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'.

Keywords: Animal models; Ecological context; Neural circuitry; Sex hormones; Social aggression.

Figure 1.. Aggression varies across the estrous cycle.

Fluctuations in aggression across the estrous cycle are commonly reported, though effects vary in magnitude among rodent species. Syrian hamsters are a species in which consistent variation in aggression is reported. Top: Schematic of hamster estrous cycle illustrating fluctuations in blood levels of the ovarian hormones estradiol and progesterone. Estradiol and progesterone levels both rise during Diestrus 2, peak surrounding Proestrus, and are lowest during Estrus and Diestrus 1. Bottom: Number of bites as a function of estrous cycle. During a five-minute resident-intruder test, female hamsters are most aggressive when estradioland progesterone levels are lowest. In contrast, during Proestus, when estradiol and progesterone levels are highest, the number of bites decreases.

Figure 2.. Proposed model for molecular signaling underlying the escalation of aggression in female hamsters.

Interfemale aggressive encounters activate metabotropic glutamate receptors (e.g., mGluR5) in the nucleus accumbens (NAc). Although the source of glutamatergic input is unknown, it is likely to orginate from the prefrontal cortex, amygdala, ventral hippocampus, or ventral tegmental area. This activation leads to Gq-mediated signaling that activates PP2A, resulting in the rapid dephosphorylation of FMRP. The dephosphorylation of FMRP allows for de-repression of local translation of synaptic scaffolding proteins, such as PSD-95 and SAPAP-3 in dendrites. Repeated aggressive experience produces a long-term increase in this translation and the resulting increase in synaptic scaffolding proteins is associated with the proliferation of mature dendritic spines in the NAc core. This structural plasticity in the NAc core likely reflects an increase in excitatory inputs to the cell and presumably mediates a heightened response to future aggressive encounters, leading to escalated aggressive behavior. Reprinted with permission from Been et al. (2016).

Figure 3.. Towards a neurocircuit of female aggression.

Compared to our knowledge of the neurobiology of aggression in males, we know much less about the neural substrates of aggression in females. Still, from the existing data, a circuit can be generated in which the hypothalamus, extended amygdala, and mesolimbic circuitry are key nodes. Within the hypothalamus, the medial preoptic area (MPOA) facilitates the expression of aggressive behavior, whereas the anterior hypothalamus (AH) and ventromedial hypothalamus (VMH) play an inhibory role. Interestingly, recent data suggests that the ventrolateral portion of the VMH (VMHvl) is an excitatory sub-population within the VMH, perhaps due to its glutamatergic projections to the mesolimbic reward circuitry. Within the mesolimbic circuitry, the role of the ventral tegmental area (VTA) is largely unknown. In contrast, the primary efferent target of the VTA, the nucleus accumbens (NAc), motivates aggressive behavior and confers long-term escalation of aggressive behavior with repeated experience via a molecular signaling pathway that depends on activation of metabotropic glutamate receptors. The NAc interacts structurally and functionally with the extended amygdala, including the medial amygdala (MeA) and bed nucleus of the stria terminalis (BNST), both of which play a excitatory role in female aggression. It is interesting to note that the BNST in particular seems well-positioned to interact with each of the identified neural substrates of female aggression. Future work should take advantage of modern functional neuroanatomical methods to investigate the BNST as a potential coordinator of female aggressive behavior.