The neurobiology of human aggressive behavior: Neuroimaging, genetic, and neurochemical aspects

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Highlights

  • In this review several neurobiological aspects of aggressive behavior are critically discussed.

  • We give a general overview of anatomical, molecular and environmental causes that influence aggressiveness, focusing on brain networks of aggressive behavior.

  • We have reviewed alterations in genes of neurotransmitter systems mainly involved in aggressive and antisocial behavior.

  • Factors besides single gene mutations have been discussed, such as gene-gene and gene-environment interactions.

Abstract

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.

Introduction

Amongst neuroscientists, there is a long-lasting debate over the burden of genetic and environmental factors in determining human behavioral differences: the nature versus nurture debate (Ridley, 2003). However, studies on biological mechanisms of aggressive behavior showed a great expansion only in the last 20 years. This field of research is promoted by the development of high-resolution brain imaging techniques and high-throughput genomics analyses, both of which considerably developed after the 1990s. Over the past decades, scientists began to identify brain networks involved in aggressive behavior, in order to recognize anatomical and/or functional abnormalities characterizing antisocial behaviors (Blake et al., 1995; Tiihonen et al., 1997; Tonkonogy, 1991; Volkow and Tancredi, 1987; Yang et al., 2008). Furthermore, neuroscientists have identified genetic predispositions that influence the functionality of the neural networks thereby finding significant associations between genetic mutations and antisocial behavior (Brunner et al., 1993; Ferguson, 2010). Additionally, the possibility to predict the risk of elevated levels of aggression and violence based on emotional reactivity, and the correlations between emotional reactivity rate and neural activity of different brain areas have been demonstrated by means of functional imaging (Prehn et al., 2013).

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 this comprehensive review, we discuss the neurobiology of aggression in humans based on the results of neuroanatomy, neuroimaging, neurotransmitters, genetic and environmental studies.

Section snippets

Pathology of aggressive behavior

Aggression is a common behavior into animal kingdom with evolutionary and adaptive functions, while violence is an abnormal behavior intrinsic to humans that overrides morality, in particular ethical rules, civil rights, and individual freedom.

Human aggressive behavior is promoted by multiple environmental factors (e.g., cultural and social conditions, early-life events, life experiences, pharmacological treatments, drugs and alcohol abuse) and biological elements (e.g., genetic mutations at

Imaging of brain in aggression

Impulsive aggression and violence reflect morpho-functional abnormalities and/or imbalance in emotional regulation circuitry of the brain (Davidson et al., 2000a) (Fig. 1). The brain areas and neural networks that are commonly activated during moral processing, as well as the morpho-functional alterations characterizing subjects with aggressive and antisocial behaviors, can be identified by using a variety of non-invasive imaging techniques (Raine and Yang, 2006). For example, molecular imaging

Brain areas of aggressiveness

Neuroscientists have studied what is happening in the brain behind aggressiveness by using several methods including: neuroanatomy, neuropathology, neuroimaging, neurochemistry, genetic, electrophysiology, pharmacology and others. The brain areas activated during aggressive behaviors have been deeply investigated, and several brain abnormalities leading to aggressive actions have been identified. Studies revealed that moral decision-making capability is impaired in violent, aggressive and

Genetics and neurochemistry of aggressive behavior

At the beginning of 1960s, Aprison and Ferster (Aprison and Ferster, 1961) found a correlation between aggressiveness and low activity of monoamine oxidase (MAO) enzymes, which have a key role in degradative pathways of different monoamines such as serotonin (5-HT) and other catecholamines (Fowler and Tipton, 1984). Few years later, important contributions to better understand the molecular basis of this correlation were the assignment of MAO type A gene (MAOA) to human X chromosome (Pintar et

Gene-gene interactions

Despite evidences showing that genes can predict aggressive behaviors, a single mutation is only likely to be a risk factor and unlikely can lead alone to aggressive behaviors. Researchers have analyzed in detail the genetic factors that influence antisocial behavior and have recognized the importance of both gene-gene and allele-allele interactions (Grigorenko et al., 2010). Indeed, subjects with antisocial and/or criminal behavior might carry multiple genetic risk factors for aggressive

