Violence and aggression can be found in almost all animal species. A lingering question that humans have tried to address for as long as the existence of oral and written traditions of history is why aggression and violence occurs when other more appropriate choices are available. Leaving aside the situations where culturally sanctioned aggression and violence is rewarded (eg, military combat, boxing, or self-defense against aggression), humans are particularly concerned about limiting instances of inappropriate violence and aggression when other more socially acceptable behavioral choices are potentially available. This type of aberrant aggression and violent behavior is usually broken down into two main subcategories: episodic rage or premeditated violence. Given that people who engage in this behavior may severely injure or kill other humans, societies have developed legal consequences for committing violent acts. If people have knowledge that these violent behaviors are socially frowned upon, against the law, and severely punished, why do they commit them? One answer is that the brain circuits that support inhibition of violent and aggressive behavior have not developed appropriately, are not operating effectively, or they are organized in an unusual manner. In the latter case, the suggestion is that in certain milieus, aggressive and violent behaviors are an acceptable form of response and status attainment, and therefore they are not inappropriate and do not require selective inhibition. In the former cases, the notion is that the behavior is inappropriate for the situation, that the person has not learned to behave with the normal and accepted modes of social interaction, and/or that there has been a dramatic change in their behavior leading to increased aggression and violence. Which brain circuits (and affiliated receptors, genes, etc) go awry in this case? The evidence is that the prefrontal cortex and associated basal ganglia and limbic system structures are malfunctioning when inappropriate or unusual aggression and violence occurs.1 The evidence is built upon studies of patients with selective brain damage, activation of brain circuits involved in social behavior and inhibition using functional neuroimaging, and genetic studies of families with a propensity towards violence where the gene codes for a specific receptor that has an anatomical distribution that conforms to the circuit described above.
Studies of patients with focal brain lesions has led investigators to propose that the prefrontal cortex, in particular its ventral and medial sectors, mediates the inhibition of more primitive and rapid aggressive urges.2 Damage to these areas results in an increase in aggressive and violent behavior, and impaired development of these regions can also lead to an increase in violent behavior. Damage to the amygdala and other basal structures concerned with reward and punishment can also lead to a problem in the affective labeling of stimuli that could result in an inappropriate aggressive response (eg, mistaking a neutral face as an aggressive face or one showing disgust). Functional and structural neuroimaging studies of people with violent criminal histories have also revealed abnormal metabolic rates or brain volume in the prefrontal cortex.3,4,5 Functional neuroimaging studies of normal subjects who are asked to imagine aggressive states found diminished activity in the medial prefrontal cortex, suggesting that aggression normally results in a ‘shut-down’ of frontal lobe activity—presumably inhibiting social knowledge and rules that when activated typically serve to inhibit ongoing aggressive activity.6 If you start fighting, you do not want social rules interfering with the skill in which you fight. When normal subjects simply observe violent scenes, there is activation of the dorsolateral prefrontal cortex suggesting that area of the frontal lobes is used to reflect upon observations of violent behavior (Nakic et al., submitted). Recent pharmacological and genetic studies have dramatically expanded the list of neurotransmitters, hormones, cytokines, enzymes, growth factors, and signaling molecules that influence aggression. In spite of this expansion, serotonin (5-HT) remains the primary molecular determinant of inter-male aggression, whereas other molecules appear to act indirectly through 5-HT signaling. Slight modulations in 5-HT levels, turnover, and metabolism, or in receptor subtype activation, density, and binding affinity affect aggression. The activation of specific 5-HT receptors evokes distinct, but highly interacting, second messenger systems and multiple effectors. Understanding the interactions between 5-HT receptor subtypes should lead to novel insights into the molecular mechanisms of aggression. Furthermore, a recent study by Caspi et al demonstrates that there may be a complex relationship between the molecular genetic and social environments. In their study, they found that maltreated children with a genotype conferring high levels of MAOA expression were less likely to develop antisocial problems than maltreated children with low levels of MAOA expression.
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