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Towards a neurobiology of female aggression
Abstract
Although many people think of aggression as a negative or undesirable emotion, it is a normal part of many species’ repertoire of social behaviors. Purposeful and controlled aggression can be adaptive in that it warns other individuals of perceived breaches in social contracts with the goal of dispersing conflict before it escalates into violence. Aggression becomes maladaptive, however, when it escalates inappropriately or impulsively into violence. Despite ample data demonstrating that impulsive aggression and violence occurs in both men and women, aggression has historically been considered a uniquely masculine trait. As a result, the vast majority of studies attempting to model social aggression in animals, particularly those aimed at understanding the neural underpinnings of aggression, have been conducted in male rodents. In this review, we summarize the state of the literature on the neurobiology of social aggression in female rodents, including social context, hormonal regulation and neural sites of aggression regulation. Our goal is to put historical research in the context of new research, emphasizing studies using ecologically valid methods and modern sophisticated techniques.
This article is part of the Special Issue entitled ‘Current status of the neurobiology of aggression and impulsivity’.
... Conversely, female aggression and social dominance have been relatively understudied, with most work focused on maternal aggression expressed by females when they are pregnant or during the early postpartum period where the behavioral focus is on maternal defense of offspring 7,8 . Few studies have investigated the contextual and neurobiological factors that influence female-female aggression outside of reproduction in rodents 9,10 . ...
... The neurobiological basis of female intrasexual aggression among non-reproductive females is receiving increased attention though much less is still known compared to male intrasexual aggression 9,10 . As in males, brain regions in the social behavior network (medial amygdala (meA), bed nucleus of the stria terminalis (BNST), lateral septum (LS), medial preoptic area (mPOA), anterior hypothalamus (AH), ventromedial hypothalamus (VMH) and periaqueductal grey (PAG)) as well as the mesocorticolimbic dopamine pathway have been found to form the basis of the neural circuit regulating aggression, though there are some important sex differences 10 . ...
... As in males, brain regions in the social behavior network (medial amygdala (meA), bed nucleus of the stria terminalis (BNST), lateral septum (LS), medial preoptic area (mPOA), anterior hypothalamus (AH), ventromedial hypothalamus (VMH) and periaqueductal grey (PAG)) as well as the mesocorticolimbic dopamine pathway have been found to form the basis of the neural circuit regulating aggression, though there are some important sex differences 10 . In particular, it is well-established that the VMH is a key modulator of aggression in non-reproductive female rodents 9 . Further, estradiol, the major estrogen steroid hormone, has been primarily associated with promoting aggressive behaviors in females [45][46][47] . ...
Social hierarchies emerge when animals compete for access to resources such as food, mates or physical space. Wild and laboratory male mice have been shown to develop linear hierarchies, however, less is known regarding whether female mice have sufficient intrasexual competition to establish significant social dominance relationships. In this study, we examined whether groups of outbred CD-1 virgin female mice housed in a large vivaria formed social hierarchies. We show that females use fighting, chasing and mounting behaviors to rapidly establish highly directionally consistent social relationships. Notably, these female hierarchies are less linear, steep and despotic compared to male hierarchies. Female estrus state was not found to have a significant effect on aggressive behavior, though dominant females had elongated estrus cycles (due to increased time in estrus) compared to subordinate females. Plasma estradiol levels were equivalent between dominant and subordinate females. Subordinate females had significantly higher levels of basal corticosterone compared to dominant females. Analyses of gene expression in the ventromedial hypothalamus indicated that subordinate females have elevated ERα, ERβ and OTR mRNA compared to dominant females. This study provides a methodological framework for the study of the neuroendocrine basis of female social aggression and dominance in laboratory mice.
... Abbreviations are: BDNFbrain-derived neurotrophic factor; GSK3-β-glycogen synthase kinase-3 beta; GABA-gammaaminobutyric acid; IRS-1-insulin receptor substrate-1; IRS-2-insulin receptor substrate-2; 5-HT-5-hydroxytryptamine (serotonin); ERα-α-isoform of the oestrogen receptor; D2Rß dopamine D2 receptor; V1bR-vasopressin 1b receptor. Increased aggressive behaviours in females, deficient neuroplasticity and reduced neurogenesis [68][69][70][71] ...
... Recently, the prairie vole (Microtus ochrogaster) has emerged as a new animal model for investigating the neurobiology of escalated aggression and violence because, ethologically, their mating is accompanied by aggressive behaviour directed toward both male and female conspecifics [39]. Another highly recognized model of female territorial aggression is the Syrian hamster (Mesocricetus auratus), because in this species both males and females are highly territorial and females tend to be aggressive and dominant over male intruders [70,71]. However, although there are rodent models of female aggression that mimic ethologically relevant behaviours, little research is directed towards modelling female aggression in pathology, including MDD. ...
Aggression and deficient cognitive control problems are widespread in psychiatric disorders, including major depressive disorder (MDD). These abnormalities are known to contribute significantly to the accompanying functional impairment and the global burden of disease. Progress in the development of targeted treatments of excessive aggression and accompanying symptoms has been limited, and there exists a major unmet need to develop more efficacious treatments for depressed patients. Due to the complex nature and the clinical heterogeneity of MDD and the lack of precise knowledge regarding its pathophysiology, effective management is challenging. Nonetheless, the aetiology and pathophysiology of MDD has been the subject of extensive research and there is a vast body of the latest literature that points to new mechanisms for this disorder. Here, we overview the key mechanisms, which include neuroinflammation, oxidative stress, insulin receptor signalling and abnormal myelination. We discuss the hypotheses that have been proposed to unify these processes, as many of these pathways are integrated for the neurobiology of MDD. We also describe the current translational approaches in modelling depression, including the recent advances in stress models of MDD, and emerging novel therapies, including novel approaches to management of excessive aggression, such as anti-diabetic drugs, antioxidant treatment and herbal compositions.
... In closing, we suggest that when investigating the neurobiology of social behaviour, it is important to consider the broader biology of the chosen model. In the case of aggression in female rodents, most studies include either lactating mothers or induced forms of aggression, such as those arising from social isolation or from the resident-intruder paradigm [4,6,77]. Although such paradigms may have predictive value, they may not faithfully replicate all forms of ecologically relevant aggression, potentially limiting the broad applicability and translatability of neural findings [78,79]. ...
Aggression and its neurochemical modulators are typically studied in males, leaving the mechanisms of female competitive aggression or dominance largely unexplored. To better understand how competitive aggression is regulated in the primate brain, we used receptor autoradiography to compare the neural distributions of oxytocin and vasopressin receptors in male and female members of female-dominant versus egalitarian/codominant species within the Eulemur genus, wherein dominance structure is a reliable proxy of aggression in both sexes. We found that oxytocin receptor binding in the central amygdala (CeA) was predicted by dominance structure, with the members of three codominant species showing more oxytocin receptor binding in this region than their peers in four female-dominant species. Thus, both sexes in female-dominant Eulemur show a pattern consistent with the regulation of aggression in male rodents. We suggest that derived pacifism in Eulemur stems from selective suppression of ancestral female aggression over evolutionary time via a mechanism of increased oxytocin receptor binding in the CeA, rather than from augmented male aggression. This interpretation implies fitness costs to female aggression and/or benefits to its inhibition. These data establish Eulemur as a robust model for examining neural correlates of male and female competitive aggression, potentially providing novel insights into female dominance.
... Despite the universal existence of aggression among higher-order animals (Been et al. 2019), a comprehensive explanation has remained elusive. The reasons are many. ...
The study of interpersonal aggression has been carried out for the most part in separate spheres by experts from an array of academic disciplines. To advance a deeper understanding of these issues, however, requires a more conciliatory and interdisciplinary approach. The article offers just such an integrated approach, using a multi-level heuristic framework that has direct parallels with ecological modeling. In addition, the approach expands the analytic focus to reflect different aspects of complex human behavior, which include: 1) the behavioral investment framework, or the bio-psychological reality of the human animal; 2) the socialization framework, or the social psychological aspects of human learning and development; 3) the justification framework, or the language, knowledge, and meaning systems that one acquires to facilitate interpersonal communication and to justify one’s actions; 4) the social location framework, or the social interactional dynamics of interpersonal relationships that animate one’s daily life as a member of various groups and social networks; and 5) the societal context framework, or the broader institutional forms and sociocultural conditions within which individuals and groups are situated. The current approach bridges human neurophysiology and psychology with sociology in a developmental, ecological context that examines each dimension of human behavior. While the five dimensions can be separated analytically, in practice these overlap to exert multiple influences. Such a conciliatory framing permits a more comprehensive analysis of human social animals as situated within their natural environments. The paper outlines how each of the five levels contributes to expressions of interpersonal aggression by elaborating on key mechanisms that operate across the different levels of informational complexity. Several examples of empirical research are cited to illustrate the core principles that operate within and across the five complementary frameworks. Keywords: interpersonal aggression, violence, ecological model, integrated framework
... This finding shows that the aggressive behaviors of males are influenced by heredity to a greater extent than those of females. However, there is still a dearth of research on females' aggressive behaviors from a neurobiological perspective, which imposes a barrier to accurately explaining gender differences in the hereditary basis of aggressive behaviors (Been et al., 2019). ...
The effects of the interaction between polygenes and the parent–child relationship on junior high school students' aggressive behaviors were explored through the frameworks of gene‐endophenotype‐behavior and neurophysiological basis. A total of 892 junior high school students participated in this study. They were asked to complete self‐reported questionnaires, and saliva samples were collected. Results showed that 5‐HTTLPR, MAOA‐uVNTR, COMT (rs4680), and Taq1 (rs1800497) of the DRD2 gene affected students' aggressive behaviors in an accumulative way. The polygenic risk score explained 3.4% of boys' aggression and 1.1% of girls' aggression. The interactions between polygenic risk score and parent–child conflict significantly affected the aggressive behaviors of male students, but did not show any significant effect on those of female students. The interactional effect of polygenic risk score and parent–child conflict on junior high school students' aggressive behaviors was completely mediated by frustration. However, the interaction effect of polygenic risk score and parent–child affinity on aggression was not affected by frustration. This study helps us better understand junior high school students' aggressive behaviors and promotes the prevention and correction of adolescents' problem behaviors.
... Aggression has many uses and causes in animals, and many different species display aggression in a wide range of contexts. In some species females use aggression for the same reason as their male counterparts -in defense or acquisition of resources (Been et al., 2019;Duque-Wilckens & Trainor, 2017). This could be performing aggression in defense of a territory (Goymann et al., 2008;Rosvall, 2008), in defense of a mate (Bales & Carter, 2003;Bowler et al., 2002;Goymann et al., 2008), or to maintain dominance status (Lord et al., 2021). ...
Despite how widespread female aggression is across the animal kingdom, there remains much unknown about its neuroendocrine mechanisms, especially in females that engage in aggression outside the peripartum period. Although the impact of experience in aggressive encounters on steroid hormone responses have been described, little is known about the impact of these experiences on female behavior or their neuropeptide responses. In this study, we compared behavioral responses in both male and female adult California mice based on if they had 0, 1, or 3 aggressive encounters using a modified resident intruder paradigm. We measured how arginine vasopressin and oxytocin cells in the paraventricular nucleus responded to aggression using cfos immunohistochemistry. We saw that both sexes disengaged with intruders with repeated aggressive encounters, but that on the final day of testing females were most likely to freeze when they encountered intruders compared to no aggression controls, which was not significant in males. Finally, we saw that percent of arginine vasopressin and cfos colocalizations in the posterior region of the paraventricular nucleus increased in males who fought compared to no aggression controls. No difference was observed in females. Overall, there is evidence that engaging in aggression induces stress responses in both sexes, and that females may be more sensitive to the effects of fighting.
... As reviewed by Been et al. [46], the existing body of research on human aggression has consistently shown a higher prevalence of physical aggression in boys and men compared to girls and women. However, recent evidence suggests that this sex difference is diminishing; for example, the prevalence of conduct disorder in girls is increasing [6]. ...
While aggression is an adaptive behavior mostly triggered by competition for resources, it can also in and of itself be rewarding. Based on the common notion that female rats are not aggressive, much of aggression research has been centered around males, leading to a gap in the understanding of the female aggression neurobiology. Therefore, we asked whether intact virgin female rats experience reward from an aggressive interaction and assessed aggression seeking behavior in rats of both sexes. To validate the involvement of reward signaling, we measured mesolimbic dopamine turnover and determined the necessity of dopamine signaling for expression of aggression-seeking. Together our data indicate that female rats exhibit aggressive behavior outside of maternal context, experience winning aggressive behaviors as rewarding, and do so to a similar extent as male rats and in a dopamine-dependent manner.
... Furthermore, in a sample of males and females using AAS, no signi cant associations between dose or duration of use and aggression were found (36). However, it is important to note that aggressive behavior is a complicated phenomenon, which is in uenced by interactions between many factors including neurobiological, environmental, and endocrine variables (53). This complexity contributes to the comorbidities between disorders associated with aggressive behaviors and other psychiatric conditions. ...
Background
Anabolic-androgenic steroids (AAS) are commonly taken to increase muscle size and enhance performance. However, AAS can lead to many adverse effects, including challenges with mental health and behavior. This study aims to identify behavioral and psychological correlates of AAS use and dependence among female weightlifters.
