Trends in Psychiatry and Psychotherapy
Trends in Psychiatry and Psychotherapy
Original Article

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

Paula Madeira Fortes; Lucas Albrechet-Souza; Mailton Vasconcelos; Bruna Maria Ascoli; Ana Paula Menegolla; Rosa Maria M. de Almeida

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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.


Aggression, social instigation, corticosterone, CRF, BDNF


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.


Agressão, instigação social, corticosterona, CRF, BDNF


Blanchard RJ, McKittrick CR, Blanchard DC. Animal models of social stress: effects on behavior and brain neurochemical systems. Physiol Behav. 2001;73:261-71.

Koolhaas JM, Bohus B. Animal models of human aggression. Animal models in psychiatry. II. 1992:249-71.

Réale D, Martin J, Coltman DW, Poissant J, Festa-Bianchet M. Male personality, life-history strategies and reproductive success in a promiscuous mammal. J Evol Biol. 2009;22:1599-607.

Watters J, Sih A. The mix matters: behavioural types and group dynamics in water striders. Behaviour. 2005;142:1417-31.

Armario A, Castellanos JM, Balasch J. Effect of crowding on emotional reactivity in male rats. Neuroendocrinology. 1984;39:330-3.

Blanchard RJ, Blanchard DC. Antipredator defensive behaviors in a visible burrow system. J Comp Psychol. 1989;103:70-82.

Tornatzky W, Miczek KA. Long-term impairment of autonomic circadian rhythms after brief intermittent social stress. Physiol Behav. 1993;53:983-93.

Miczek KA, Yap JJ, Covington 3rd HE. Social stress, therapeutics and drug abuse: preclinical models of escalated and depressed intake. Pharmacol Ther. 2008;120:102-28.

Haller J, Harold G, Sandi C, Neumann ID. Effects of adverse early-life events on aggression and anti-social behaviours in animals and humans. J Neuroendocrinol. 2014;26:724-38.

Lopez NL, Vazquez DM, Olson SL. An integrative approach to the neurophysiological substrates of social withdrawal and aggression. Dev Psychopathol. 2004;16:69-93.

Blair RJR. The roles of orbital frontal cortex in the modulation of antisocial behavior. Brain Cogn. 2004;55:198-208.

de Almeida RMM, Ferrari PF, Parmigiani S, Miczek KA. Escalated aggressive behavior: dopamine, serotonin and GABA. Eur J Pharmacol. 2005;526:51-64.

Adamec RE, Stark-Adamec CI. Limbic control of aggression in the cat. Prog Neuro-Psychoph. 1983;7:505-12.

Adams DB, Boudreau W, Cowan CW, Kokonowski C, Oberteuffer K, Yohay K. Offense produced by chemical stimulation of the anterior hypothalamus of the rat. Physiol Behav. 1993;53:1127-32.

Delville Y, De Vries GJ, Ferris CF. Neural connections of the anterior hypothalamus and agonistic behavior in golden hamsters. Brain Behav Evol. 2000;55:53-76.

Halász J, Tóth M, Kalló I, Liposits Z, Haller J. The activation of prefrontal cortical neurons in aggression—a double labeling study. Behav Brain Res. 2006;175:166-75.

Joppa MA, Meisel RL, Garber MA. -Fos expression in female hamster brain following sexual and aggressive behaviors. Neuroscience. 1995;68:783-92.

Kollack-Walker S, Watson SJ, Akil H. Social stress in hamsters: defeat activates specific neurocircuits within the brain. J Neurosci. 1997;17:8842-55.

Kruk MR. Ethology and pharmacology of hypothalamic aggression in the rat. Neurosci Biobehav Rev. 1991;15:527-38.

Luiten PG, Koolhaas JM, de Boer S, Koopmans SJ. The corticomedial amygdala in the central nervous system organization of agonistic behavior. Brain Res. 1985;332:283-97.

