By Laura E. Been, Ph.D.
Although many people think of aggression as a negative or undesirable emotion, it is a normal part of many species’ repertoire of social behaviors. In fact, aggressive behaviors typically serve an adaptive function—these purposeful and controlled behaviors serve to warn other individuals of perceived breaches in social contracts, typically with the goal of dispersing conflict before it escalates into physical violence. Aggression becomes maladaptive when it escalates inappropriately or impulsively into violence. This type of aggression, characterized by a loss of behavioral control, is a major problem in mental health and criminal justice settings and presents as a symptom of numerous psychiatric disorders. Despite this, the neurobiology of impulsive aggression is poorly understood.
Purposeful and controlled aggressive behaviors serve to warn others of perceived breaches in social contracts
One factor that contributes substantially to this lack of understanding is the fact that, historically, aggression has been considered a primarily male trait. Upon reflection, this seems absurd—I am confident that anyone reading this blog could easily call to mind examples of aggressive behaviors, both adaptive and maladaptive, displayed by females of many different species (including humans!). However, the vast majority of studies on the neural underpinnings of aggression have been conducted solely in males. This was particularly vexing to our research group because in the species we study, Syrian hamsters, females are more aggressive than males. We therefore set out to model escalated or impulsive aggression in female hamsters with the goal of characterizing long-term neural changes related to this behavior.
Impulsive aggression is major problem in mental health and criminal justice but its neurobiology is poorly understood
Previous research in our laboratory had demonstrated that when female hamsters repeatedly experience brief aggressive encounters, the amount of time it takes them to attack a non-aggressive intruder in their cage significantly decreases across time. Put another way, their aggressive behavior escalates into a maladaptive response, modeling the “short fuse” seen in pathological, impulsive aggression. Furthermore, this escalated aggressive behavior is associated with structural changes in the brain. In females who had experienced repeated aggressive encounters, the density of mature dendritic spines was increased on neurons in the nucleus accumbens, an integral part of the pathway that regulates motivated behaviors. This increase in dendritic spines is thought to increase excitatory neurotransmitter signaling in the nucleus accumbens, potentially accounting for the change in aggressive behavioral responding. However, the intracellular signaling events leading to these neural changes were unknown.
We hypothesized that the Fragile X Mental Retardation Protein (FMRP) signaling pathway mediated both the neural and behavioral changes we saw in female hamsters following repeated aggressive encounters. FMRP was first characterized (and named) in the context of Fragile X syndrome, a genetic disorder in which silencing of the Fragile X gene results in intellectual disabilities, autism, and heightened aggression. In the typically developing brain, however, FMRP acts locally in dendritic spines to regulate the translation of proteins involved in long-term plasticity. Changes in the phosphorylation state of FMRP are correlated with changes in the translation of synaptic scaffolding proteins, such as PSD-95 and SAPAP-3, that are involved in the stabilization of dendritic spines. FMRP itself is regulated by group I metabotropic glutamate receptors (mGluRs), including mGluR5. As such, this pathway was a logical target to investigate as a potential mediator of the neural and behavioral changes seen following repeated aggressive encounters in female hamsters.
Using a combination of behavioral, molecular biology, and pharmacology approaches, we demonstrated that aggressive experience resulted in a rapid, transient dephosphorylation of FMRP in the nucleus accumbens of female hamsters. This dephosphorylation drives the local increase in synaptic scaffolding proteins, such as PSD-95 and SAPAP-3, consistent with a proliferation of excitatory inputs. Furthermore, the escalation of aggressive behavior and the concomitant increase in PSD-95 mRNA each depend on the activation of mGluR5 receptors. Taken these findings together, we proposed a model in which aggressive experience activates mGluR5 receptors on neurons in the nucleus accumbens, leading to a rapid decrease in the phosphorylation of FMRP and long-lasting increases in the transcription and translation of post-synaptic scaffolding proteins. With repeated experiences, these changes may result in a change in neural signaling that mediate the escalated aggressive behavior seen in future encounters.
A pathway within nucleus accumbens is novel target 4 preclinical studies of the treatment of escalated aggression
Not only do these data demonstrate for the first time that neural plasticity following aggressive experience depends on a signaling cascade involving group I mGluRs, FMRP, and PSD-95 in female hamsters, but they also suggest this pathway within the nucleus accumbens as a novel target for preclinical studies of the treatment of escalated aggression. Moreover, preliminary data from our lab suggest that this pathway is activated in both male and female hamsters following aggressive experience, suggesting that this type of therapeutic approach may be more likely to be effective in treating pathologic aggression in female and male subjects, unlike previous approaches that have focused on treating aggression only in males.
Research presented here was supported by NIH R01DA013680 (RLM) and also by NIH T32DA0077234 (LEB and KMM) and T32GM008471 (KMM). We thank Kiara Vega, Calyn Maske, Kerry Trotter, and Natalia Rodriguez for their assistance in collecting these data.
About the Author
Laura E. Been, Ph.D., is a behavioral neuroscientist at Haverford College. Her primary research interests lie in understanding the neurobiology of motivated behaviors. Specifically, she is interested in how motivated behaviors that occur as a part of an individual’s everyday life, such as social and reproductive behaviors, result in long-lasting changes in the brain that can influence the future expression of those behaviors. In addition, she is interested in how experience with naturally motivated behaviors can impact an individual’s vulnerability to abnormal motivated behaviors, such as drug addiction.
For more info, see https://www.haverford.edu/users/lbeen.