Methods
A sample of n = 32 female weightlifters, including 16 with reported AAS use completed questionnaires including the Achenbach System of Empirically Based Assessment (ASEBA) and Buss-Perry Aggression Questionnaire (BPAQ). AAS dependence was evaluated using the Structure Clinical Interview for DSM-IV. Group comparisons were made using Welch’s t-tests between control and AAS groups, and AAS dependent and non-dependent groups. Correlations were computed between symptoms of dependence and behavioral and psychiatric scales.
Results
Females who had used AAS had higher levels of both externalizing and internalizing psychopathology, as well as aggressive traits. Several ASEBA scales including antisocial, externalizing problems and ADHD were correlated with aggressive traits. The most prevalent dependence symptoms were time spent on activities surrounding AAS use (n = 7, 50%), and using more or for longer than planned (n = 6, 42.9%). Dependence symptoms were associated with several ASEBA scales: tolerance was correlated with aggressive behavior (ρ = 0.79, p < 0.001), withdrawal was correlated with attention problems (ρ = 0.78, p < 0.001), and being unable to quit use was associated with anxious/depressive (ρ = 0.80, p < 0.001) and internalizing problems (ρ = 0.79, p < 0.001).
Conclusions
Females who currently or previously used AAS demonstrated significantly more difficulties with maladaptive functioning and aggressive traits compared to those who have never used. Attention problems may represent an underlying shared risk factor for both aggressive traits and symptoms of AAS dependence.
... Leban and Delacruz [18] specifically noted increased odds of violent delinquency in both boys and girls having experienced ACEs but also stated this effect to be more pronounced in boys. However, Been and colleagues [19] referred to it an archaic belief that women would not readily engage in violence, even though it is noteworthy that there is some evidence men and women express aggression differently [20]. ...
Background
Violence occurs frequently in the life of forensic psychiatric patients, both as active aggression and in the form of victimization. Undoubtedly, these incidents shape personality, behavior, and affect the ability to interact adequately socially. Thus, such experiences may influence criminal recidivism and serve as forensic psychiatric/psychological predictors upon hospital discharge.
Methods
Hence, this study aimed at characterizing two distinct female forensic psychiatric patient populations (nonsubstance use mental disorders [ n = 110] versus substance use disorder [ n = 415]) regarding their active and passive violent experiences as well as contextualizing these with their individual crime recidivism rates. The analysis followed a record-based, retrospective approach.
Results
While both groups experienced aggression throughout childhood and youth equally often, substance use disorder patients were significantly more often exposed to violence during adulthood. On the other hand, severely mentally ill patients tended to react more often with violence during their hospital confinement. However, regarding their violent recidivism rate, no intergroup effects were observed. Finally, within the addicted group, a violent index crime as well as physical aggression during hospital confinement increased the odds for violent reoffending by approximately 2.4-fold (95% confidence interval 1.3–4.5) and 2.5-fold (95% confidence interval 1.1–5.9), respectively.
Conclusion
In summary, these findings underline the importance of active aggression rather than victimization as an influencing factor on resocialization especially in a substance use disorder patient population.
... Artificially extending this cycle in females with chronic estradiol exposure reduces aggression toward males (at the same time increasing the females' sexual responses), yet maintains high levels of aggression toward other female hamsters (Meisel et al. 1988). It is this pattern of behavior that has made Syrian hamsters a good model of aggression for both males and females (Albers et al. 2002;Been et al. 2019). ...
... Along with these types of observations, a recent study was able to link VTA hyper-reactivity to impulsive aggression and anti-sociality [96]. It is also worthwhile to note that Been and colleagues [10] underlined the VTA as a key node in the female rather than male circuitry of aggression. ...
Aggression can be conceptualized as any behavior, physical or verbal, that involves attacking another person or animal with the intent of causing harm, pain or injury. Because of its high prevalence worldwide, aggression has remained a central clinical and public safety issue. Aggression can be caused by several risk factors, including biological and psychological, such as genetics and mental health disorders, and socioeconomic such as education, employment, financial status, and neighborhood. Research over the past few decades has also proposed a link between alcohol consumption and aggressive behaviors. Alcohol consumption can escalate aggressive behavior in humans, often leading to domestic violence or serious crimes. Converging lines of evidence have also shown that trauma and posttraumatic stress disorder (PTSD) could have a tremendous impact on behavior associated with both alcohol use problems and violence. However, although the link between trauma, alcohol, and aggression is well documented, the underlying neurobiological mechanisms and their impact on behavior have not been properly discussed. This article provides an overview of recent advances in understanding the translational neurobiological basis of aggression and its intricate links to alcoholism and trauma, focusing on behavior. It does so by shedding light from several perspectives, including in vivo imaging, genes, receptors, and neurotransmitters and their influence on human and animal behavior.
... however, revise existing approaches for studying physical aggression. Ethnographic evidence continues to reveals a gap between public perception and extant literature on female aggression; and in spite of this, female subjects continue to be excluded from this portion of the empirical literature(Denson et al., 2018;Been, Gibbons, & Meisel, 2019) and, there is a clear need for additional work. Although aggression among females has been almost entirely unexplored in humans, there is one form of female aggression that is well-known in the natural world for both its ferocity and relentless efficacy. ...
In the present article, we examine the relatively recent and substantial increase in physical aggression among adolescent females. We review what is known about the prevalence and specific characteristics of aggression among adolescent females, and then propose a novel way of understanding this behavior. Existing evidence from multiple academic disciplines is reviewed and integrated to propose a new framework for considering the underpinnings of physical aggression in females. Most examinations of physical aggression in females have focused on non-human animal models of maternal aggression. In spite of this, the growing prevalence of physical aggression among adolescent females continues to be poorly understood. We endeavor to integrate multiple viewpoints on female aggression and posit a conceptualization of female aggression among adolescents that reflects an immature, socially inexperienced, precursor to functional maternal aggression.
... Artificially extending this cycle in females with chronic estradiol exposure reduces aggression toward males (at the same time increasing the females' sexual responses), yet maintains high levels of aggression toward other female hamsters (Meisel et al. 1988). It is this pattern of behavior that has made Syrian hamsters a good model of aggression for both males and females (Albers et al. 2002;Been et al. 2019). ...
Syrian hamsters are a valuable, if underused, model system for studying the neurobiology of aggression. Male and female hamsters live in fields where they defend territories surrounding their individual burrows. With repeated aggressive experience, hamsters show an escalation of aggression as measured by a reduction in the time to initiate an attack. In contrast, defeated hamsters develop passivity and subordination. Both the escalation of aggression and development of submission activate the mesolimbic system, though through different circuits. Plasticity in the mesolimbic system mediates these changes in behavior, engaging synaptic transmission via both classic neurotransmitters and neuropeptides. At the same time that both male and female hamsters engage in territorial defense and aggression, there are sex differences in the underlying neurobiological control. These characteristics of hamsters make them an ideal model for studying normal and pathological aggression, along with developing therapeutics to treat pathological aggression separately in males and females.
... However, aggression is a natural behavior commonly displayed throughout the animal kingdom and is essential for the allocation of resources, fitness and mental health [1][2][3][4]. Furthermore, in addition to the adaptive consequences of aggression being understudied, aggression is also historically understudied in females [5]. In fact, due to male-centered societal constructs and the poor to non-existent models for eliciting aggression in female mice and rats, almost nothing is known about the neural mechanisms of aggression in females [6]. ...
Like many social behaviors, aggression can be rewarding, leading to behavioral plasticity. One outcome of reward-induced aggression is the long-term increase in the speed in which future aggression-based encounters is initiated. This form of aggression impacts dendritic structure and excitatory synaptic neurotransmission in the nucleus accumbens, a brain region well known to regulate motivated behaviors. Yet, little is known about the intracellular signaling mechanisms that drive these structural/functional changes and long-term changes in aggressive behavior. This study set out to further elucidate the intracellular signaling mechanisms regulating the plasticity in neurophysiology and behavior that underlie the rewarding consequences of aggressive interactions. Female Syrian hamsters experienced zero, two or five aggressive interactions and the phosphorylation of proteins in reward-associated regions was analyzed. We report that aggressive interactions result in a transient increase in the phosphorylation of extracellular-signal related kinase 1/2 (ERK1/2) in the nucleus accumbens. We also report that aggressive interactions result in a transient decrease in the phosphorylation of mammalian target of rapamycin (mTOR) in the medial prefrontal cortex, a major input structure to the nucleus accumbens. Thus, this study identifies ERK1/2 and mTOR as potential signaling pathways for regulating the long-term rewarding consequences of aggressive interactions. Furthermore, the recruitment profile of the ERK1/2 and the mTOR pathways are distinct in different brain regions.
... Moreover, laboratory animals were selected over generations for phenotypes that fit the needs of experimentalists, and this selection may have a profound effect on social behaviors in both males and females. For example, female aggression is more profound in wild-caught mice than in laboratory mice (see e.g., Been et al., 2019). Emerging tools now make it possible to manipulate neural circuits in non-genetic model systems (Ding et al., 2019;Navabpour et al., 2020). ...
Mating is essential for the reproduction of animal species. As mating behaviors are high-risk and energy-consuming processes, it is critical for animals to make adaptive mating decisions. This includes not only finding a suitable mate, but also adapting mating behaviors to the animal’s needs and environmental conditions. Internal needs include physical states (e.g., hunger) and emotional states (e.g., fear), while external conditions include both social cues (e.g., the existence of predators or rivals) and non-social factors (e.g., food availability). With recent advances in behavioral neuroscience, we are now beginning to understand the neural basis of mating behaviors, particularly in genetic model organisms such as mice and flies. However, how internal and external factors are integrated by the nervous system to enable adaptive mating-related decision-making in a state- and context-dependent manner is less well understood. In this article, we review recent knowledge regarding the neural basis of flexible mating behaviors from studies of flies and mice. By contrasting the knowledge derived from these two evolutionarily distant model organisms, we discuss potential conserved and divergent neural mechanisms involved in the control of flexible mating behaviors in invertebrate and vertebrate brains.
... Cellular activity in core structures of the neuroaxis is increased during intense social conflict such as in female and male hamsters, and in rats during attempts to copulate or during fighting as indicated by increased c-fos expression (Been et al. 2019;Kollack-Walker and Newman 1995;Newman 1999). One view of these initial immediate early gene data holds that aggressive, sexual, parental, and other social behavior share many overlapping neurobiological mechanisms. ...
Rationale
Alcohol consumption is a common antecedent of aggressive behavior. The effects of alcohol on the decision to engage in aggression in preference over pro-social interaction are hypothesized to arise from augmented function within the medial prefrontal cortex (mPFC).
Objective
In a newly developed procedure, we studied social decision-making in male C57BL/6 J mice based on preferentially seeking access to either sociosexual interactions with a female partner or the opportunity to attack an intruder male. While deciding to engage in aggressive vs. sociosexual behavior, corresponding neural activation was assessed via c-Fos immunoreactivity in cortical, amygdaloid and tegmental regions of interest. A further objective was to investigate how self-administered alcohol impacted social choice.
Methods
During repeated confrontations with an intruder male in their home cage, experimental mice engaged in species-specific sequence of pursuit, threat, and attack behavior within < 2 min. Mice were then conditioned to respond at one of two separate illuminated operanda in an experimental chamber (octagon) attached to their home cage; completion of 10 responses (fixed ratio 10; FR10) was reinforced by access to either a female or a male intruder which were presented in the resident’s home cage. Brains were harvested following choice between the concurrently available aggressive and sociosexual options and processed for c-Fos immunoreactivity across 10 brain regions. In two separate groups, mice were trained to rapidly self-administer ethanol prior to a social choice trial in order to examine the effects of alcohol on social choice, sociosexual, aggressive acts and postures, and concurrent c-Fos activity in the mPFC and limbic regions.
Results and discussion
Eight out of 65 mice consistently chose to engage in aggressive behavior in preference to sociosexual contact with a female when each outcome was concurrently available. Self-administered alcohol (experiment 1: 1.2 ± 0.02 g/kg; experiment 2: 0, 1.0, 1.5, and 1.8 g/kg) increased responding for the aggressive option in mice that previously opted predominantly for access to sociosexual interactions with the female. When choosing the aggressive, but not the sociosexual option, the prelimbic area of the mPFC revealed increased c-Fos activity, guiding future detailed inquiry into the neural mechanisms for aggressive choice.
... A knockout study in mice with ERα deletion showed reduced aggression (41), whereas another study with ERβ knockout mice demonstrated an increased level of aggression (42). Additionally, female rodents showed increased aggression following ovariectomy, with the aggression levels reduced after treatment with estrogen and progesterone (43). As an estrogen-regulated gene, the loss of Ttc9a might disrupt estrogen activities, leading to the impaired social-related behaviors seen in this study. ...
Objectives:
The involvement of tetratricopeptide repeat domain 9A (TTC9A) in anxiety-like behaviors through estrogen action has been reported in female mice, this study further investigated its effects on social anxiety and aggressive behaviors.
Materials and smethods:
Using female Ttc9a knockout (Ttc9a-/-) mice, the role of TTC9A in anxiety was investigated in non-social and social environments through home-cage emergence and social interaction tests, respectively, whereas aggressive behaviors were examined under the female intruder test.
