Aggression In Male Mice Research Articles

The effects of the dopamine stabilizer (-)-OSU6162 on aggressive and sexual behavior in rodents.

The dopamine stabilizer (−)-OSU61612 dampens locomotion in rodents rendered hyperactive by exposure to a novel environment or treatment with amphetamine, but stimulates locomotion in habituated animals displaying low motor activity, tentatively exerting this profile by selectively blocking extrasynaptic D2 receptors. The major aim of the present study was to explore the possible usefulness of (−)-OSU61612 as an anti-aggressive drug. To this end, the effect of (−)-OSU61612 on isolation-induced aggression in male mice and estrous cycle-dependent aggression in female rats were studied using the resident intruder test; in addition, the possible influence of (−)-OSU61612 on sexual behavior in male mice and on elevated plus maze (EPM) performance in male rats were assessed. (−)-OSU61612 at doses influencing neither locomotion nor sexual activity reduced aggression in male mice. The effect was observed also in serotonin-depleted animals and is hence probably not caused by the antagonism of serotonin receptors displayed by the drug; refuting the possibility that it is due to 5-HT1B activation, it was also not counteracted by isamoltane. (−)-OSU61612 did not display the profile of an anxiogenic or anxiolytic drug in the EPM but caused a general reduction in activity that is well in line with the previous finding that it reduces exploratory behavior of non-habituated animals. In line with the observations in males, (−)-OSU61612 reduced estrus cycle-related aggression in female Wistar rats, a tentative animal model of premenstrual dysphoria. By stabilizing dopaminergic transmission, (−)-OSU61612 may prove useful as a well-tolerated treatment of various forms of aggression and irritability.

Effective Modulation of Male Aggression through Lateral Septum to Medial Hypothalamus Projection

Aggression is a prevalent behavior in the animal kingdom that is used to settle competition for limited resources. Given the high risk associated with fighting, the central nervous system has evolved an active mechanism to modulate its expression. Lesioning the lateral septum (LS) is known to cause "septal rage," a phenotype characterized by a dramatic increase in the frequency of attacks. To understand the circuit mechanism of LS-mediated modulation of aggression, we examined the influence of LS input on the cells in and around the ventrolateral part of the ventromedial hypothalamus (VMHvl)-a region required for male mouse aggression. We found that the inputs from the LS inhibited the attack-excited cells but surprisingly increased the overall activity of attack-inhibited cells. Furthermore, optogenetic activation of the projection from LS cells to the VMHvl terminated ongoing attacks immediately but had little effect on mounting. Thus, LS projection to the ventromedial hypothalamic area represents an effective pathway for suppressing male aggression.

Glutamate input in the dorsal raphe nucleus as a determinant of escalated aggression in male mice.

Although the dorsal raphe nucleus (DRN) has long been linked to neural control of aggression, little is known about the regulatory influences of the DRN when an animal engages in either adaptive species-typical aggressive behavior or escalated aggression. Therefore it is important to explore which neurotransmitter inputs into the DRN determine the escalation of aggression in male mice. Previously, we observed that microinjection of the GABAB receptor agonist baclofen into the DRN escalates aggressive behavior in male mice. Here, we used a serotonin (5-HT) neuron-specific GABAB receptor knock-out mouse to demonstrate that baclofen acts on nonserotonergic neurons to escalate aggression. Intra-DRN baclofen administration increased glutamate release, but did not alter GABA release, within the DRN. Microinjection of l-glutamate into the DRN escalated dose-dependently attack bites toward an intruder. In vivo microdialysis showed that glutamate release increased in the DRN during an aggressive encounter, and the level of glutamate was further increased when the animal was engaged in escalated aggressive behavior after social instigation. Finally, 5-HT release was increased within the DRN and also in the medial prefrontal cortex when animals were provoked by social instigation, and during escalated aggression after social instigation, but this increase in 5-HT release was not observed when animals were engaged in species-typical aggression. In summary, glutamate input into the DRN is enhanced during escalated aggression, which causes a phasic increase of 5-HT release from the DRN 5-HT neurons.