Martinez M, Phillips PJ, Herbert J. Adaptation in patterns of c-fos expression in the brain associated with exposure to either single or repeated social stress in male rats. Eur J Neurosci. 1998;10:20-33.

Siegel A, Roeling TA, Gregg TR, Kruk MR. Neuropharmacology of brain-stimulation-evoked aggression. Neurosci Biobehav Rev. 1999;23:359-89.

de Bruin JP, van Oyen HG, Van de Poll N. Behavioural changes following lesions of the orbital prefrontal cortex in male rats. Behav Brain Res. 1983;10:209-32.

Hawkins KA, Trobst KK. Frontal lobe dysfunction and aggression: conceptual issues and research findings. Aggress Violent Beh. 2000;5:147-57.

Boyson CO, Holly EN, Shimamoto A, Albrechet-Souza L, Weiner LA, DeBold JF, Miczek KA. Social stress and CRF-dopamine interactions in the VTA: role in long-term escalation of cocaine self-administration. J Neurosci. 2014;34:6659-67.

Smagin DA, Park JH, Michurina TV, Peunova N, Glass Z, Sayed K, Bondar NP, Kovalenko IN, Kudryavtseva NN, Enikolopov G. Altered hippocampal neurogenesis and amygdalar neuronal activity in adult mice with repeated experience of aggression. Front Neurosci. 2015;9:443.

Vale W, Spiess J, Rivier C, Rivier J. Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin. Science. 1981;213:1394-7.

Ninan I. Synaptic regulation of affective behaviors; role of BDNF. Neuropharmacology. 2014;76:684-95.

Bale TL, Vale WW. CRF and CRF receptors: role in stress responsivity and other behaviors. Annu Rev Pharmacol Toxicol. 2004;44:525-57.

Koob GF. A role for brain stress systems in addiction. Neuron. 2008;59:11-34.

Swanson LW, Sawchenko PE, Rivier J, Vale WW. Organization of ovine corticotropin-releasing factor immunoreactive cells and fibers in the rat brain: an immunohistochemical study. Neuroendocrinology. 1983;36:165-86.

Chen Y, Bender RA, Frotscher M, Baram TZ. Novel and transient populations of corticotropin-releasing hormone-expressing neurons in developing hippocampus suggest unique functional roles: a quantitative spatiotemporal analysis. J Neurosci. 2001;21:7171-81.

Valentino RJ, Van Bockstaele E. Convergent regulation of locus coeruleus activity as an adaptive response to stress. Eur J Pharmacol. 2008;583:194-203.

Britton KT, Lee G, Vale W, Rivier J, Koob GF. Corticotropin releasing factor (CRF) receptor antagonist blocks activating and ‘anxiogenic’ actions of CRF in the rat. Brain Res. 1986;369:303-6.

Coste SC, Heard AD, Phillips TJ, Stenzel-Poore MP. Corticotropin-releasing factor receptor type 2-deficient mice display impaired coping behaviors during stress. Genes Brain Behav. 2006;5:131-8.

Klampfl SM, Neumann ID, Bosch OJ. Reduced brain corticotropin-releasing factor receptor activation is required for adequate maternal care and maternal aggression in lactating rats. Eur J Neurosci. 2013;38:2742-50.

Klampfl SM, Brunton PJ, Bayerl DS, Bosch OJ. Hypoactivation of CRF receptors, predominantly type 2, in the medial-posterior BNST is vital for adequate maternal behavior in lactating rats. J Neurosci. 2014;34:9665-76.

Sahuque LL, Kullberg EF, McGeehan AJ, Kinder JR, Hicks MP, Blanton MG, Janak PH, Olive MF. Anxiogenic and aversive effects of corticotropin-releasing factor (CRF) in the bed nucleus of the stria terminalis in the rat: role of CRF receptor subtypes. Psychopharmacology (Berl). 2006;186:122-32.

Backström T, Winberg S. Central corticotropin releasing factor and social stress. Front Neurosci. 2013;7:117.