Results:
We observed significant social behavioral deficits with pronounced social and non-social anxiogenic phenotypes in female Ttc9a-/- mice. When tested for aggressive-like behaviors, we found a reduction in offense in Ttc9a-/- animals, suggesting that TTC9A deficiency impairs the offense responses in female mice.
Conclusion:
Future study investigating mechanisms underlying the social anxiety-like behavioral changes in Ttc9a-/- mice may promote the understanding of social and anxiety disorders.
... Two recent reviews of female aggression highlight the need for studying female aggression across species, including humans (Duque-Wilckens & Trainor, 2017). With respect to specific brain areas, Been et al. (2019) provide an excellent summary of steroid hormone manipulations that influence female aggression and implicate brain regions including the VMH, AH, amygdala, medial preoptic area (mPOA), and BNST. ...
Exploration into the biological bases of aggression has demonstrated the existence of many forms of aggression. Here we investigate the neuroendocrine bases of these types of aggression in rodents. With this, a new emphasis on appetitive and consummatory aggression, and how this framework illuminates our understanding of human aggression, is reviewed. This article reviews several specific types of aggression, starting with the development of aggression, maternal aggression, male-male and femalefemale aggression, and ending with seasonal aggression. We take an initial ethological perspective and then provide evidence for links between neuroendocrine compounds and aggression. Applications to the understanding of human aggression are provided when appropriate. The review reveals the many neuroendocrine drivers of aggression, including sex steroid hormones, hormones involved in the stress axis, the neuropeptides oxytocin and vasopressin, the neurotransmitters GABA, glutamate, serotonin, and dopamine, and the hormone melatonin. We further incorporate brain circuits integrating aggression and neuroendocrinology that includes the social neural network. Overall, the neuroendocrine control of aggression is sophisticated and allows for a significant level of control of aggression through both stimulatory and inhibitory mechanisms.
... As a response to protect their parental investment, females will vigorously defend their pups from them. This maternal aggression [see (17)], via a mechanism involving the Irs4 gene (18), is observed in rats and mice from approximately day 16 of gestation to day 19 of lactation (19). The aggression involves signaling from both the olfactory and vomeronasal epithelia and does not require (but is enhanced in) the presence of pups (20,21). ...
In an attempt to improve reproducibility, more attention is being paid to potential sources of stress in the laboratory environment. Here, we report that the mere proximity of pregnant or lactating female mice causes olfactory-mediated stress-induced analgesia, to a variety of noxious stimuli, in gonadally intact male mice. We show that exposure to volatile compounds released in the urine of pregnant and lactating female mice can themselves produce stress and associated pain inhibition. This phenomenon, a novel form of female-to-male chemosignaling, is mediated by female scent marking of urinary volatiles, such as n -pentyl-acetate, and likely signals potential maternal aggression aimed at defending against infanticide by stranger males.
... [64,65]). However, aggression is also a prominent behaviour in females, which still lacks detailed characterization at the neurobiological and genetic levels [66]. In fish, species-specific sex differences in aggressive behaviour have also been reported [67]. ...
Background
Aggression is an adaptive behaviour that animals use to protect offspring, defend themselves and obtain resources. Zebrafish, like many other animals, are not able to recognize themselves in the mirror and typically respond to their own reflection with aggression. However, mirror aggression is not an all-or-nothing phenomenon, with some individuals displaying high levels of aggression against their mirror image, while others show none at all. In the current work, we have investigated the genetic basis of mirror aggression by using a classic forward genetics approach - selective breeding for high and low mirror aggression zebrafish (HAZ and LAZ).
Results
We characterized AB wild-type zebrafish for their response to the mirror image. Both aggressive and non-aggressive fish were inbred over several generations. We found that HAZ were on average more aggressive than the corresponding LAZ across generations and that the most aggressive adult HAZ were less anxious than the least aggressive adult LAZ after prolonged selective breeding. RNAseq analysis of these fish revealed that hundreds of protein-encoding genes with important diverse biological functions such as arsenic metabolism ( as3mt ), cell migration ( arl4ab ), immune system activity ( ptgr1 ), actin cytoskeletal remodelling ( wdr1 ), corticogenesis ( dgcr2 ), protein dephosphorylation ( ublcp1 ), sialic acid metabolism ( st6galnac3 ) and ketone body metabolism ( aacs ) were differentially expressed between HAZ and LAZ, suggesting a strong genetic contribution to this phenotype. DAVID pathway analysis showed that a number of diverse pathways are enriched in HAZ over LAZ including pathways related to immune function, oxidation-reduction processes and cell signalling. In addition, weighted gene co-expression network analysis (WGCNA) identified 12 modules of highly correlated genes that were significantly associated with aggression duration and/or experimental group.
Conclusions
The current study shows that selective breeding based of the mirror aggression phenotype induces strong, heritable changes in behaviour and gene expression within the brain of zebrafish suggesting a strong genetic basis for this behaviour. Our transcriptomic analysis of fish selectively bred for high and low levels of mirror aggression revealed specific transcriptomic signatures induced by selective breeding and mirror aggression and thus provides a large and novel resource of candidate genes for future study.
... On the other hand, ERα-deficient females show increased aggression (Ogawa et al., 1998), and ERβ-deficient female mice show no aggression (Ogawa et al., 1999), indicating that ERα and ERβ have the opposite effects on aggression in males and females. In addition to hormonal regulation, there are some sex differences within the SBN including the MeA, BNST, LS, PAG and hypothalamus (Been et al., 2019;Hashikawa et al., 2017;Lee et al., 2014;Yang et al., 2013). (see review by Duque-Wilckens and Trainor, 2017). ...
Habenula is an evolutionarily conserved structure in the brain of vertebrates. Recent reports have drawn attention to the habenula as a processing centre for emotional decision-making and its role in psychiatric disorders. Emotional decision-making process is also known to be closely associated with reproductive conditions. The habenula receives innervations from reproductive centres within the brain and signals from key reproductive neuroendocrine regulators such as gonadal steroids, gonadotropin-release hormone (GnRH), and kisspeptin. In this review, based on morphological, biochemical, physiological, and pharmacological evidence we discuss an emerging role of the habenula in reproduction. Further, we discuss the modulatory role of reproductive endocrine factors in the habenula and their association with socio-reproductive behaviours such as mating, anxiety and aggression.
... Maternal infanticide has also been suggested as a behavioural strategy in response to unusually large or small litter size, reduced food supply or disturbance [19,45]. However, the underlying causes of pup infanticide are not always understood since both physiological state and environmental factors may interfere and motivate mice to actively kill newborns [25,30,46]. No male was seen killing a pup. ...
Perinatal mortality is a major issue in laboratory mouse breeding. We compared a counting method using daily checks (DAILY_CHECK) with a method combining daily checks with detailed video analyses to detect cannibalisms (VIDEO_TRACK) for estimating the number of C57BL/6 pups that were born, that died and that were weaned in 193 litters from trios with (TRIO-OVERLAP) or without (TRIO-NO_OVERLAP) the presence of another litter. Linear mixed models were used at litter level. To understand whether cannibalism was associated with active killing (infanticide), we analysed VIDEO_TRACK recordings of 109 litters from TRIO-OVERLAP, TRIO-NO_OVERLAP or SOLO (single dams). We used Kaplan-Meier method and logistic regression at pup level. For DAILY_CHECK, the mean litter size was 35% smaller than for VIDEO_TRACK (p < 0.0001) and the number of dead pups was twice lower (p < 0.0001). The risk of pup loss was higher for TRIO-OVERLAP than TRIO-NO_OVERLAP (p < 0.0001). A high number of pup losses occurred between birth and the first cage check. Analyses of VIDEO_TRACK data indicated that pups were clearly dead at the start of most of the cannibalism events and infanticide was rare. As most pups die and disappear before the first cage check, many breeding facilities are likely to be unaware of their real rates of mouse pup mortality.
... This is also the case in the best-studied rodent models in laboratory settings, including mice, rats, prairie voles, and hamsters. However, in all of these species, both males and females exhibit patterns of agonistic behavior, although often in different contexts (Been et al., 2019). Although female-female aggression is usually considered a behavior displayed almost exclusively to protect offspring, there are multiple instances of competitive aggression among females, both over high-value mates and food sources, in invertebrate and vertebrate species. ...
Aggressive behavior is thought to have evolved as a strategy for gaining access to resources such as territory, food, and potential mates. Across species, secondary sexual characteristics such as competitive aggression and territoriality are considered male-specific behaviors. However, although female–female aggression is often a behavior that is displayed almost exclusively to protect the offspring, multiple examples of female–female competitive aggression have been reported in both invertebrate and vertebrate species. Moreover, cases of intersexual aggression have been observed in a variety of species. Genetically tractable model systems such as mice, zebrafish, and fruit flies have proven extremely valuable for studying the underlying neuronal circuitry and the genetic architecture of aggressive behavior under laboratory conditions. However, most studies lack ethological or ecological perspectives and the behavioral patterns available are limited. The goal of this review is to discuss each of these forms of aggression, male intrasexual aggression, intersexual aggression and female intrasexual aggression in the context of the most common genetic animal models and discuss examples of these behaviors in other species.
... Thus, our findings suggest that the social dominance hierarchy among both male and female groups is more nuanced than the presence of one dominant mouse and a group of subordinate mice as well as that female mice form hierarchies just as male mice do. These findings match with those from Williamson et al. and several other papers reviewed by them [20], most importantly the paper by Been et al. [69]. Notably, this study confirms the finding that female mice also have dominance hierarchies [20], [21, ch. ...
In this study, we investigated the effect of social environment on circadian patterns in activity by group housing either six male or six female mice together in a cage, under regular light–dark cycles. Based on the interactions among the animals, the social dominance rank of individual mice was quantitatively established by calculating Elo ratings. Our results indicated that, during our experiment, the social dominance hierarchy was rapidly established, stable yet complex, often showing more than one dominant mouse and several subordinate mice. Moreover, we found that especially dominant male mice, but not female mice, displayed a significantly higher fraction of their activity during daytime. This resulted in reduced rhythm amplitude in dominant males. After division into separate cages, male mice showed an enhancement of their 24 h rhythm, due to lower daytime activity. Recordings of several physiological parameters showed no evidence for reduced health as a potential consequence of reduced rhythm amplitude. For female mice, transfer to individual housing did not affect their daily activity pattern. We conclude that 24 h rhythms under light–dark cycles are influenced by the social environment in males but not in females, and lead to a decrement in behavioural rhythm amplitude that is larger in dominant mice.
... Thus, social interaction, or more specifically assertiveness, may serve as an effective and drug free treatment strategy for drug addiction and psychiatric disorders like depression (Francis and Lobo, 2017;Nagy and Moore, 2017;Komori et al., 2019). Syrian hamsters are the ideal model for studies of the reinforcing properties of aggressive interactions because like primates, both males and females, naturally and reliably establish dominance relationships (Digby and Kahlenberg, 2002;Stockley and Bro-Jorgensen, 2011;Been et al., 2019). Furthermore, recent studies of social reward in Syrian hamsters have had significant translational application to studies in humans (Terranova et al., 2017;Borland et al., 2019b). ...
Our social relationships determine our health and well-being. In rodent models, there is now strong support for the rewarding properties of aggressive or assertive behaviors to be critical for the expression and development of adaptive social relationships, buffering from stress and protecting from the development of psychiatric disorders such as depression. However, due to the false belief that aggression is not a part of the normal repertoire of social behaviors displayed by females, almost nothing is known about the neural mechanisms mediating the rewarding properties of aggression in half the population. In the following study, using Syrian hamsters as a well-validated and translational model of female aggression, we investigated the effects of aggressive experience on the expression of markers of postsynaptic structure (PSD-95, Caskin I) and excitatory synaptic transmission (GluA1, GluA2, GluA4, NR2A, NR2B, mGluR1a, and mGluR5) in the nucleus accumbens (NAc), caudate putamen and prefrontal cortex. Aggressive experience resulted in an increase in PSD-95, GluA1 and the dimer form of mGluR5 specifically in the NAc 24 h following aggressive experience. There was also an increase in the dimer form of mGluR1a 1 week following aggressive experience. Aggressive experience also resulted in an increase in the strength of the association between these postsynaptic proteins and glutamate receptors, supporting a common mechanism of action. In addition, 1 week following aggressive experience there was a positive correlation between the monomer of mGluR5 and multiple AMPAR and NMDAR subunits. In conclusion, we provide evidence that aggressive experience in females results in an increase in the expression of postsynaptic density, AMPARs and group I metabotropic glutamate receptors, and an increase in the strength of the association between postsynaptic proteins and glutamate receptors. This suggests that aggressive experience may result in an increase in excitatory synaptic transmission in the NAc, potentially encoding the rewarding and behavioral effects of aggressive interactions.
... In contrast, selection as a product of mate choice has been stressed in females with almost no attention paid to the importance of female agonistic behaviors such as offensive aggression. Recently, however, it has been more fully recognized that females compete for resources and for mates to achieve reproductive benefits and that female competition is a widespread and significant evolutionary selective pressure (Been et al., 2019;Huchard and Cowlishaw, 2011;Rosvall, 2011;Stockley and Bro-Jorgensen, 2011). ...