Ephrin-A5 regulates inter-male aggression in mice

The Eph family of receptor tyrosine kinases play key roles in both the patterning of the developing nervous system and neural plasticity in the mature brain. To determine functions of ephrin-A5, a GPI-linked ligand to the Eph receptors, in animal behavior regulations, we examined effects of its inactivation on male mouse aggression. When tested in the resident-intruder paradigm for offensive aggression, ephrin-A5-mutant animals (ephrin-A5−/−) exhibited severe reduction in conspecific aggression compared to wild-type controls. On the contrary, defensive aggression in the form of target biting was higher in ephrin-A5−/− mice, indicating that the mutant mice are capable of attacking behavior. In addition, given the critical role of olfaction in aggressive behavior, we examined the ability of the ephrin-A5−/− mice to smell and found no differences between the mutant and control animals. Testosterone levels in the mutant mice were also found to be within the normal range. Taken together, our data reveal a new role of ephrin-A5 in the regulation of aggressive behavior in mice.

Modification of female and male social behaviors in estrogen receptor beta knockout mice by neonatal maternal separation.

Maternal separation (MS) is an animal model mimicking the effects of early life stress on the development of emotional and social behaviors. Recent studies revealed that MS stress increased social anxiety levels in female mice and reduced peri-pubertal aggression in male mice. Estrogen receptor (ER) β plays a pivotal role in the regulation of stress responses and anxiety-related and social behaviors. Behavioral studies using ERβ knockout (βERKO) mice reported increased social investigation and decreased social anxiety in βERKO females, and elevated aggression levels in βERKO males compared to wild-type (WT) mice. In the present study, using βERKO and WT mice, we examined whether ERβ contributes to MS effects on anxiety and social behaviors. βERKO and WT mice were separated from their dam daily (4 h) from postnatal day 1–14 and control groups were left undisturbed. First, MS and ERβ gene deletion individually increased anxiety-related behaviors in the open field test, but only in female mice. Anxiety levels were not further modified in βERKO female mice subjected to MS stress. Second, βERKO female mice showed higher levels of social investigation compared with WT in the social investigation test and long-term social preference test. However, MS greatly reduced social investigation duration and elevated number of stretched approaches in WT and βERKO females in the social investigation test, suggesting elevated levels of social anxiety in both genotypes. Third, peri-pubertal and adult βERKO male mice were more aggressive than WT mice as indicated by heightened aggression duration. On the other hand, MS significantly decreased aggression duration in both genotypes, but only in peri-pubertal male mice. Altogether, these results suggest that βERKO mice are sensitive to the adverse effects of MS stress on subsequent female and male social behaviors, which could then have overrode the ERβ effects on female social anxiety and male aggression.

Mice in Bion-M 1 space mission: training and selection.

After a 16-year hiatus, Russia has resumed its program of biomedical research in space, with the successful 30-day flight of the Bion-M 1 biosatellite (April 19–May 19, 2013). The principal species for biomedical research in this project was the mouse. This paper presents an overview of the scientific goals, the experimental design and the mouse training/selection program. The aim of mice experiments in the Bion-M 1 project was to elucidate cellular and molecular mechanisms, underlying the adaptation of key physiological systems to long-term exposure in microgravity. The studies with mice combined in vivo measurements, both in flight and post-flight (including continuous blood pressure measurement), with extensive in vitro studies carried out shortly after return of the mice and in the end of recovery study. Male C57/BL6 mice group housed in space habitats were flown aboard the Bion-M 1 biosatellite, or remained on ground in the control experiment that replicated environmental and housing conditions in the spacecraft. Vivarium control groups were used to account for housing effects and possible seasonal differences. Mice training included the co-adaptation in housing groups and mice adaptation to paste food diet. The measures taken to co-adapt aggressive male mice in housing groups and the peculiarities of “space” paste food are described. The training program for mice designated for in vivo studies was broader and included behavioral/functional test battery and continuous behavioral measurements in the home-cage. The results of the preliminary tests were used for the selection of homogenous groups. After the flight, mice were in good condition for biomedical studies and displayed signs of pronounced disadaptation to Earth's gravity. The outcomes of the training program for the mice welfare are discussed. We conclude that our training program was effective and that male mice can be successfully employed in space biomedical research.

