Unchecked aggression and violence exact a significant toll on human societies. Aggression is an umbrella term for behaviours that are intended to inflict harm. These behaviours evolved as adaptations to deal with competition, but when expressed out of context, they can have destructive consequences. Uncontrolled aggression has several components, such as impaired recognition of social cues and enhanced impulsivity. Molecular approaches to the study of aggression have revealed biological signals that mediate the components of aggressive behaviour. These signals may provide targets for therapeutic intervention for individuals with extreme aggressive outbursts. This Review summarizes the complex interactions between genes, biological signals, neural circuits and the environment that influence the development and expression of aggressive behaviour.

Stressful life experiences are known to be a precipitating factor for many mental disorders. The social defeat model induces behavioral responses in rodents (e.g. reduced social interaction) that are similar to behavioral patterns associated with mood disorders. The model has contributed to the discovery of novel mechanisms regulating behavioral responses to stress, but its utility has been largely limited to males. This is disadvantageous because most mood disorders have a higher incidence in women versus men. Male and female California mice (Peromyscus californicus) aggressively defend territories, which allowed us to observe the effects of social defeat in both sexes. In two experiments, mice were exposed to three social defeat or control episodes. Mice were then behaviorally phenotyped, and indirect markers of brain activity and corticosterone responses to a novel social stimulus were assessed. Sex differences in behavioral responses to social stress were long lasting (4 wks). Social defeat reduced social interaction responses in females but not males. In females, social defeat induced an increase in the number of phosphorylated CREB positive cells in the nucleus accumbens shell after exposure to a novel social stimulus. This effect of defeat was not observed in males. The effects of defeat in females were limited to social contexts, as there were no differences in exploratory behavior in the open field or light-dark box test. These data suggest that California mice could be a useful model for studying sex differences in behavioral responses to stress, particularly in neurobiological mechanisms that are involved with the regulation of social behavior.

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The Kv2.1 delayed rectifier potassium channel exhibits high-level expression in both principal and inhibitory neurons throughout the central nervous system, including prominent expression in hippocampal neurons. Studies of in vitro preparations suggest that Kv2.1 is a key yet conditional regulator of intrinsic neuronal excitability, mediated by changes in Kv2.1 expression, localization and function via activity-dependent regulation of Kv2.1 phosphorylation. Here we identify neurological and behavioral deficits in mutant (Kv2.1−/−) mice lacking this channel. Kv2.1−/− mice have grossly normal characteristics. No impairment in vision or motor coordination was apparent, although Kv2.1−/− mice exhibit reduced body weight. The anatomic structure and expression of related Kv channels in the brains of Kv2.1−/− mice appears unchanged. Delayed rectifier potassium current is diminished in hippocampal neurons cultured from Kv2.1−/− animals. Field recordings from hippocampal slices of Kv2.1−/− mice reveal hyperexcitability in response to the convulsant bicuculline, and epileptiform activity in response to stimulation. In Kv2.1−/− mice, long-term potentiation at the Schaffer collateral – CA1 synapse is decreased. Kv2.1−/− mice are strikingly hyperactive, and exhibit defects in spatial learning, failing to improve performance in a Morris Water Maze task. Kv2.1−/− mice are hypersensitive to the effects of the convulsants flurothyl and pilocarpine, consistent with a role for Kv2.1 as a conditional suppressor of neuronal activity. Although not prone to spontaneous seizures, Kv2.1−/− mice exhibit accelerated seizure progression. Together, these findings suggest homeostatic suppression of elevated neuronal activity by Kv2.1 plays a central role in regulating neuronal network function.

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Our results suggest that OTR activation in anteromedial BNST induces a vigilance response in which individuals avoid, yet attend to, unfamiliar social contexts. Our results suggest that OTR antagonists may have unappreciated therapeutic potential for stress-induced psychiatric disorders.

Although high testosterone (T) levels inhibit paternal behaviour in birds breeding in temperate zones many paternal mammals have a very different breeding biology, characterized by a post-partum oestrus. In species with post-partum oestrus, males may engage in T-dependent behaviours such as aggression and copulation simultaneously with paternal behaviour. We previously found that T promotes paternal behaviour in the California mouse, Peromyscus californicus. We examine whether this effect is mediated by the conversion of T to oestradiol (E 2 ) by aromatase. In the ® rst experiment, gonadectomized males treated with T or E 2 implants showed higher levels of huddling and pup grooming behaviour than gonadectomized males treated with dihydrotestosterone or empty implants. In the second experiment, we used an aromatase inhibitor (fadrozole) (FAD) to con® rm these results. Gonadectomized males treated with T 1 vehicle or E 2 1 FAD showed higher levels of huddling and pup grooming behaviour than gonadectomized males treated with T 1 FAD or empty implants. Although E 2 is known to promote the onset of maternal behaviour to our knowledge our results are the ® rst to demonstrate that E 2 can promote paternal behaviour in a paternal mammal. These results may explain how mammals express paternal behaviour while T levels are elevated.

Despite recent discoveries of the specific contributions of genes to behavior, the molecular mechanisms mediating contributions of the environment are understudied. We demonstrate that the behavioral effects of estrogens on aggression are completely reversed by a discrete environmental signal, day length. Selective activation of either estrogen receptor ␣ or ␤ decreases aggression in long days and increases aggression in short days. In the bed nucleus of the stria terminalis, one of several nuclei in a neural circuit that controls aggression, estrogen-dependent gene expression is increased in long days but not in short days, suggesting that estrogens decrease aggression by driving estrogen-dependent gene expression. Estradiol injections increased aggression within 15 min in short days but not in long days, suggesting that estrogens increase aggression in short days primarily via nongenomic pathways. These data demonstrate that the environment can dictate how hormones affect a complex behavior by altering the molecular pathways targeted by steroid receptors.estrogen receptor ͉ social behavior ͉ Peromyscus polionotus ͉ seasonality G enes code for the molecular machinery that interacts with the environment to regulate behavior. Despite the importance of gene-environment interactions, relatively few studies have explored the mechanistic bases of these processes (1). These interactions may generate apparent inconsistencies in relationships between neurochemical systems and behavior (2). For example, in most birds and domesticated mice estrogens increase aggression, whereas estrogens decrease aggression or its components in Bluebanded gobies, California mice, and humans (3). This complexity in estrogenic modulation of aggression could be mediated by several factors including differential expression of estrogen receptor (ER) subtypes or differences in receptor activity after estrogen binding. In male vertebrates estrogens can be produced in the testes or synthesized in the brain from androgens. ERs can modulate physiology and behavior via both genomic and nongenomic pathways (4). Estrogens can alter the transcription of other genes by translocating to the nucleus and binding to estrogen response elements (ERE) or other response elements (5), a process mediated by an array of cofactors (6). Estrogens can also exert a variety of nongenomic effects that may be mediated by unique membrane-bound receptors (7) or the well characterized ER␣ (8) and ER␤ (9). Recent studies suggest ER␣ and ER␤ can be located at the membrane (10) and may facilitate phosphorylation of MAP kinase and CREB (11). Although the transduction of estrogenic signals has been studied intensively, comparatively little is known about how the environment affects estrogen action.Using a discrete environmental signal, day length (photoperiod), we have discovered a striking gene-environment interaction. Similar to other rodents, male beach mice (Peromyscus polionotus) exhibit testicular regression and are more aggressive when housed in winter-like short days (12...