Dominance status in hamsters is driven by interactions between arginine-vasopressin V1a, oxytocin (OT), and serotonin 1A (5-HT1A) receptors. Activation of V1a and OT receptors in the anterior hypothalamus (AH) increases aggression in males, while decreasing aggression in females. In contrast, activation of 5-HT1A receptors in the AH decreases aggression in males and increases aggression in females. The mechanism underlying these differences is not known. The purpose of this study was to determine if dominance status and sex interact to regulate V1a, OT, and 5-HT1A receptor binding. Same-sex hamsters (N = 47) were paired 12 times across six days in five min sessions. Brains from paired and unpaired (non-social control) hamsters were collected immediately after the last interaction and processed for receptor binding using autoradiography. Differences in V1a, OT, and 5-HT1A receptor binding densities were observed in several brain regions as a function of social status and sex. For example, in the AH, there was an interaction between sex and social status, such that V1a binding in subordinate males was lower than in subordinate females and V1a receptor density in dominant males was higher than in dominant females. There was also an interaction in 5-HT1A receptor binding, such that social pairing increased 5-HT1A binding in the AH of males but decreased 5-HT1A binding in females compared with unpaired controls. These results indicate that dominance status and sex play important roles in shaping the binding profiles of key receptor subtypes across the neural circuitry that regulates social behavior.
... Several reviews on neurobiology of aggression have been published in the last few years. Some of these discuss the issue focusing on specific aspects like genes, neurotransmitters, circuitry and methodology (Asherson and Cormand, 2016;Been et al., 2019;Bortolato et al., 2018). Other reviews reported human and animal studies and dealt separately with genetics, diseases, neuroimaging and neuroendocrinology (Fanning et al., 2017;Haller, 2017;Perez-Rodriguez et al., 2018;Rosell and Siever, 2015;Zilioli and Bird, 2017). ...
In modern societies, there is a strive to improve the quality of life related to risk of crimes which inevitably requires a better understanding of brain determinants and mediators of aggression. Neurobiology provides powerful tools to achieve this end. Pre-clinical and clinical studies show that changes in regional volumes, metabolism-function and connectivity within specific neural networks are related to aggression. Subregions of prefrontal cortex, insula, amygdala, basal ganglia and hippocampus play a major role within these circuits and have been consistently implicated in biology of aggression. Genetic variations in proteins regulating the synthesis, degradation, and transport of serotonin and dopamine as well as their signal transduction have been found to mediate behavioral variability observed in aggression. Gene-gene and gene-environment interactions represent additional important risk factors for aggressiveness. Considering the social burden of pathological forms of aggression, more basic and translational studies should be conducted to accelerate applications to clinical practice, justice courts, and policy making.
... The Special Issue is rounded off with three review articles, which cover important topics related to aggression and impulsivity. The first, by Been et al. (2019) covers an often understudied and neglected aspect in the field, namely the neurobiology of female aggression. In their review, the authors collate the current status of female aggression research, including topics such as neural sites and hormonal regulation of aggression, as well as summarizing the methods and techniques that should be employed to assess the underpinnings of female aggression. ...
... Fadem (1989) reported that males display higher levels of aggression than females [13]. Inclusion of female subjects is commendable because inter-male aggression is the most common paradigm in aggression research, which has led to the exclusion of females from studies on aggression and has fueled the misguided assumption that aggression falls solely in the domain of male social behaviors [14]. In fact, both males and females display offensive aggression that can be modulated by environmental, neuroendocrine, and/or experiential factors [15,16]. ...
Social behavior is critical for relationship formation and is influenced by myriad environmental and individual factors. Basic and preclinical research typically relies on rodent models to identify the mechanisms that underlie behavior; however, it is important to use non-rodent models as well. A major objective of the present study was to test the hypothesis that biological sex and social experience modulate the expression of social behavior in the adult gray short-tailed opossum (Monodelphis domestica), a non-traditional model. We also investigated the non-associative learning abilities of these animals. Following a period of social isolation, animals of both sexes were paired with a non-familiar, same-sex partner for 10 min on three different occasions, with 24-hour inter-trial intervals. We are the first research group to find significant sex differences in submissive and nonsocial behaviors in Monodelphis. Females displayed significantly higher durations of nonsocial behavior that increased over trials. Males were more aggressive; their latencies to the first attack and submissive behavior decreased over trials whereas these latencies increased for females; males' duration of submissive behavior increased over trials whereas it decreased for females. A different group of subjects habituated in response to repeated presentations to neutral odors and dishabituated in response to novel odors. In addition, both males and females demonstrated the ability to form social memories in a standard individual (social) recognition test. Our results contribute to the characterization of this marsupial species, an important first step in developing it as a model of complex social behaviors.
... Exposure to infant vocalizations alone increases plasma cortisol in marmosets (Barbosa et al., 2017), and it is likely that the capture and removal from the home cage induced some level of stress on the subjects. In general, OT tends to act as an anxiolytic and AVP tends to be anxiogenic and aggressogenic (Neumann, 2008;Neumann & Slattery, 2016;Takayanagi et al., 2005;Viviani & Stoop, 2008), though there are important sex and species differences in the expression of aggression (Been, Gibbons, & Meisel, 2018;Terranova, Ferris, & Albers, 2017). Aggression is an important component of parental behavior, as protection of offspring from conspecifics often requires aggressive responses by parents, and this parental aggression is influenced by anxiety and the OT and AVP systems in rodents (Bosch & Neumann, 2012;Nephew & Bridges, 2008;Nephew, Byrnes, & Bridges, 2010;Trainor, Finy, & Nelson, 2008). ...
In family‐living species, the quality and patterning of caregiving is the product of an individual's role within the family (mother, father, sibling) and parental experience, both of which interact with underlying neurobiological substrates. Among these substrates are the nonapeptides vasopressin and oxytocin, which modulate maternal, paternal, and alloparental care. We used a nonhuman primate model of the “nuclear family,” the marmoset (Callithrix jacchus), to investigate relationships between caregiving experience, role within the family, and activation of either the oxytocin or vasopressin systems in shaping responsiveness to offspring. During two phases of offspring development (early infancy, juvenile), mothers, fathers, and older siblings were treated with vasopressin, oxytocin, or saline via intranasal application, and tested for responses to infant distress stimuli in a within‐subjects design. Interest in infant stimuli was highest among marmosets that were caring for infants compared to those caring for juveniles, and parentally experienced marmosets were quicker to respond to infant stimuli than first‐time caregivers. Moreover, marmosets treated with vasopressin showed enhanced responsiveness to infant stimuli compared to control stimuli only when caring for infants. Thus, in all classes of marmoset caregivers, vasopressin enhances responsiveness to infant‐associated stimuli in caregivers during periods in which infant care is most crucial.
... Vaginal cytology was monitored in experimental mice during the 10-day social defeat stress protocol using the lavage technique (40). Cyclicity was also evaluated in a subset of highly aggressive nulliparous resident CFWs (n = 23) housed with castrated male mice to determine if aggression varied according to estrous cycle phase [ (41)(42)(43), but see (44,45)]. ...
Background: Despite the two-fold higher prevalence of major depressive disorder and posttraumatic stress disorder in females compared to males, most clinical and preclinical studies focus on male subjects. We introduce an ethological murine model to study several cardinal symptoms of affective disorders in the female targets of female aggression.
Methods: Intact Swiss Webster (CFW) female mice, housed alone or with intact or castrated males, were tested for aggression toward female intruders. For 10 days, aggressive CFW females defeated C57BL/6J (B6) females during 5-min encounters. Measures of plasma corticosterone, c-Fos activation in hypothalamic and limbic structures, and species-typical behaviors were collected from defeated and non-defeated mice. Ketamine (20 mg/kg) was tested for its potential to reverse stress-induced deficits in social interactions.
Results: Housed with a castrated male, most intact CFW females readily attacked unfamiliar B6 females, inflicting >40 bites in a 5-min encounter. Compared to controls, defeated B6 females exhibited elevated plasma corticosterone and increased c-Fos activation in the medial amygdala, ventral lateral septum, ventromedial hypothalamus, and hypothalamic paraventricular nucleus. Chronically defeated females also showed vigilance-like behavior, deficits in social interactions and novel object investigation, and poor nesting. Social interactions recovered 24 hrs after chronically defeated females received a systemic dose of ketamine.
Conclusions: These findings demonstrate that CFW females living with male conspecifics can be used as aggressive residents in an ethological model of female social defeat stress. These novel behavioral methods will encourage further studies of sex-specific neural, physiological, and behavioral adaptations to chronic stress and on the biological bases for interfemale aggression.
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Aggression is ubiquitous among social species and can function to maintain social dominance hierarchies. The African cichlid fish Astatotilapia burtoni is an ideal study species for studying aggression due to their dominance hierarchy and robust behavioral repertoire. To further understand the potential sex differences in aggression in this species, we characterized aggression in male and female A. burtoni in a mirror assay. We then quantified neural activation patterns in brain regions of the social behavior network (SBN) to investigate if differences in behavior are reflected in the brain with immunohistochemistry by detecting the phosphorylated ribosome marker phospho-S6 ribosomal protein (pS6), a marker for neural activation. We found that A. burtoni perform both identical and sex-specific aggressive behaviors in response to a mirror assay. Females had greater pS6 immunoreactivity than males in the Vv (ventral part of the ventral telencephalon), a homolog of the lateral septum in mammals. Males but not females had higher pS6 immunoreactivity in the ATn after the aggression assay. The ATn (anterior tuberal nucleus) is a homolog of the ventromedial hypothalamus in mammals, which is strongly implicated in the regulation of aggression in males. Several regions also have higher pS6 immunoreactivity in negative controls than fish exposed to a mirror, implicating a role for inhibitory neural processes in suppressing aggression until a relevant stimulus is present. Male and female A. burtoni display both similar and different behavioral patterns in aggression in response to a mirror assay. There are also sex differences in the corresponding neural activation patterns in the SBN. In mirror males but not females, the ATn clusters with the POA, revealing a functional connectivity of these regions that is triggered in an aggressive context in males. These findings suggest that distinct neural circuitry underlie aggressive behavior in male and female A. burtoni, serving as a foundation for future work investigating the molecular and neural underpinnings of sex differences in behavior in this species to reveal fundamental insights into understanding aggression.
The marble-burying test is a pharmacologically validated paradigm used to study anxiety-like behaviors in laboratory rodents. Our laboratory has employed this assay as part of a behavioral screen to examine drug-induced negative affective states. Historically, the majority of our prior binge alcohol-drinking studies employed male subjects exclusively and reliably detected adolescent-adult differences in both basal and alcohol withdrawal-induced negative affect. However, age-related differences in marble-burying behavior were either absent or opposite those observed in our prior work when female subjects were included in the experimental design. As chemosensory cues from females are reported to be anxiolytic in males, the present study examined how odors from adult members of the opposite and same sex (obtained from soiled bedding) influence marble-burying behavior in adult, as well as adolescent, mice. Control studies examined the responsiveness of mice in the presence of novel neutral (vanilla) and aversive (tea tree) odors. Adult males exhibited reduced signs of anxiety-like behavior in the presence of female-soiled bedding, while adult females and adolescent mice of both sexes increased marble-burying behavior in the presence of both male- and female-soiled bedding. All mice exhibited increased burying in the presence of an aversive odor, while only adolescents increased marble-burying in response to the novel neutral odor. These data indicate sex by age interactions in the effects of volatile and nonvolatile odors from sexually-naive adult conspecifics on indices of anxiety-like behavior in the marble-burying test of relevance to the experimental design and procedural timing of experiments including sex as a biological variable.
Background: Aggression is ubiquitous among social species and functions to maintains social dominance hierarchies. The African cichlid fish Astatotilapia burtoni is an ideal study species for studying aggression due to their unique and flexible dominance hierarchy. However, female aggression in this species and the neural mechanisms of aggression in both sexes is not well understood.
Methods: To further understand the potential sex differences in aggression in this species, we characterized aggression in male and female A. burtoni in a mirror assay. We then quantified neural activation patterns in regions of the social behavior network (SBN) to investigate if differences in behavior are reflected in the brain with immunohistochemistry by detecting the phosphorylated ribosome marker phospho-S6 ribosomal protein (pS6), a marker for neural activation.
Results: We found that A. burtoni perform both identical and sex-specific aggressive behaviors in response to a mirror assay. We observed sex differences in pS6 immunoreactivity in the Vv, a homolog of the lateral septum in mammals. Males but not females had higher ps6 immunoreactivity in the ATn after the aggression assay. The ATn is a homolog of the ventromedial hypothalamus in mammals, which is strongly implicated in the regulation of aggression in males. Several regions also have higher pS6 immunoreactivity in negative controls than fish exposed to a mirror, implicating inhibitory neurons in suppressing aggression until a relevant stimulus is present.
Conclusions: Male and female A. burtoni display both similar and sexually dimorphic behavioral patterns in aggression in response to a mirror assay. There are also sex differences in the corresponding neural activation patterns in the SBN. These findings suggest that distinct neural circuitry underlie aggressive behavior in male and female A. burtoni, serving as a foundation for future work investigating the molecular and neural underpinnings of sexually dimorphic behaviors in this species to reveal fundamental insights into understanding aggression.