Impairment of interstrain social recognition during territorial aggressive behavior in oxytocin receptor-null mice

In humans, oxytocin has been shown to be involved in in-group cooperative behaviors and out-group aggression. Studies have also demonstrated that oxytocin plays a pivotal role in social recognition. However, no empirical research has investigated the effect of oxytocin on in-group and out-group aggressiveness. We employed a resident-intruder paradigm to assess the ability of resident male mice to discriminate intruder male strain differences. We found that resident male mice exhibited higher frequencies of attack bites against intruders of different strains than against intruders of their own strain. Subsequently, we examined whether the interstrain recognition was regulated by the oxytocin system using oxytocin receptor (OTR)-null mice. OTR wild-type or heterozygous residents displayed higher aggression toward intruders of a strain different from their own (C57BL/6J). On the other hand, OTR-null residents exhibited greater aggression toward intruders of the same strain compared to OTR wild-type or heterozygous residents, and aggression levels were not different compared to those exhibited toward other strains. Our findings demonstrated that the oxytocin system contributes to interstrain social recognition in territorial aggression in male mice, implying that one function of oxytocin is to promote an in-group “tend-and-defend” response, such as in-group favoritism, which could be evolutionarily conserved in mammals.

Decoding ventromedial hypothalamic neural activity during male mouse aggression.

The ventromedial hypothalamus, ventrolateral area (VMHvl) was identified recently as a critical locus for inter-male aggression. Optogenetic stimulation of VMHvl in male mice evokes attack toward conspecifics and inactivation of the region inhibits natural aggression, yet very little is known about its underlying neural activity. To understand its role in promoting aggression, we recorded and analyzed neural activity in the VMHvl in response to a wide range of social and nonsocial stimuli. Although response profiles of VMHvl neurons are complex and heterogeneous, we identified a subpopulation of neurons that respond maximally during investigation and attack of male conspecific mice and during investigation of a source of male mouse urine. These "male responsive" neurons in the VMHvl are tuned to both the inter-male distance and the animal's velocity during attack. Additionally, VMHvl activity predicts several parameters of future aggressive action, including the latency and duration of the next attack. Linear regression analysis further demonstrates that aggression-specific parameters, such as distance, movement velocity, and attack latency, can model ongoing VMHvl activity fluctuation during inter-male encounters. These results represent the first effort to understand the hypothalamic neural activity during social behaviors using quantitative tools and suggest an important role for the VMHvl in encoding movement, sensory, and motivation-related signals.

Oxytocin modulates social interaction but is not essential for sexual behavior in male mice

Recently, several studies have shown different conclusions regarding the effect of oxytocin (OT) on the social behaviors of male mice. Most of these studies used exogenous OT, but currently, investigations of the neural bases of social behavior are increasingly employing gene inactivation. This study aimed to analyze the role of OT in the modulation of social behaviors (i.e., sexual and social interaction behaviors) in male mice with selective deletions of the OT gene (OTKO) and the influence of this deletion in basal vasopressin (AVP) plasma concentrations. Our results showed that in the social interaction test, OTKO mice exhibited lower levels of social behaviors and higher levels of non-social behaviors compared to the wild type (WT) group. Additionally, the OTKO group showed a decrease in the number of agonistic behaviors delivered, and consequently, their dominance score was lower than that of the WT group. In the ethological analysis, the OTKO group had a lower aggressive performance and increased social investigation than the WT group. No significant differences were observed in the sexual behavior between groups. Finally, we found lower AVP plasma concentrations in the OTKO compared with the WT group. In conclusion, our data suggest that OT modulates social investigation behavior and the aggressiveness of male mice. The decrease in AVP concentrations in the OTKO group allows us to infer that AVP is physiologically relevant to these behavioral modulations. However, sexual behaviors do not seem to be affected by the lack of OT or by a decrease in the AVP concentration.