Regulation of gene expression by epigenetic mechanisms

The epigenome regulates gene expression through non-mutagenic mechanisms: DNA methylation, modification of histone-protein and via non-coding RNA. In the CNS, epigenetic regulation of gene expression is involved in brain development, and in a variety of neural networks, including those for cognitive processes, such as learning and memory (Brunner et al., 2012). Dysregulation of epigenetic profile has been associated with neurodevelopmental, neurodegenerative and neuropsychiatric disorders (

Conclusions and perspectives

In this review we have discussed several studies related to neurobiological alterations and environmental influences on aggression. It seems that neurobiological abnormalities relate to aggression more than adverse environment, but in most cases their synergistic effect is required to produce such a behavior. Prenatal conditions like mother exposure to alcohol (Disney et al., 2008), cigarette smoking and substance abuse (Bada et al., 2007), nutritional deficits and birth complications can

Declaration of Competing Interest

None

Acknowledgements

This work was supported by Italian Ministry of Education, University, and Research (MIUR) - National Research Council of Italy (CNR) - Progetto Premiale "L’amministrazione della giustizia in Italia: il caso della neurogenetica e delle neuroscienze". FAC, FAZ and LZ were also supported by MIUR - National Research Programme (PNR) - CNR Flagship InterOmics Project (PB.P05) and by MIUR - PNR - CNR Aging Program 2012-2014. LP is funded by the Medical Research Council (MRC) (MR/P01271X/1) at the

Glossary

Aggression
range of behaviors deliberately aimed to harm or pain to another person and/or objects. Hostile aggression can be physical and/or verbal and is performed with the primary goal of intentional physical injury, psychological harm, damage of social relationships, taking advantage or pleasure.
Anger
defined as "a strong feeling of annoyance, displeasure, or hostility", anger is a basic human emotional state in response to the unwanted and unexpected behavior of others, and consists of

References (416)

  • M.E. Berman et al.

    The serotonin hypothesis of aggression revisited

    Clin. Psychol. Rev.

    (1997)
  • S.G. Bhakta et al.

    The COMT Met158 allele and violence in schizophrenia: a meta-analysis

    Schizophr. Res.

    (2012)
  • M. Bianciardi et al.

    A probabilistic template of human mesopontine tegmental nuclei from in vivo 7T MRI

    Neuroimage

    (2018)
  • R.J. Blair

    The roles of orbital frontal cortex in the modulation of antisocial behavior

    Brain Cogn.

    (2004)
  • N.J. Bray et al.

    A haplotype implicated in schizophrenia susceptibility is associated with reduced COMT expression in human brain

    Am. J. Hum. Genet.

    (2003)
  • S.A. Burt

    Are there meaningful etiological differences within antisocial behavior? Results of a meta-analysis

    Clin. Psychol. Rev.

    (2009)
  • G. Bush et al.

    Cognitive and emotional influences in anterior cingulate cortex

    Trends Cogn. Sci.

    (2000)
  • A.L. Byrd et al.

    MAOA, childhood maltreatment, and antisocial behavior: meta-analysis of a gene-environment interaction

    Biol. Psychiatry.

    (2014)
  • R.J. Cadoret et al.

    Associations of the serotonin transporter promoter polymorphism with aggressivity, attention deficit, and conduct disorder in an adoptee population

    Compr. Psychiatry

    (2003)
  • X. Caldú et al.

    Impact of the COMT Val108/158 Met and DAT genotypes on prefrontal function in healthy subjects

    Neuroimage

    (2007)
  • A. Campbell et al.

    Can ‘risky’ impulsivity explain sex differences in aggression?

    Pers. Individ. Differ.

    (2009)
  • T. Canli et al.

    Additive effects of serotonin transporter and tryptophan hydroxylase-2 gene variation on neural correlates of affective processing

    Biol. Psychol.

    (2008)
  • D. Caramaschi et al.

    Differential role of the 5-HT1A receptor in aggressive and non-aggressive mice: an across-strain comparison

    Physiol. Behav.

    (2007)
  • J. Chen et al.

    Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain

    Am. J. Hum. Genet.

    (2004)
  • T.J. Chen et al.

    Are dopaminergic genes involved in a predisposition to pathological aggression? Hypothesizing the importance of "super normal controls" in psychiatricgenetic research of complex behavioral disorders

    Med. Hypotheses

    (2005)
  • S.T. Chermack et al.