This narrative review article summarizes the current state of knowledge regarding the relationship between the endocannabinoid system (ECS) and aggression across multiple vertebrate species. Experimental evidence indicates that acute administration of phytocannabinoids, synthetic cannabinoids, and the pharmacological enhancement of endocannabinoid signaling decreases aggressive behavior in several animal models. However, research on the chronic effects of cannabinoids on animal aggression has yielded inconsistent findings, indicating a need for further investigation. Cannabinoid receptors, particularly cannabinoid receptor type 1, appear to be an important part of the endogenous mechanism involved in the dampening of aggressive behavior. Overall, this review underscores the importance of the ECS in regulating aggressive behavior and provides a foundation for future research in this area.
Physical exercise can lower lung cancer incidence. However, its effect on lung cancer progression is less understood. Studies on exercising mice have shown decreased ectopic lung cancer growth through the secretion of interleukin-6 from muscles and the recruitment of natural killer (NK) cells to tumors. We asked if exercise suppresses lung cancer in an orthotopic model also. Single-housed C57Bl/6 male mice in cages with running wheels were tail vein-injected with LLC1.1 lung cancer cells, and lung tumor nodules were analyzed. Exercise did not affect lung cancer. Therefore, we also tested the effect of exercise on a subcutaneous LLC1 tumor and a tail vein-injected B16F10 melanoma model. Except for one case of excessive exercise, tumor progression was not influenced. Moderately exercising mice did not increase IL-6 or recruit NK cells to the tumor. Our data suggest that the exercise dose may dictate how efficiently the immune system is stimulated and controls tumor progression.
Classically the neurobiology of aggression has been studied exclusively in males. Thus, females have been considered mildly aggressive except during lactation. Interestingly, recent studies in rodents and humans have revealed that non-lactating females can show exacerbated and pathological aggression similarly to males. This review provides an overview of recent findings on the neuroendocrine mechanisms regulating aggressive behavior in females. In particular, the focus will be on novel rodent models of exaggerated aggression established in non-lactating females. Among the neuromodulatory systems influencing female aggression, special attention has been given to sex-steroids and sex-steroid-sensitive neuronal populations (i.e., the core nuclei of the neural pathway of aggression) as well as to the neuropeptides oxytocin and vasopressin which are major players in the regulation of social behaviors.
Exacerbated aggression is a high-impact, but poorly understood core symptom of several psychiatric disorders, which can also affect women. Animal models have successfully been employed to unravel the neurobiology of aggression. However, despite increasing evidence for sex-specificity, little is known about aggression in females. Here, we studied the role of the oxytocin (OXT) and arginine vasopressin (AVP) systems within the central amygdala (CeA) on aggressive behavior displayed by virgin female Wistar rats using immunohistochemistry, receptor autoradiography, and neuropharmacology. Our data show that CeA GABAergic neurons are activated after an aggressive encounter in the female intruder test. Additionally, neuronal activity (pERK) negatively correlated with the display of aggression in low-aggressive group-housed females. Binding of OXT receptors, but not AVP-V1a receptors, was increased in the CeA of high-aggressive isolated and trained (IST) females. Finally, local infusion of either synthetic OXT or AVP enhanced aggression in IST females, whereas blockade of either of these receptors did not affect aggressive behavior. Altogether, our data support a moderate role of the CeA in female aggression. Regarding neuropeptide signaling, our findings suggest that synthetic, but not endogenous OXT and AVP modulate aggressive behavior in female Wistar rats.
Perinatal mortality is a major issue in laboratory mouse breeding. We compared a counting method using daily checks (DAILY_CHECK) with a method combining daily checks with detailed video analyses to detect cannibalisms (VIDEO_TRACK) for estimating the number of C57BL/6 pups born, died and weaned in 193 litters from trios with (TRIO-OVERLAP) or without (TRIO-NO_OVERLAP) the presence of another litter. Linear mixed models were used at litter level. To understand if cannibalism was associated with active killing (infanticide), we analysed VIDEO_TRACK recordings of 109 litters from TRIO-OVERLAP, TRIO-NO_OVERLAP or SOLO (single dams). We used Kaplan-Meier method and logistic regression at pup level. For DAILY_CHECK, the mean litter size was 35% smaller than for VIDEO_TRACK (P<0.0001) and the number of dead pups was twice lower (P<0.0001). The risk of pup loss was higher for TRIO-OVERLAP than TRIO-NO_OVERLAP (P<0.0001). A high number of pup losses occurred between birth and the first cage checking. Analyses of VIDEO_TRACK data indicated that pups were clearly dead at the start of most of the cannibalism events and infanticide was rare. As most pups die and disappear before the first cage check, many breeding facilities are likely to be unaware of their real rates of mouse pup mortality.
Aggression takes several forms and can be offensive or defensive. Aggression between animals of the same species or society aims to inflict harm upon another for the purpose of protecting a resource such as food, reproductive partners, territory, or status. This chapter explores the neurobiology of aggression. We summarize the behavior of aggression, rodent models of aggression, and the correlates of aggressive behavior in the context of neuroendocrinology, neurotransmitter systems, and neurocircuitry. Translational implications of rodent studies are briefly discussed, applying basic research to brain imaging data and therapeutic approaches to conditions where aggression is problematic.
Neuropsychiatric disorders are frequently complicated by aggressive behaviors. For some individuals, existing behavioral and psychopharmacological treatments are ineffective or confer significant side effects, necessitating development of new ways to treat patients with severe aggression. Nicotinic acetylcholine receptors (nAChRs) are a large and diverse family of ligand-gated ion channels expressed throughout the brain that influence behaviors highly relevant for neuropsychiatric disorders, including attention, mood, and impulsivity. Nicotine and other drugs targeting nAChRs can reduce aggression in animal models of offensive, defensive, and predatory aggression, as well as in human laboratory studies. Human genetic studies have suggested a relationship between the CHRNA7 gene encoding the alpha-7 nAChR and aggressive behavior, although these effects are heterogeneous and strongly influenced by genetic background and environment. Here we review animal, human genetic, and clinical studies supporting a consistent role of nicotine and nAChR signaling in modulation of aggressive behaviors. We integrate findings from recent studies of aggression neuroscience, discuss the circuitry that may be involved in these effects of nAChRs, and identify multiple key questions that must be answered prior to safe and effective translation for human patients.
This article is part of the special issue on ‘Contemporary Advances in Nicotine Neuropharmacology’.
Social hierarchies emerge when animals compete for access to resources such as food, mates or physical space. Wild and laboratory male mice have been shown to develop linear hierarchies, however, less is known regarding whether female mice have sufficient intrasexual competition to establish significant social dominance relationships. In this study, we examined whether groups of outbred CD-1 virgin female mice housed in a large vivaria formed social hierarchies. We show that females use fighting, chasing and mounting behaviors to rapidly establish highly directionally consistent social relationships. Notably, these female hierarchies are less linear, steep and despotic compared to male hierarchies. Female estrus state was not found to have a significant effect on aggressive behavior, though dominant females had elongated estrus cycles (due to increased time in estrus) compared to subordinate females. Plasma estradiol levels were equivalent between dominant and subordinate females. Subordinate females had significantly lower levels of basal corticosterone compared to dominant females. Analyses of gene expression in the ventromedial hypothalamus indicated that subordinate females have elevated ERα, ERβ and OTR mRNA compared to dominant females. This study provides a methodological framework for the study of the neuroendocrine basis of female social aggression and dominance in laboratory mice.
Spousal physical aggression at 30 months after marriage was predicted for 393 young couples who were interviewed for a longitudinal study. The prerelationship predictor variables were history of violence in the family of origin, aggression against others during childhood and adolescence, and personality characteristics. Relationship predictor variables were marital discord and spouse-specific psychological aggression, both measured at 18 months after marriage. The findings suggest that predictive models are different for husbands and wives. For both sexes, there were direct paths to marital violence that were not mediated by characteristics of the relationship, as well as paths that originated in or flowed through indicators of the marital relationship. Implications for intervention through marital therapy, individual therapy, or both are discussed.
The basomedial amygdala (BM) influences the ventromedial nucleus of the hypothalamus (VMH) through direct glutamatergic projections as well as indirectly, through the anterior part of the bed nucleus of the stria terminalis (BNSTa). However, BM and BNSTa axons end in a segregated fashion in VMH. BM projects to the core of VMH, where VMH’s projection cells are located, whereas BNSTa projects to the shell of VMH, where GABAergic cells that inhibit core neurons are concentrated. However, the consequences of this dual regulation of VMH by BM and BNSTa are unknown. To study this question, we recorded the responses of VMH’s shell and core neurons to the optogenetic activation of BM or BNSTa inputs in transgenic mice that selectively express Cre-recombinase in glutamatergic or GABAergic neurons. Glutamatergic BM inputs fired most core neurons but elicited no response in GABAergic shell neurons. Following BM infusions of AAV-EF1α-DIO-hChR2-mCherry in Vgat-ires-Cre-Ai6 mice, no anterograde labeling was observed in the VMH, suggesting that GABAergic BM neurons do not project to the VMH. In contrast, BNSTa sent mostly GABAergic projections that inhibited both shell and core neurons. However, BNSTa-evoked IPSPs had a higher amplitude in shell neurons. Since we also found that activation of GABAergic shell neurons causes an inhibition of core neurons, these results suggest that depending on the firing rate of shell neurons, BNSTa inputs could elicit a net inhibition or disinhibition of core neurons. Thus, the dual regulation of VMH by BM and BNSTa imparts flexibility to this regulator of defensive and social behaviors.
Conduct disorder (CD) is a common and highly impairing psychiatric disorder of childhood and adolescence that frequently leads to poor physical and mental health outcomes in adulthood. The prevalence of CD is substantially higher in males than females, and partly due to this, most research on this condition has used all-male or predominantly male samples. Although the number of females exhibiting CD has increased in recent decades, the majority of studies on neurobiological measures, neurocognitive phenotypes, and treatments for CD have focused on male subjects only, despite strong evidence for sex differences in the aetiology and neurobiology of CD. Here, we selectively review the existing literature on CD and related phenotypes in females, focusing in particular on sex differences in CD symptoms, patterns of psychiatric comorbidity, and callous–unemotional personality traits. We also consider studies investigating the neurobiology of CD in females, with a focus on studies using genetic, structural and functional neuroimaging, psychophysiological, and neuroendocrinological methods. We end the article by providing an overview of the study design of the FemNAT-CD consortium, an interdisciplinary, multi-level and multi-site study that explicitly focuses on CD in females, but which is also investigating sex differences in the causes, developmental course, and neurobiological correlates of CD.
'Sundowning' in dementia and Alzheimer's disease is characterized by early-evening agitation and aggression. While such periodicity suggests a circadian origin, whether the circadian clock directly regulates aggressive behavior is unknown. We demonstrate that a daily rhythm in aggression propensity in male mice is gated by GABAergic subparaventricular zone (SPZGABA) neurons, the major postsynaptic targets of the central circadian clock, the suprachiasmatic nucleus. Optogenetic mapping revealed that SPZGABA neurons receive input from vasoactive intestinal polypeptide suprachiasmatic nucleus neurons and innervate neurons in the ventrolateral part of the ventromedial hypothalamus (VMH), which is known to regulate aggression. Additionally, VMH-projecting dorsal SPZ neurons are more active during early day than early night, and acute chemogenetic inhibition of SPZGABA transmission phase-dependently increases aggression. Finally, SPZGABA-recipient central VMH neurons directly innervate ventrolateral VMH neurons, and activation of this intra-VMH circuit drove attack behavior. Altogether, we reveal a functional polysynaptic circuit by which the suprachiasmatic nucleus clock regulates aggression.
Aggression is a costly behavior, sometimes with severe consequences including death. Yet aggression is prevalent across animal species ranging from insects to humans, demonstrating its essential role in the survival of individuals and groups. The question of how the brain decides when to generate this costly behavior has intrigued neuroscientists for over a century and has led to the identification of relevant neural substrates. Various lesion and electric stimulation experiments have revealed that the hypothalamus, an ancient structure situated deep in the brain, is essential for expressing aggressive behaviors. More recently, studies using precise circuit manipulation tools have identified a small subnucleus in the medial hypothalamus, the ventrolateral part of the ventromedial hypothalamus (VMHvl), as a key structure for driving both aggression and aggression-seeking behaviors. Here, we provide an updated summary of the evidence that supports a role of the VMHvl in aggressive behaviors. We will consider our recent findings detailing the physiological response properties of populations of VMHvl cells during aggressive behaviors and provide new understanding regarding the role of the VMHvl embedded within the larger whole-brain circuit for social sensation and action.
As an essential means of resolving conflicts, aggression is expressed by both sexes but often at a higher level in males than
in females. Recent studies suggest that cells in the ventrolateral part of the ventromedial hypothalamus (VMHvl) that express
estrogen receptor- (Esr1) and progesterone receptor are essential for male but not female mouse aggression. In contrast, here we show that VMHvl Esr1+ cells are indispensable for female aggression. This population was active when females attacked naturally. Inactivation of these cells reduced female aggression whereas their activation elicited attack. Additionally, we found that female VMHvl contains two anatomically distinguishable subdivisions that showed differential gene expression, projection and activation patterns after mating and fighting. These results support an essential role of the VMHvl in both male and female aggression and reveal the existence of two previously unappreciated subdivisions in the female VMHvl that are involved in distinct social behaviors.