Reduction of serotonergic gene expression in the raphe nuclei of the midbrain under positive fighting experience in male mice

The concept of a major inhibitory role of serotonin in aggressive behavior is widely accepted by investigators. There was ample evidence that a pharmacologically-induced increase in the serotonin activity attenuates agonistic behavior in animals, and that the manipulations inhibiting the brain serotonergic system can elicit aggressiveness in male mice and rats. Repeated experience of aggression in daily agonistic interactions has been shown to reduce serotonin activity in brain of victorious male mice. The study aimed to analyze expression of the serotonergic genes -Tph2, Sert, Maoa and Htr1a, as well as the Bdnf and Creb genes in the midbrain raphe nuclei of male mice with positive fighting experience in daily encounters and male mice with the same track record of aggression followed by two-week no-fight period. It has been shown that mRNA levels of the serotonergic and Creb genes are reduced in the winners in comparison with male mice without consecutive positive fighting experience of aggression. After the fighting deprivation the Tph2, Sert, Bdnf and Creb genes recover their expression while mRNA levels of the Maoa and Htr1a genes proceed at a significantly higher level as compared with the respective controls. Downregulation of serotonergic genes is indicative of the inhibition of serotonergic activity under repeated experience of aggression. Nevertheless recovering of Tph2 and Sert gene expression and overexpression of the Maoa and Htr1a genes after no-fight period suggest that changes in brain serotonergic activity are not main cause of the behavioral pathology developing in male mice in this experimental context.

P.1.c.006 Naltrexone effects on aggression in male mice with positive fighting history

P.1.c.006 Naltrexone effects on aggression in male mice with positive fighting history

Urine from Sexually Mature Intact Male Mice Contributes to Increased Cardiovascular Responses during Free-Roaming and Restrained Conditions

Pheromones in the urine regulate aggression of male mice and castrated males produce less of these pheromones. We tested the hypothesis that pheromones in the urine of sexually mature-intact (SMI) males placed in the cage bedding of an individually housed male mouse or in a mouse restrainer would contribute to a significant increase in mean arterial pressure (MAP), heart rate (HR), and activity. Sexually mature male C57BL/6 mice were implanted with a biotelemetry transmitter to measure MAP, HR, and activity. Urine (200 μL) from SMI mice placed in the cages of singularly housed male mice caused significant changes above baseline values for MAP (21 ± 4 mmHg), HR (145 ± 25 bpm), and activity (9 ± 2 counts) when compared to urine from castrated mice-induced MAP (11 ± 3 mmHg), HR (70 ± 15 bpm), and activity (5 ± 1 counts). Pretreatment with terazosin significantly reduced the change in MAP (9 ± 3 mmHg), heart rate (90 ± 15 bpm), and activity (4 ± 2 counts) responses to urine from SMI males. Saline did not significantly increase MAP, HR, or activity in any group. During restraint, urine from SMI mice caused a significant change in MAP (5 ± 0.4 mmHg) and HR (17 ± 1 bpm); urine from castrated mice did not cause a significant increase in MAP and HR. Our results demonstrate that a significant increase in MAP, HR, and activity occurs when male mice are exposed to urine pheromones from SMI males. In summary, pheromones in the urine of SMI male excreted in the cage bedding and mouse restrainers contribute to a significant increase in cardiovascular responses in the absence of direct physical contact with a different male mouse or animal handler.

Early life stress disrupts peripubertal development of aggression in male mice

To investigate the effects of early life stress on the development of social behaviors in male mice, we examined behavioral responses toward same sex stimulus mice in the social investigation test and aggressive behaviors in peripubertal male mice exposed to maternal separation (MS) during the first 2 weeks of life. MS suppressed aggressive behaviors from 5-9 weeks of age, but had no effect on social investigative behaviors in the social investigation test. Investigation of neuroendocrine bases of behavioral effects of MS showed that MS reduced plasma testosterone levels and decreased arginine vasopressin and increased oxytocin immunoreactivity in the paraventricular nucleus of peripubertal males. These results collectively suggest that early life stress disrupts the development of male aggressive behaviors and associated neuroendocrine systems.