Farrokhi C, Blanchard DC, Griebel G, Yang M, Gonzales C, Markham C, Blanchard RJ. Effects of the CRF1 antagonist SSR125543A on aggressive behaviors in hamsters. Pharmacol Biochem Behav. 2004;77:465-9.

Gammie SC, Hasen NS, Stevenson SA, Bale TL, D’Anna KL. Elevated stress sensitivity in corticotropin-releasing factor receptor 2 deficient mice decreases maternal, but not intermale aggression. Behav Brain Res. 2005;160:169-77.

Mele A, Cabib S, Oliverio A, Melchiorri P, Puglisi-Allegra S. Effects of corticotropin releasing factor and sauvagine on social behavior of isolated mice. Peptides. 1987;8:935-8.

Holly EN, Boyson CO, Montagud-Romero S, Stein DJ, Gobrogge KL, DeBold JF. Episodic social stress-escalated cocaine self-administration: role of phasic and tonic corticotropin releasing factor in the anterior and posterior ventral tegmental area. Journal of Neuroscience. 2016;36:4093-105.

Maynard KR, Hill JL, Calcaterra NE, Palko ME, Kardian A, Paredes D. Functional role of BDNF production from unique promoters in aggression and serotonin signaling. Neuropsychopharmacology. 2016;41:1943-55.

Berton O, McClung CA, Dileone RJ, Krishnan V, Renthal W, Russo SJ, Graham D, Tsankova NM, Bolanos CA, Rios M, Monteggia LM, Self DW, Nestler EJ. Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science. 2006;311:864-8.

Remie R. Experimental surgery. The laboratory rat. 2000:523-68.

Harris BN, Saltzman W. Effect of reproductive status on hypothalamic-pituitary-adrenal (HPA) activity and reactivity in male Californiamice (Peromyscus californicus). Physiol Behav. 2013:70-6.

Miczek KA, O’Donnell JM. Alcohol and chlordiazepoxide increase suppressed aggression in mice. Psychopharmacology (Berl). 1980;69:39-44.

Paxinos G, Franklin K. The mouse brain in stereotaxic coordinates. 2001.

Haller J. Related Biochemical background for an analysis of cost-benefit interrelations in aggression. Neurosci Biobehav Rev. 1995;19:599-604.

Haller J, Millar S, Kruk MR. Mineralocorticoid receptor blockade inhibits aggressive behaviour in male rats. Stress. 1998;2:2017.

Kruk MR, Haller J, Meelis W, de Kloet ER. Mineralocorticoid receptor blockade during a rat's first violent encounter inhibits its subsequent propensity for violence. Behav Neurosci. 2013;127:505-14.

Fish EW, Faccidomo S, Miczek KA. Aggression heightened by alcohol or social instigation in mice: reduction by the 5-HT(1B) receptor agonist CP-94,253. Psychopharmacology (Berl). 1999;146:391-9.

Finn DA, Sinnott RS, Ford MM, Long SL, Tanchuck MA, Phillips TJ. Sex differences in the effect of ethanol injection and consumption on brain allopregnanolone levels in C57BL/6 mice. Neuroscience. 2004;123:813-9.

Panksepp J, Burgdorf J, Beinfeld MC, Kroes RA, Moskal JR. Brain regional neuropeptide changes resulting from social defeat. Behav Neurosci. 2007;121:1364-71.

Joëls M, Baram TZ. The neuro-symphony of stress. Nat Rev Neurosci. 2009;10:459-66.

Taylor SL, Stanek LM, Ressler KJ, Huhman KL. Differential brain-derived neurotrophic factor expression in limbic brain regions following social defeat or territorial aggression. Behav Neurosci. 2011;125:911-20.

Haller J, Kruk MR. Normal and abnormal aggression: human disorders and novel laboratory models. Neurosci Biobehav Rev. 2006;30:292-303.

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