Significance
There are profound sex differences in the expression of social behavior and in the incidence of many psychiatric disorders, and yet little is known about how the brain mechanisms underlying these phenomena differ in females and males. Here, we report that serotonin (5-HT) and arginine–vasopressin (AVP) act in opposite ways within the hypothalamus to regulate dominance and aggression in females and males. Dominance and aggression are promoted by 5-HT in females and by AVP in males. Because dominance and aggressiveness have been linked to the resistance to stress-related psychiatric disorders, these disorders may be more effectively treated with 5-HT–targeted drugs in females and AVP-targeted drugs in males.
We recently developed a conditioned place preference (CPP) procedure, commonly used to study rewarding drug effects, to demonstrate that dominant sexually-experienced CD-1 male mice form CPP to contexts previously associated with defeating subordinate male C57BL/6J mice. Here we further characterized conditioned and unconditioned aggression behavior in CD-1 mice. In Exp. 1 we used CD-1 mice that displayed a variable spectrum of unconditioned aggressive behavior toward younger subordinate C57BL/6J intruder mice. We then trained the CD-1 mice in the CPP procedure where one context was intruder-paired, while a different context was not. We then tested for aggression CPP 1 day after training. In Exp. 2, we tested CD-1 mice for aggression CPP 1 day and 18 days after training. In Exp. 3-4, we trained the CD-1 mice to lever-press for palatable food and tested them for footshock punishment-induced suppression of food-reinforced responding. In Exp. 5, we characterized unconditioned aggression in hybrid CD-1xC57BL/6J D1-Cre or D2-Cre F1 generation crosses. Persistent aggression CPP was observed in CD-1 mice that either immediately attacked C57BL/6J mice during all screening sessions or mice that gradually developed aggressive behavior during the screening phase. In contrast, CD-1 mice that did not attack the C57BL/6J mice during screening didn't develop CPP to contexts previously paired with C57BL/6J mice. The aggressive phenotype did not predict resistance to punishment-induced suppression of food-reinforced responding. CD-1xD1-Cre or D2-Cre F1 transgenic mice showed strong unconditioned aggression. Our study demonstrates that aggression experience causes persistent CPP and introduces transgenic mice for circuit studies of aggression.
Maladaptive aggressive behaviour is associated with a number of neuropsychiatric disorders and is thought to result partly from the inappropriate activation of brain reward systems in response to aggressive or violent social stimuli. Nuclei within the ventromedial hypothalamus, extended amygdala and limbic circuits are known to encode initiation of aggression; however, little is known about the neural mechanisms that directly modulate the motivational component of aggressive behaviour. Here we established a mouse model to measure the valence of aggressive inter-male social interaction with a smaller subordinate intruder as reinforcement for the development of conditioned place preference (CPP). Aggressors develop a CPP, whereas non-aggressors develop a conditioned place aversion to the intruder-paired context. Furthermore, we identify a functional GABAergic projection from the basal forebrain (BF) to the lateral habenula (lHb) that bi-directionally controls the valence of aggressive interactions. Circuit-specific silencing of GABAergic BF-lHb terminals of aggressors with halorhodopsin (NpHR3.0) increases lHb neuronal firing and abolishes CPP to the intruder-paired context. Activation of GABAergic BF-lHb terminals of non-aggressors with channelrhodopsin (ChR2) decreases lHb neuronal firing and promotes CPP to the intruder-paired context. Finally, we show that altering inhibitory transmission at BF-lHb terminals does not control the initiation of aggressive behaviour. These results demonstrate that the BF-lHb circuit has a critical role in regulating the valence of inter-male aggressive behaviour and provide novel mechanistic insight into the neural circuits modulating aggression reward processing.
Intimate Partner Abuse (IPA), a major social problem, can lead to mental health conditions and is implicated in 30 % of female and 5 % of male homicide deaths. We hypothesized that due to distinct relationship structures and power dynamics which are immersed in varying sociocultural contexts, victims of male-male, female-female and female-male dyads experience different patterns of IPA. Our objectives were: (1) To examine the demographic and clinical characteristics of victims of male victim-male abuser (M-M), female victim-male abuser (F-M), male victim-female abuser (M-F), and female victim-female abuser (F-F) dyads. (2) To compare patterns of IPA reported by the victims in these groups. Out of 397 subjects in the general population that attempted this Internet-based study, 214 English-speaking subjects were older than 18 years, had experienced IPA, and provided complete information for the analysis. Victims of IPA were screened and specific methods of abuse were evaluated. M-Ms were significantly more educated (70 %) than other groups. F-Fs experienced more abuse before age 18 by a parent or relative. F-Fs experienced the most physical abuse while M-Ms the least (p = 0.004). Physical abuse or threats of abuse in front of children was reported more in F-Fs (p < 0.01) and least in M-Ms. IPA patterns differ significantly with F-Fs presenting the most physical profile and M-Ms presenting the least.
The hamster has been shown to share a variety of metabolic similarities with humans. To replicate human acute pancreatitis with hamsters, we comparatively studied the efficacy of common methods, such as the peritoneal injections of caerulein, L-arginine, the retrograde infusion of sodium taurocholate, and another novel model with concomitant administration of ethanol and fatty acid. The severity of pancreatitis was evaluated by serum amylase activity, pathological scores, myeloperoxidase activity, and the expression of inflammation factors in pancreas. The results support that the severity of pathological injury is consistent with the pancreatitis induced in mice and rat using the same methods. Specifically, caerulein induced mild edematous pancreatitis accompanied by minimal lung injury, while L-arginine induced extremely severe pancreatic injury including necrosis and neutrophil infiltration. Infusion of Na-taurocholate into the pancreatic duct induced necrotizing pancreatitis in the head of pancreas and lighter inflammation in the distal region. The severity of acute pancreatitis induced by combination of ethanol and fatty acids was between the extent of caerulein and L-arginine induction, with obvious inflammatory cells infiltration. In view of the advantages in lipid metabolism features, hamster models are ideally suited for the studies of pancreatitis associated with altered metabolism in humans.
The bed nucleus of the stria terminalis (BNST) is a center of integration for limbic information and valence monitoring. The BNST, sometimes referred to as the extended amygdala, is located in the basal forebrain and is a sexually dimorphic structure made up of between 12 and 18 sub-nuclei. These sub-nuclei are rich with distinct neuronal subpopulations of receptors, neurotransmitters, transporters and proteins. The BNST is important in a range of behaviors such as: the stress response, extended duration fear states and social behavior, all crucial determinants of dysfunction in human psychiatric diseases. Most research on stress and psychiatric diseases has focused on the amygdala, which regulates immediate responses to fear. However, the BNST, and not the amygdala, is the center of the psychogenic circuit from the hippocampus to the paraventricular nucleus. This circuit is important in the stimulation of the hypothalamic-pituitary-adrenal axis. Thus, the BNST has been largely overlooked with respect to its possible dysregulation in mood and anxiety disorders, social dysfunction and psychological trauma, all of which have clear gender disparities. In this review, we will look in-depth at the anatomy and projections of the BNST, and provide an overview of the current literature on the relevance of BNST dysregulation in psychiatric diseases.Molecular Psychiatry advance online publication, 16 February 2016; doi:10.1038/mp.2016.1.
Aromatase-expressing neuroendocrine neurons in the vertebrate male brain synthesize estradiol from circulating testosterone. This locally produced estradiol controls neural circuits underlying courtship vocalization, mating, aggression, and territory marking in male mice. How aromatase-expressing neuronal populations control these diverse estrogen-dependent male behaviors is poorly understood, and the function, if any, of aromatase-expressing neurons in females is unclear. Using targeted genetic approaches, we show that aromatase-expressing neurons within the male posterodorsal medial amygdala (MeApd) regulate components of aggression, but not other estrogen-dependent male-typical behaviors. Remarkably, aromatase-expressing MeApd neurons in females are specifically required for components of maternal aggression, which we show is distinct from intermale aggression in pattern and execution. Thus, aromatase-expressing MeApd neurons control distinct forms of aggression in the two sexes. Moreover, our findings indicate that complex social behaviors are separable in a modular manner at the level of genetically identified neuronal populations.
Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
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.
Capacity to form progesterone (P4)’s 5α-reduced metabolite, 5α-pregnan-3α-ol-20-one (3α,5α-THP; a.k.a. allopregnanolone) in the brain may be related to facilitation of lordosis among estrogen–primed (E2) mice. We investigated this idea further by comparing effects of endogenous and exogenous progestogens in mice that are deficient in the Type One 5α-reductase enzyme (5α-reductase knockout mice; 5α-RKO), and their wildtype counterparts for sexual behavior. Comparisons were made following administration of progestogens that are expected to increase 3α,5α-THP or not. Sexual receptivity of 5α-RKO mice and their wildtype counterparts was examined when mice were naturally-cycling (Experiment 1); ovariectomized (OVX), E2-primed (10 μg, subcutaneous; SC) and administered P4 (0, 125, 250, or 500 μg SC; Experiment 2); and OVX, E2-primed and administered P4, medroxyprogesterone acetate (MPA, 4 mg/kg, SC, which does not convert to 3α,5α-THP) or 3α ,5α-THP (4 mg/kg, SC; Experiment 3). The percentage of mounts that elicited lordosis (lordosis quotient) or aggression/rejection behavior (aggression quotient), as well as the quality of lordosis (lordosis rating), was scored. Wildtype, but not 5α-RKO, mice in behavioral estrus demonstrated significantly greater lordosis quotients and lordosis ratings, but similar aggression quotients, compared to their diestrous counterparts. Among OVX and E2-primed mice, P4 facilitated lordosis of wildtype, but not 5α-RKO, mice. MPA neither facilitated lordosis of wildtype, nor 5α-RKO mice. 3α,5α-THP administered to wildtype or 5α-RKO mice increased lordosis quotients and lordosis ratings and decreased aggression quotients. 3α,5α-THP levels in the midbrain, one brain region important for sexual behavior, were increased during behavioral estrus, with P4 administered to WT, but not 5α-RKO mice, and 3α,5α-THP administered to WT and 5α-RKO mice. MPA did not increase 3α,5α-THP. Thus, deletion of Type One 5α-reductase among female mice may attenuate reproductive responding during the estrous cycle and after hormone-priming.
The costs of violence and aggression in our society have stimulated the scientific search for the predictors and causes of aggression. The majority of studies have focused on males, which are considered to be more aggressive than females in most species. However, rates of offensive behavior in girls and young women are considerable and are currently rising in Western society. The extrapolation of scientific results from males to young, non-maternal females is a priori limited, based on the profound sex differences in brain areas and functioning of neurotransmitters involved in aggression. Therefore, we established a paradigm to assess aggressive behavior in young virgin female rats, i.e. the female intruder test (FIT). We found that approximately 40% of un-manipulated adult (10-11 weeks old) female Wistar rats attack an intruder female during the FIT, independent of their estrous phase or that of their intruder. In addition, adolescent (7-8 weeks old) female rats selected for high anxiety behavior (HABs) displayed significantly more aggression than non-selected (NAB) or low-anxiety (LAB) rats. Intracerebroventricular infusion of oxytocin (OXT, 0.1 µg/5 µl) inhibited aggressive behavior in adult NAB and LAB, but not HAB females. Adolescent NAB rats that had been aggressive towards their intruder showed increased pERK immunoreactivity (IR) in the hypothalamic attack area and reduced pERK-IR in OXT neurons in the paraventricular hypothalamic nucleus compared to non-aggressive NAB rats. Taken together, aggressive behavior in young virgin female rats is partly dependent on trait anxiety, and appears to be under considerable OXT control.
Cell death and differentiation is a monthly research journal focused on the exciting field of programmed cell death and apoptosis. It provides a single accessible source of information for both scientists and clinicians, keeping them up-to-date with advances in the field. It encompasses programmed cell death, cell death induced by toxic agents, differentiation and the interrelation of these with cell proliferation.
Evidence is emerging of the role of membrane progestin receptors (referred to as mPRs herein: members of Progestin and AdipoQ Receptor (Paqr) family) as a novel brain target in mammals, such as rats. In the present study, the role of mPRs in mice was assessed to further elucidate the conservation of this mechanism across species. The brain target investigated was the midbrain ventral tegmental area (VTA) given its described role for rapid actions of progestins for reproduction. Studies tested the hypothesis that if mPRs are required for progestin-facilitated lordosis through actions in the VTA, then knockdown of mPRs in the VTA will attenuate lordosis. Ovariectomized (OVX) mice were subcutaneously injected with estradiol (E2) and progesterone (P4), and infused with antisense oligodeoxynucleotides (AS-ODNs) to mPRα (Paqr7) and/or mPRβ (Paqr8) or vehicle to the lateral ventricle or VTA. Mice were assessed for reproductive behavior (lordosis and aggression/rejection quotients) in a standard mating task. Results supported our hypothesis. E2 + P4-facilitated lordosis was significantly reduced, and aggression/rejection increased, with infusions of mPRα, mPRβ, or mPRαβ AS-ODNs to the lateral ventricle, compared to vehicle. E2 + P4-facilitated lordosis was significantly lower, and aggression/rejection increased, with mPRβ or mPRαβ AS-ODNs to the VTA of C57/BL6 mice. Both mPRɑ and mPRβ AS-ODNs reduced lordosis, and increased aggression/rejection, of wildtype (C57/BL6x129) mice, but not nuclear PR knockout mice. Thus, mPRs may be a novel target of progestins for reproductive behavior of mice.