Modeling fighting deprivation effect in mouse repeated aggression paradigm

Male mice with a long positive fighting history develop behavioral psychopathology, which includes abnormal aggression, hostility, hyperactivity, stereotypic reactions and other behavioral phenotypes. We also found that the "winners" (mice that had each won 20 daily encounters in succession) develop an enhanced level of aggression after a no-fight period, compared to their respective levels of aggressive behavior before the fighting deprivation. Natural hedonic stimuli (such as access to females or sweet water), supplied to the winners during this no-fight period, appear to play a minor role in triggering this phenomenon. Therefore, it appears that fighting deprivation per se stimulates an elevated aggression in male mice, which also display aberrant behaviors formed under repeated experience of aggression accompanied by victories. This behavioral approach may be useful for modeling the effect of fighting deprivation in mouse paradigms based on repeated aggression.

GABABReceptor Modulation of Serotonin Neurons in the Dorsal Raphé Nucleus and Escalation of Aggression in Mice

The serotonin (5-HT) system in the brain has been studied more than any other neurotransmitter for its role in the neurobiological basis of aggression. However, which mechanisms modulate the 5-HT system to promote escalated aggression is not clear. We here explore the role of GABAergic modulation in the raphé nuclei, from which most 5-HT in the forebrain originates, on escalated aggression in male mice. Pharmacological activation of GABA(B), but not GABA(A), receptors in the dorsal raphé nucleus (DRN) escalated aggressive behaviors. In contrast, GABA agonists did not escalate aggressive behaviors after microinjection into the median raphé nucleus. The aggression-heightening effect of the GABA(B) agonist baclofen depended on the activation of 5-HT neurons in the DRN because it was blocked by coadministration of the 5-HT(1A) agonist 8-OH-DPAT [((+/-)-8-hydroxy-2-(di-n-propylamino)tetralin) hydrobromide] (DPAT), which acts on autoreceptors and inhibits 5-HT neural activity. In vivo microdialysis showed that GABA(B) activation in the DRN increased extracellular 5-HT level in the medial prefrontal cortex. This may be attributable to an indirect action via presynaptic GABA(B) receptors. The presynaptic GABA(B) receptors suppress Ca(2+) channel activity and inhibit neurotransmission, and the coadministration of N-type Ca(2+) channel blocker facilitated the effect of baclofen. These findings suggest that the indirect disinhibition of 5-HT neuron activity by presynaptic GABA(B) receptors on non-5-HT neurons in the DRN is one of the neurobiological mechanisms of escalated aggression.

Effects of LY379268, A Selective Agonist of mGLu2/3 Receptors, on Isolation-Induced Aggression in Male Mice

Recent studies indicate that glutamate metabotropic receptors (mGlu) 1 and 5 are involved in the regulation of aggressive behaviour. Brain distribution of mGlu2/3 receptors suggests that they may also play important roles in emotional responses, including aggression. This study examines the effects of LY379268 (0.25- 4 mg/kg, ip), a selective agonist of the mGlu2/3 receptors, on agonistic interactions between male mice using an animal model of isolation-induced aggression. Individually housed mice were exposed to anosmic “standard opponents” 30 min after drug administration. Ten min of diadic interactions were staged between a singly housed and an anosmic mouse in a neutral area. The encounters were videotaped and the accumulated time allocated by subjects to ten broad behavioural categories was estimated using an ethologically based analysis. LY379268 (2 mg/kg) significantly reduced attack behaviour, as compared with the control group, without affecting immobility, whereas the highest dose of the drug (4 mg/kg) also decreased offensive behaviours (threat and attack), but with a marked increase of immobility (non-selective effect). These results indicate that mGlu2/3 receptors might be implicated in the modulation of aggression.