    Violence among individuals in substance abuse treatment: the role of alcohol and cocaine consumption

    Drug. Alcohol Depend.

    (2002)
  • E.F. Coccaro et al.

    Heritability of irritable impulsiveness: a study of twins reared together and apart

    Psychiatry Res.

    (1993)
  • E.F. Coccaro et al.

    Serotonin function in human subjects: intercorrelations among central 5-HT indices and aggressiveness

    Psychiatry Res.

    (1997)
  • E.F. Coccaro et al.

    Amygdala and orbitofrontal reactivity to social threat in individuals with impulsive aggression

    Biol. Psychiatry

    (2007)
  • E.F. Coccaro et al.

    Corticolimbic function in impulsive aggressive behavior

    Biol. Psychiatry

    (2011)
  • S. Comai et al.

    Tryptophan via serotonin/kynurenine pathways abnormalities in a large cohort of aggressive inmates: markers for aggression

    Prog. Neuropsychopharmacol. Biol. Psychiatry

    (2016)
  • R. Adolphs et al.

    Impaired recognition of emotion in facial expressions following bilateral damage to the human amygdala

    Nature

    (1994)
  • R. Adolphs et al.

    Impaired declarative memory for emotional material following bilateral amygdala damage in humans

    Learn. Mem.

    (1997)
  • N. Alexander et al.

    DNA methylation profiles within the serotonin transporter gene moderate the association of 5-HTTLPR and cortisol stress reactivity

    Transl. Psychiatry

    (2014)
  • F.R. Ali et al.

    Combinatorial interaction between two human serotonin transporter gene variable number tandem repeats and their regulation by CTCF

    J. Neurochem.

    (2010)
  • S.W. Anderson et al.

    Impairment of social and moral behavior related to early damage in human prefrontal cortex

    Nat. Neurosci.

    (1999)
  • M.H. Aprison et al.

    Neurochemical correlates of behavior II. Correlation of brain monoamine oxidase activity with behavioural changes after iproniazid and 5-hydroxytryptophan administration

    J. Neurochem.

    (1961)
  • V. Asghari et al.

    Dopamine D4 receptor repeat: analysis of different native and mutant forms of the human and rat genes

    Mol. Pharmacol.

    (1994)
  • V. Asghari et al.

    Modulation of intracellular cyclic AMP levels by different human dopamine D4 receptor variants

    J. Neurochem.

    (1995)
  • P. Asherson et al.

    The genetics of aggression: where are we now?

    Am. J. Med. Genet. B Neuropsychiatr. Genet.

    (2016)
  • E. Audero et al.

    Suppression of serotonin neuron firing increases aggression in mice

    J. Neurosci.

    (2013)
  • J.R. Augustine

    The insular lobe in primates including humans

    Neurol. Res.

    (1985)
  • E.C. Azmitia et al.

    Awakening the sleeping giant: anatomy and plasticity of the brain serotonergic system

    J. Clin. Psychiatry

    (1991)
  • H.S. Bada et al.

    Impact of prenatal cocaine exposure on child behavior problems through school age

    Pediatrics

    (2007)
  • C.J. Bailey et al.

    Transcranial magnetic stimulation as a tool for cognitive studies

    Scand. J. Psychol.

    (2001)
  • K.G. Baker et al.

    Cytoarchitecture of the human dorsal raphe nucleus

    J. Comp. Neurol.

    (1990)
  • K.G. Baker et al.

    Cytoarchitecture of serotonin-synthesizing neurons in the pontine tegmentum of the human brain

    Synapse

    (1991)
  • C. Ballard et al.

    Agitation and aggression in people with Alzheimer's disease

    Curr. Opin. Psychiatry

    (2013)
  • I.C. Ballard et al.

    Dorsolateral prefrontal cortex drives mesolimbic dopaminergic regions to initiate motivated behavior

    J. Neurosci.

    (2011)
  • J.C. Barnes et al.

    Genetic risk for violent behavior and environmental exposure to disadvantage and violent crime: the case for gene-environment interaction

    J. Interpers. Violence

    (2013)
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    1

    These authors contributed equally to this work and wish to be considered as co-first authors.

    2

    These authors are co-corresponding authors.

    3

    Present affiliation: Interdepartmental Center for Research Ethics and Integrity, National Research Council of Italy, Rome, Italy.

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