Evolutionary researchers have identified age, operational sex ratio and high variance in male resources as factors that intensify female competition. These are discussed in relation to escalated intrasexual competition for men and their resources between young women in deprived neighbourhoods. For these women, fighting is not seen as antithetical to cultural conceptions of femininity, and female weakness is disparaged. Nonetheless, even where competitive pressures are high, young women's aggression is less injurious and frequent than young men's. From an evolutionary perspective, I argue that the intensity of female aggression is constrained by the greater centrality of mothers, rather than fathers, to offspring survival. This selection pressure is realized psychologically through a lower threshold for fear among women. Neuropsychological evidence is not yet conclusive but suggests that women show heightened amygdala reactivity to threatening stimuli, may be better able to exert prefrontal cortical control over emotional behaviour and may consciously register fear more strongly via anterior cingulate activity. The impact of testosterone and oxytocin on the neural circuitry of emotion is also considered.
The role of gene expression of the estrogen receptor-a form (ERa) in the regulation of female reproductive behavior was investigated in estrogen receptor knockout (ERKO) mice, deficient specifically for the ERa, but not the ERb, gene. Estrogen- or estrogen- plus progesterone- treated gonadectomized ERKO mice did not show any lordosis re- sponse. Detailed behavioral analysis revealed that ERKO females were also deficient in sexual behavioral interactions preceding the lordosis response. They were extremely rejective toward attempted mounts by stud male mice, which could not show any intromissions. During resident-intruder aggression tests, gonadally intact ERKO females were more aggressive toward female intruder mice than wild- type (WT) mice. Gonadectomy did not influence the levels of aggres- sive behavior, and their genotype differences when mice were tested both before and after gonadectomy. However, when mice were tested after gonadectomy for the first time, very few ERKO mice showed aggression. In contrast to aggression, male-type sexual behavior shown by resident mice toward female intruder mice during aggres- sion tests was not different between ERKO and WT mice and was completely abolished after gonadectomy of the resident mice. Finally, it was also found that ERKO females showed greatly reduced levels of parental behavior toward newborn pups placed in their home cage. These changes in parental behavior were not influenced by gonad- ectomy. ERKO females retrieved significantly fewer numbers of pups with longer latencies compared with wild-type (WT) or heterozygous (HZ) littermates when they were tested as gonadally intact or 20 - 65 days after gonadectomy. In addition, during parental behavior tests, a significantly higher percentage of ERKO mice exhibited infanticide compared with WT and HZ mice, which rarely showed infanticide. Taken together, these findings suggest that ERa gene expression plays a key role in female mice, not only for sexual behavior but also for other interrelated behaviors, such as parental and aggressive behaviors. In addition, persistence of genotype differences in parental and aggressive behavior after gonadectomy indicates that ERa acti- vation during neural developmental processes may also be involved in the regulation of these behaviors. (Endocrinology 139: 5070 -5081, 1998)
Motivated behaviors, including sexual experience, activate the mesolimbic dopamine system and produce long-lasting molecular and structural changes in the nucleus accumbens. The transcription factor ΔFosB is hypothesized to partly mediate this experience-dependent plasticity. Previous research in our laboratory has demonstrated that overexpressing ΔFosB in the nucleus accumbens of female Syrian hamsters augments the ability of sexual experience to cause the formation of a conditioned place preference. It is unknown, however, whether ΔFosB-mediated transcription in the nucleus accumbens is required for the behavioral consequences of sexual reward. We therefore used an adeno-associated virus to overexpress ΔJunD, a dominant negative binding partner of ΔFosB that decreases ΔFosB-mediated transcription by competitively heterodimerizing with ΔFosB before binding at promotor regions on target genes, in the nucleus accumbens. We found that overexpression of ΔJunD prevented the formation of a conditioned place preference following repeated sexual experiences. These data, when coupled with our previous findings, suggest that ∆FosB is both necessary and sufficient for behavioral plasticity following sexual experience. Furthermore, these results contribute to an important and growing body of literature demonstrating the necessity of endogenous ΔFosB expression in the nucleus accumbens for adaptive responding to naturally rewarding stimuli.
The effects of intracranial implants of estradiol in the ventromedial hypothalamus (VMH), the anterior hypothalamus (AH), or the medial amygdala (AMG) on aggression, sexual behavior, and serum estradiol were examined in female Syrian hamsters. Estradiol implants in the VMH, followed by systemic progesterone, stimulated sexual behavior and inhibited aggression. Estradiol implants in other intracranial sites activated sexual behavior but did not reliably inhibit aggression. Intracranially implanted and systemically treated animals had equivalent peripheral estradiol concentrations at sacrifice. These results suggest that: (a) the VMH is an important neural site for estradiol actions on sexual and aggressive behavior, (b) the caudal AH and AMG also may be sites of estradiol action on sexual behavior, and (c) these intracranial implants may only be effective given systemic estradiol exposure or the concurrent stimulation of multiple brain areas.
Male–male and female–female dyads of two species of Phodopus, the Djungarian hamster, P. campbelli, and the Siberian hamster, P. sungorus, interacted daily for 10 min on each of 4 successive days. Animals were acclimatized to large habitats which contained small, defensible nest boxes. Real time behavioral records were kept of agonistic, social, and scent marking behaviors. The results indicated that there were major behavioral differences between P. campbelli and P. sungorus in their agonistic interactions with like-sexed conspecifics. Male P. campbelli were significantly more aggressive towards conspecific males than male P. sungorus, attacking (19.7 ± 2.2 vs. 9.6 ± 1.2) and biting (30.0 ± 4.6 vs. 12.7 ± 2.1) more often, and could inflict serious injury. Conversely, female P. campbelli were less aggressive than female P. sungorus towards like-sexed conspecifics, attacking (2.6 ± 0.7 vs. 7.5 ± 1.5) and biting (1.0 ± 0.4 vs. 2.4 ± 0.6) less frequently. The absolute levels of aggression were higher for males than for females although the magnitude of the difference was much less in P. sungorus than in P. campbelli. Dominant animals showed a tendency to spend most of the time available in the home area of the subordinate animal and to scent mark more frequently while there. The time distributions of dominant and subordinate animals within pairs (except for P. sungorus males) were significantly positively correlated. Dominant animals of both sexes scent marked with similar frequencies. When interpreted in light of the literature concerning the possible social structure of Djungarian hamster populations, this study suggests that the differences between the two species are sufficiently large that it is important to carefully distinguish between them in the published record.
Sexual dimorphisms in the brain underlie behavioral sex differences, but the function of individual sexually dimorphic neuronal populations is poorly understood. Neuronal sexual dimorphisms typically represent quantitative differences in cell number, gene expression, or other features, and it is unknown whether these dimorphisms control sex-typical behavior exclusively in one sex or in both sexes. The progesterone receptor (PR) controls female sexual behavior, and we find many sex differences in number, distribution, or projections of PR-expressing neurons in the adult mouse brain. Using a genetic strategy we developed, we have ablated one such dimorphic PR-expressing neuronal population located in the ventromedial hypothalamus (VMH). Ablation of these neurons in females greatly diminishes sexual receptivity. Strikingly, the corresponding ablation in males reduces mating and aggression. Our findings reveal the functions of a molecularly defined, sexually dimorphic neuronal population in the brain. Moreover, we show that sexually dimorphic neurons can control distinct sex-typical behaviors in both sexes.
Two expeditions were carried out during September 1997 and March 1999 to confirm the current existence of Mesocricetus auratus in northern Syria. Six females and seven males were caught at different sites near Aleppo. One female was pregnant and gave birth to six pups. Altogether, 30 burrows were mapped and the structures of 23 golden hamster burrows investigated. None of the inhabited burrows contained more than one adult. Burrow depths ranged from 36 to 106 cm (mean 65 cm). Their structure was simple, consisting of a single vertical entrance (gravity pipe) that proceeded to a nesting chamber and at least one additional food chamber. The mean length of the entire gallery system measured 200 cm and could extend up to 900 cm. Most burrows were found on agricultural fields preferentially on leguminous cultures. The distribution of golden hamsters is discussed in association with historical data, soil types, geography, climate and human activities. All 19 golden hamsters were transferred to Germany and, together with three wild individuals supplied by the University of Aleppo, form a new breeding stock.
Despite numerous studies that report the preponderance of domestic violence is perpetrated by men against women, other empirical studies suggest that rates of domestic violence by women and men are equivalent. This article explores these claims of gender symmetry in intimate partners' use of violence by reviewing the empirical foundations of the research and critiquing existing sources of data on domestic violence. The author suggests methods to reconcile the disparate data and encourages researchers and practitioners to acknowledge women's use of violence while understanding why it tends to be very different from violence by men toward their female partners.
Aggression is an innate behavior that helps individuals succeed in environments with limited resources. Over the past few decades, neurobiologists have identified neural circuits that promote and modulate aggression; however, far less is known regarding the motivational processes that drive aggression. Recent research suggests that aggression can activate reward centers in the brain to promote positive valence. Here, we review major recent findings regarding neural circuits that regulate aggression, with an emphasis on those regions involved in the rewarding or reinforcing properties of aggressive behavior.
Gender specific personality profiles in association with the level of aggressive antisocial behavior in offenders have not been previously investigated. In the present study we analyzed data collected from 65 male and 50 female offenders using structured protocols regarding criminal history (by criminal register data), trait aggression (by the Life History of Aggression (LHA) questionnaire), and personality profiles (by the Temperament and Character Inventory (TCI)). Prison inmates differed significantly on several personality dimensions, most pronouncedly were they characterized with low character maturity (low scores in the Self-Directedness and Cooperativeness dimensions of TCI) when compared to gender and age matched controls of the general population. The majority of offenders scored distinctively high on trait aggression. There were moderate to strong associations between the personality dimensions and each of the subscales of LHA (Aggression, Self-directed Aggression and Antisocial behavior). These associations were stronger in the female offender sample. Trait aggression could be best explained by a model, which included male gender, younger age, high novelty seeking temperament and low character maturity. Our results suggest that therapies aiming at strengthening self-governance and increasing cooperativeness (focusing on character maturity) may alleviate aggressive antisocial behavior in offenders.
[examines] developmental trends in the new research on human female aggression, considering the present stage of knowledge about, and discussing the reasons for, its various forms in different cultures as well as its occurrence during diverse life stages and situations / since much of this research has been an attempt to describe in what way such aggression varies from its male counterpart, attention is necessarily drawn here to the question of differences between the sexes
female aggression: definition and forms / the "male" perspective / the danger of ethnocentrism / the problem of methodology / recent studies: methodological and cultural change / are males more aggressive than females (PsycINFO Database Record (c) 2012 APA, all rights reserved)
In many vertebrate species, certain individuals will seek out opportunities for aggression, even in the absence of threat-provoking cues. Although several brain areas have been implicated in the generation of attack in response to social threat, little is known about the neural mechanisms that promote self-initiated or 'voluntary' aggression-seeking when no threat is present. To explore this directly, we utilized an aggression-seeking task in which male mice self-initiated aggression trials to gain brief and repeated access to a weaker male that they could attack. In males that exhibited rapid task learning, we found that the ventrolateral part of the ventromedial hypothalamus (VMHvl), an area with a known role in attack, was essential for aggression-seeking. Using both single-unit electrophysiology and population optical recording, we found that VMHvl neurons became active during aggression-seeking and that their activity tracked changes in task learning and extinction. Inactivation of the VMHvl reduced aggression-seeking behavior, whereas optogenetic stimulation of the VMHvl accelerated moment-to-moment aggression-seeking and intensified future attack. These data demonstrate that the VMHvl can mediate both acute attack and flexible seeking actions that precede attack.
The sex difference in physical and verbal aggression is one of the most robust, universal, and durable. In the United States, men constitute eighty six percent of all violent offenders. The proportionate involvement of men rises with the seriousness of the offence. Meta-analyses of psychological studies using experimental, observational, and self- or other-report methods also find that men are more verbally and physically aggressive than women and that this difference is greater for physical aggression. The ubiquity of this effect, its early developmental onset, and its consistency with other primate species suggest the utility of an explanation on evolution. This article suggests that the psychological instantiation of the reluctance to directly expose oneself to physical danger is fear. Fear also forms the developmental infrastructure for behavioural inhibition so that females are better able to control the behavioural expression of anger when provoked than are men.
Background:
Escalated aggression is a behavioral sign of numerous psychiatric disorders characterized by a loss of control. The neurobiology underlying escalated aggression is unknown and is particularly understudied in females. Research in our laboratory demonstrated that repeated aggressive experience in female hamsters resulted in an escalated response to future aggressive encounters and an increase in dendritic spine density on nucleus accumbens (NAc) neurons. We hypothesized that the activation of group I metabotropic glutamate receptor signaling though the fragile X mental retardation protein (FMRP) pathway may underlie synaptic plasticity associated with aggression escalation.
