira e na última sessão. Em contraste com instigação social apenas, confrontos agressivos repetidos promoveram aumento na corticosterona plasmática. Após 10 sessões de confrontos agressivos, os camundongos apresentaram uma tendência não significativa de redução dos níveis de CRF no hipocampo, que se correlacionaram inversamente com os níveis plasmáticos de corticosterona. Por outro lado, sessões repetidas de instigação social ou confronto agressivo não alteraram as concentrações de BDNF no córtex pré-frontal e hipocampo. Conclusão: A exposição a episódios repetidos de encontros agressivos não promoveu habituação ao longo do tempo. Adicionalmente, o CRF parece estar envolvido nas respostas fisiológicas aos estressores sociais.

Estudio de la instigación social en un modelo de agresión inducida por aislamiento: efectos de la administración de JNJ16259685, un antagonista de receptores mGlu1 / Study of the Social Instigation in a Model of Isolation-Induced Aggression: Effects of JNJ16259685 Administration, an mGlu1 Receptor Antagonist

La instigación social intensifica la conducta agresiva permitiendo observar niveles más extremos de agresión. Estudios recientes indican que el receptor metabotrópico del glutamato mGlu1 está implicado en la regulación de la conducta agresiva en un modelo de agresión inducida por aislamiento. El objetivo de este trabajo fue evaluar los efectos de la administración de un antagonista del receptor mGlu1 (JNJ16259685) sobre la conducta agresiva normal e intensificada, utilizando instigación social en un modelo animal de agresión inducida por aislamiento. Varios grupos de animales aislados fueron expuestos a 5 minutos de instigación social, recibiendo la mitad de ellos JNJ16259685 (0.5 mg/kg, ip) o vehículo. Las interacciones agonísticas de 10 min de duración se realizaron en un área neutral 30 min después de la inyección. Dichos encuentros fueron grabados en vídeo para el posterior análisis etológico de diez categorías conductuales. La instigación redujo la latencia de ataque y aumentó la frecuencia y duración de los ataques frente a los animales no instigados. La administración de JNJ16259685 redujo de forma significativa la conducta agresiva en ambos casos, sugiriendo la implicación del receptor mGlu1 en la modulación de la agresión normal e intensificada.

Social instigation intensifies aggressive behavior in rodents allowing observe more extreme levels of aggression. Recent studies indicate that glutamate metabotropic receptor 1 (mGlu1) are involved in the regulation of aggressive behavior in isolation-induced aggression model. The object of this work was to examine social instigation in an animal model of isolation-induced aggression and assess the anti-aggressive effects of an mGlu1 receptor antagonist (JNJ16259685) on normal and heightened aggressive behavior. Several groups of individually housed mice were exposed to 5 minutes of social instigation, and half of them received an acute administration ofJNJ16259685 (0.5 mg/kg, ip) or vehicle. Ten minute of dyadic interactions were staged between a singly housed and an anosmic mouse in a neutral area 30 min after drug or vehicle administration. The encounters were videotaped for subsequent analysis of ten ethological behavioural categories. Social instigation reduced latency of attack and increased the frequency and duration of attacks against not instigated animals. JNJ16259685 administration significantly reduced aggressive behavior in both cases, suggesting the involvement of mGlu1 receptor in the modulation of normal and heightened aggression.

Fos expression in the prefrontal cortex and mesencephalic dorsal raphe nucleus in lactating rats after social instigation

Females are often less aggressive than males, but they exhibit high levels of agonistic behavior against an intruder in the area of ​​the nest during lactation. This behavior is referred to as maternal aggression. In rats, maternal aggressive behavior occurs more often from postpartum day 3 (PPD 3) to PPD 12. Social instigation is an experimental protocol used to increase the levels of aggression that are typical of the species. In the present study we used social instigation to analyze the expression of a marker of neuronal activity, c-fos. Lactating rats on PPD 5, in the presence of their pups, were divided into four groups: (1) no social instigation and no aggressive behavior, (2) social instigation and no aggressive behavior, (3) no social instigation and aggressive behavior, and (4) social instigation and aggressive behavior. Sixty minutes after the aggression test we used immunohistochemistry to detect Fos in two brain regions, the ventral-orbital region of the prefrontal cortex (VO PFC) and dorsal raphe nucleus (DRN). Our results showed that rats with aggressive behavior that were provoked exhibited an increase in Fos expression in the VO PFC compared with the control group (i.e., no social instigation and no aggressive behavior). No change in Fos expression was found in the DRN. These results complement previous findings with microinjection of serotonin 5-hydroxytryptamine-1B receptor agonists into the same region, demonstrating that the VO PFC is an important region in the modulation of maternal aggressive behavior.

Effect of social instigation and aggressive behavior on hormone levels of lactating dams and adult male Wistar rats

Among rodents, maternal aggression in the postpartum period represents a species-typical adaptation, but when aggressive behavior increases beyond this adaptive level, it can represent a model of excessive aggression. This study assessed the neuroendocrine response of lactating rats and socially instigated male rats. The aim of the present study was to assess neuroendocrine responses and the behavioral pattern of lactating rats and males that were subjected to an emotional stressor using the social instigation protocol. We measured plasma corticosterone levels as the key hormonal parameter of the hypothalamic-pituitary-adrenal (HPA) axis and oxytocin, prolactin, and progesterone, which are released in response to several types of stressors. Our results showed that lactating rats that were subjected to only social instigation or aggressive confrontation in the presence of their pups had lower plasma corticosterone levels, and this response was similar to oxytocin, prolactin, and progesterone levels. By contrast, male rats showed increased corticosterone levels after being subjected only to social instigation. Male rats also engaged in aggressive behavior compared with the control group. In conclusion, this study demonstrated that lactating rats subjected to social instigation exhibited an attenuation of the HPA axis response, which is considered to be crucial to the dam's welfare so that it can care for its offspring. Thus, we can infer that lactation is a relevant factor in neuroendocrine responses to stress because of the increased levels of corticosterone in males.