Effects of progesterone on male-mediated infant-directed aggression

Many species that engage in parental behavior exhibit infanticide under certain circumstances. The neural signals regulating the transition from infant care giver to infant killer and back remain unclear. Previously we demonstrated that progesterone (P) and its receptor (PR) have inhibitory effects on parental behavior and increase infant-directed aggression in male mice. In the present studies we sought to elucidate the mechanisms by which the effects of P are manifested. Because the onset of parental behavior in females is associated with the withdrawal of P at the end of pregnancy we tested the hypothesis that withdrawal of P would similarly enhance parental behavior in males. Virgin male mice were implanted with P or vehicle for 21 days, replicating the duration of pregnancy in females. Tests were run for parental and infanticidal behavior 5 days after removal of the capsules. P increased the proportion of nonparental males that attacked pups. However, neither the number of males exhibiting parental care nor the quality of care was affected by P treatment. Serum P and testosterone (T) levels were not different from controls at the time of behavioral testing indicating continued elevations in peripheral hormones are not required for the expression of infanticide. In conclusion, withdrawal of P does not trigger the onset of parental behavior in males. Rather, prior exposure to P induces persistent infanticidal behavior in adult male mice.

P.1.d.001 A selective mglu1 receptor antagonist, jnj16259685, suppresses isolation-induced aggression in male mice

P.1.d.001 A selective mglu1 receptor antagonist, jnj16259685, suppresses isolation-induced aggression in male mice

P.1.d.006 Effects of LY379268, a selective agonist of mGlu2/3 receptors, on isolation-induced aggression in male mice

Recent studies indicate that glutamate metabotropic receptors (mGlu) 1 and 5 are involved in the regulation of aggressive behaviour. Brain distribution of mGlu2/3 receptors suggests that they may also play important roles in emo- tional responses, including aggression. This study examines the effects of LY379268 (0.25- 4 mg/kg, ip), a selective ago- nist of the mGlu2/3 receptors, on agonistic interactions between male mice using an animal model of isolation-induced aggression. Individually housed mice were exposed to anosmic standard opponents 30 min after drug administration. Ten min of diadic interactions were staged between a singly housed and an anosmic mouse in a neutral area. The encoun- ters were videotaped and the accumulated time allocated by subjects to ten broad behavioural categories was estimated us- ing an ethologically based analysis. LY379268 (2 mg/kg) significantly reduced attack behaviour, as compared with the control group, without affecting immobility, whereas the highest dose of the drug (4 mg/kg) also decreased offensive be- haviours (threat and attack), but with a marked increase of immobility (non-selective effect). These results indicate that mGlu2/3 receptors might be implicated in the modulation of aggression.

Influences of Pre- and Postnatal Early Life Environments on the Inhibitory Properties of Familiar Urine Odors in Male Mouse Aggression

For group-living animals, discriminating among individuals and chasing unfamiliar strangers away from the home range are important to protect their territory. Previously, we reported that the familiar individual information conveyed by urine results in less aggressive behavior by resident male mice toward intruders. A resident male is aggressive toward an intruding unfamiliar castrated C57BL/6J mouse (unfamiliar castrated male [UFC]), whereas there is less aggression by the resident male when the UFC is swabbed with urine collected from the resident's cage mate. Urine is affected by various factors, including the environment. In this study, we investigated the effect of 2 living environments, the early developmental environment and the adult diet, on individual information conveyed in urine. Aggressive behavior toward UFCs was lower when UFCs were swabbed with cage mate urine or urine from a cage mate's littermate that was not living with the resident male (UFCL). Litters were cross-fostered, and we examined whether the pre- or postnatal period was important for formation of individual urine odor. The resident male displayed attack bites toward UFCs that were his cage mate's littermates but were fostered by another C57BL/6J dam. In addition, a castrated male that was reared with a cage mate (sharing the same postnatal environment) but that was not his littermate was also attacked by the resident male, suggesting that littermates that share the same pre- and postnatal environments provide similar (or identical) information, which inhibits aggression. In adulthood, even after dietary changes, the resident male showed less aggression toward UFCs when the UFCs were swabbed with the cage mate's urine, which was collected before a dietary change, indicating that individual information was not affected by dietary conditions in adulthood. In a habituation-dishabituation test, resident mice could discriminate among all pairs of mouse urine from each group. These results suggest that olfactory cues containing individual information are shared among littermates, and both the pre- and postnatal environments are important for formation of the information that inhibits aggressive behavior. This individual information might differ from the odor that is used for discriminating in the habituation-dishabituation test.