Methods:
Female hamsters were given five daily aggression tests with or without prior treatment with the metabotropic glutamate receptor 5 (mGluR5) antagonist 2-methyl-6-(phenylethynyl)-pyridine. Following aggression testing, messenger RNA expression and protein levels were measured in the nucleus accumbens for postsynaptic density protein 95 (PSD-95) and SAP90/PSD-95-associated protein 3, as well as the levels of phosphorylated FMRP.
Results:
Experience-dependent escalation of aggression in female hamsters depends on activation of mGluR5 receptors. Furthermore, aggressive experience decreases phosphorylation of FMRP in the NAc, which is coupled to a long-term increase in the expression of the synaptic scaffolding proteins PSD-95 and SAP90/PSD-95-associated protein 3. Finally, the experience-dependent increase in PSD-95 is prevented by antagonism of the mGluR5 receptor.
Conclusions:
Activation of the FMRP pathway by group I metabotropic glutamate receptors is involved in regulating synaptic plasticity following aggressive experience. The NAc is a novel target for preclinical studies of the treatment of escalated aggression, with the added benefit that emerging therapeutic approaches are likely to be effective in treating pathologic aggression in both female and male subjects.
In many species, testosterone treatment facilitates offensive aggression tested in resident-intruder models. As the mechanisms of action of testosterone remain unclear, we hypothesized that testosterone interacts with neurotransmitter systems involved in the regulation of offensive aggression. We tested this hypothesis with the vasopressinergic system in golden hamsters in three separate experiments. First, we compared the density of V-1 vasopressin (AVP) receptor binding between castrated animals treated with testosterone and their untreated controls. The most noticeable difference was found within the ventrolateral hypothalamus (VLH), a site involved in the control of aggression in several species of mammals. Within this area, V-1 AVP receptor binding disappeared after castration, while being maintained by testosterone-treatment. Second, we tested behavioral effects of AVP within the VLH. Microinjections of AVP (100 nl, 1 or 100 mu M) within the VLH accelerated the onset of offensive aggression in testosterone-treated animals. However, AVP-injected animals did not bite more than their vehicle-injected controls. Third, microinjections of AVP failed to activate offensive aggression in animals deprived of testosterone. As AVP receptors appeared to overlay previously described distributions of androgen and estrogen receptors in golden hamsters, we propose that testosterone facilitates the onset of offensive aggression, at least partly, through an activation of AVP receptors within the VLH.
Social encounters often start with routine investigatory behaviors before developing into distinct outcomes, such as affiliative or aggressive actions. For example, a female mouse will initially engage in investigatory behavior with a male but will then show copulation or rejection, depending on her reproductive state. To promote adaptive social behavior, her brain must combine internal ovarian signals and external social stimuli, but little is known about how socially evoked neural activity is modulated across the reproductive cycle [1]. To investigate this, we performed single-unit recordings in the ventrolateral region of the ventromedial hypothalamus (VMHvl) in freely behaving, naturally cycling, female mice interacting with conspecifics of both genders. The VMHvl has been implicated in rodent sociosexual behavior [2, 3]: it has access to social sensory stimuli [4-8] and is involved in aggression and mating [9-11]. Furthermore, many VMHvl neurons express ovarian hormone receptors [12, 13], which play a central role in female sociosexual behavior [14-16]. We found that a large fraction of VMHvl neurons was activated in the presence of conspecifics with preference to male stimuli and that the activity of most VMHvl neurons was modulated throughout social interactions rather than in response to specific social events. Furthermore, neuronal responses to male, but not female, conspecifics in the VMHvl were enhanced during the sexually receptive state. Thus, male-evoked VMHvl responses are modulated by the reproductive state, and VMHvl neural activity could drive gender-specific and reproductive state-dependent sociosexual behavior.
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The effects of FLA 336 on the attack by resident groups of female mice on strange female intruders were assessed. This MAO-type A inhibitor clearly suppressed attack in treated subjects without producing major alterations in other activities but there was no clear dose-response relationship. The substance also increased attack on treated animals, an effect largely mediated via changes in the odor characteristics of the urine. The data emphasize the need for appropriate controls in studies with psychoactive compounds to distinguish direct (CNS-mediated) from indirect (mediated via changed signalling or perception) actions.
Social behaviours, such as aggression or mating, proceed through a series of appetitive and consummatory phases that are associated with increasing levels of arousal. How such escalation is encoded in the brain, and linked to behavioural action selection, remains an unsolved problem in neuroscience. The ventrolateral subdivision of the murine ventromedial hypothalamus (VMHvl) contains neurons whose activity increases during male-male and male-female social encounters. Non-cell-type-specific optogenetic activation of this region elicited attack behaviour, but not mounting. We have identified a subset of VMHvl neurons marked by the oestrogen receptor 1 (Esr1), and investigated their role in male social behaviour. Optogenetic manipulations indicated that Esr1(+) (but not Esr1(-)) neurons are sufficient to initiate attack, and that their activity is continuously required during ongoing agonistic behaviour. Surprisingly, weaker optogenetic activation of these neurons promoted mounting behaviour, rather than attack, towards both males and females, as well as sniffing and close investigation. Increasing photostimulation intensity could promote a transition from close investigation and mounting to attack, within a single social encounter. Importantly, time-resolved optogenetic inhibition experiments revealed requirements for Esr1(+) neurons in both the appetitive (investigative) and the consummatory phases of social interactions. Combined optogenetic activation and calcium imaging experiments in vitro, as well as c-Fos analysis in vivo, indicated that increasing photostimulation intensity increases both the number of active neurons and the average level of activity per neuron. These data suggest that Esr1(+) neurons in VMHvl control the progression of a social encounter from its appetitive through its consummatory phases, in a scalable manner that reflects the number or type of active neurons in the population.
The dominant-subordinate hierarchy in animals often needs to be established via agonistic encounters and consequently affects reproduction and survival. Differences in brain neuropeptides and sociality among dominant and subordinate males and females remain poorly understood. Here we explore neuropeptide levels and sociality during agonistic encounter tests in mandarin voles. We found that dominant mandarin voles engaged in higher levels of approaching, investigating, self-grooming and exploring behavior than subordinates. Dominant males habituated better to a stimulus vole than dominant females. Dominant males displayed significantly less oxytocin-immunoreactive neurons in the paraventricular nuclei and more vasopressin-immunoreactive neurons in the paraventricular nuclei, supraoptic nuclei, and the lateral and anterior hypothalamus than subordinates. Dominant females displayed significantly more vasopressin-immunoreactive neurons in the lateral hypothalamus and anterior hypothalamus than subordinates. Sex differences were found in the level of oxytocin and vasopressin. These results indicate that distinct parameters related to central nervous oxytocin and vasopressin are associated with behaviors during agonistic encounters in a sex-specific manner in mandarin voles.
Human literature has linked adverse early life experiences with an increased risk to develop violent behaviors in both boys and girls. We have previously shown that male rats submitted to stress during the peripuberty period display as adults abnormal aggressive behavior against both male intruders and female partners. In the present study, we examined whether the same stress protocol would affect the development of aggressive behaviors in female rats. We evaluated the behavior of these peripuberty stressed female rats when confronted, at adulthood, with either female or male intruders, and during their cohabitation with male partners. Given that estrus cycle influences mood and aggressive behaviors, female aggressive behavior was assessed at different estrus cycle phases: estrus and diestrus, and during pregnancy and lactancy. Additionally, we evaluated postpartum plasma levels of vasopressin, oxytocin and corticosterone, hormones associated with aggression and the regulation of social behavior. Compared to control females, females submitted to stressful events during puberty exhibited higher and more sustained rates of aggression during adulthood independently on the estrus cycle or the sex of the intruder, and they had higher levels of plasma vasopressin. Significant correlations between plasma levels of vasopressin and corticosterone and aggressive behavior were also found. Strikingly, our results showed opposite intragroup correlations suggesting a different role of these hormones on aggression depending on life experiences. We provide here an animal model, devoid of cultural influences strongly supporting a role for biological factors in the development of aggressive behaviors following exposure to stressful events at puberty in females.
The effects of intracranial implants of estradiol in the ventromedial hypothalamus (VMH), the anterior hypothalamus (AH), or the medial amygdala (AMG) on aggression, sexual behavior, and serum estradiol were examined in female Syrian hamsters. Estradiol implants in the VMH, followed by systemic progesterone, stimulated sexual behavior and inhibited aggression. Estradiol implants in other intracranial sites activated sexual behavior but did not reliably inhibit aggression. Intracranially implanted and systemically treated animals had equivalent peripheral estradiol concentrations at sacrifice. Results suggest that (1) the VMH is an important neural site for estradiol actions on sexual and aggressive behavior, (2) the caudal AH and AMG may also be sites of estradiol action on sexual behavior, and (3) intracranial implants may only be effective given systemic estradiol exposure or the concurrent stimulation of multiple brain areas. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Aggression research was for long dominated by the assumption that aggression-related psychopathologies result from the excessive activation of aggression-promoting brain mechanisms. This assumption was recently challenged by findings with models of aggression that mimic etiological factors of aggression-related psychopathologies. Subjects submitted to such procedures show abnormal attack features (mismatch between provocation and response, disregard of species-specific rules, and insensitivity towards the social signals of opponents). We review here 12 such laboratory models and the available human findings on the neural background of abnormal aggression. We focus on the hypothalamus, a region tightly involved in the execution of attacks. Data show that the hypothalamic mechanisms controlling attacks (general activation levels, local serotonin, vasopressin, substance P, glutamate, GABA, and dopamine neurotransmission) undergo etiological factor-dependent changes. Findings suggest that the emotional component of attacks differentiates two basic types of hypothalamic mechanisms. Aggression associated with increased arousal (emotional/reactive aggression) is paralleled by increased mediobasal hypothalamic activation, increased hypothalamic vasopressinergic, but diminished hypothalamic serotonergic neurotransmission. In aggression models associated with low arousal (unemotional/proactive aggression), the lateral but not the mediobasal hypothalamus is over-activated. In addition, the anti-aggressive effect of serotonergic neurotransmission is lost and paradoxical changes were noticed in vasopressinergic neurotransmission. We conclude that there is no singleneurobiological road' to abnormal aggression: the neural background shows qualitative, etiological factor-dependent differences. Findings obtained with different models should be viewed as alternative mechanisms rather than conflicting data. The relevance of these findings for understanding and treating of aggression-related psychopathologies is discussed.
Activity within the mesolimbic dopamine system is associated with the performance of naturally motivated behaviors, one of which is aggression. In male rats, aggressive behavior induces neurochemical changes within the nucleus accumbens, a key structure within the mesolimbic dopamine system. Corresponding studies have not been done in females. Female Syrian hamsters live as isolates and when not sexually responsive are aggressive toward either male or female intruders, making them an excellent model for studying aggression in females. We took advantage of this naturally expressed behavior to examine the effects of repeated aggressive experience on the morphology of medium spiny neurons in the nucleus accumbens and caudate nucleus, utilizing a DiOlistic labeling approach. We found that repeated aggressive experience significantly increased spine density within the nucleus accumbens core, with no significant changes in any other brain region examined. At the same time, significant changes in spine morphology were observed in all brain regions following repeated aggressive experience. These data are significant in that they demonstrate that repeated exposure to behaviors that form part of an animal's life history will alter neuronal structure in a way that may shift neurobiological responses to impact future social interactions.
This paper describes the behavioural effects of a new class of psychotropic drugs, the serenics, which exert specific antiaggressive effects in animal paradigms of (offensive) agonistic behaviour. Serenics specifically inhibit offensive aggression, leaving defensive behaviour intact. Ethological profiling of serenics and reference drugs from different drug classes shows the unique profile of the serenics: antiaggressive action without impairment of sensoric or motoric functions and without sedation or muscle relaxation. This contrasts sharply with drugs from other drug classes, eg neuroleptics, psychostimulants or anxiolytics, which all have non-specific antiaggressive or even proaggressive actions.
The behavioural profile of serenics is illustrated in this paper in a male aggression paradigm (resident-intruder in rats) and a female aggression paradigm (maternal aggression of lactating rats). For comparative reasons, drugs from several different classes have also been tested in these paradigms to compare the profiles of action.
The use and possible future applications of specific antiaggressive drugs are discussed.
The visible burrow system (VBS) is a habitat providing burrows and an open area for mixed-set rat colonies. Provisioning of food and water in the burrows makes it unnecessary for potentially defensive animals to leave the burrows to eat/drink on the surface, and enables evaluation of new types of agonistic interactions that may emerge when this necessity is removed. In such colonies, subordinate males showed high magnitude tunnel guarding behavior, occupying a tunnel opening onto the surface and confronting the dominant. Dominants, in response, made lunges into the tunnels, but quickly retreated without gaining entry, apparently stopped by contact with the defender's vibrissae. Dominants also made and continued to make lateral attacks to the wall adjacent to the tunnels guarded by subordinates, although these were useless in terms of affording contact with the subordinate. Dominant-female agonistic interactions were more frequent than those of dominants and subordinates. These were largely initiated by the male, and involved female defensive behavior. Nonetheless, females, unlike subordinates, failed to show tunnel guarding and continued to utilize the surface freely. They also spent more time in the vicinity of the dominant over days of colony formation. This apparent paradox may reflect that females were seldom wounded, and that the initial site of male contact with females was the female's anogenital area, findings suggesting that interactions of males and females often reflect male sexual advances, countered by female defenses that effectively protect nonestrus females from mounting and copulation.