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The role of monoamine oxidase A in the neurobiology of aggressive, antisocial, and violent behavior: A tale of mice and men
Abstract
Over the past two decades, research has revealed that genetic factors shape the propensity for aggressive, antisocial, and violent behavior. The best-documented gene implicated in aggression is MAOA (Monoamine oxidase A), which encodes the key enzyme for the degradation of serotonin and catecholamines. Congenital MAOA deficiency, as well as low-activity MAOA variants, has been associated with a higher risk for antisocial behavior (ASB) and violence, particularly in males with a history of child maltreatment. Indeed, the interplay between low MAOA genetic variants and early-life adversity is the best-documented gene × environment (G × E) interaction in the pathophysiology of aggression and ASB. Additional evidence indicates that low MAOA activity in the brain is strongly associated with a higher propensity for aggression; furthermore, MAOA inhibition may be one of the primary mechanisms whereby prenatal smoke exposure increases the risk of ASB. Complementary to these lines of evidence, mouse models of Maoa deficiency and G × E interactions exhibit striking similarities with clinical phenotypes, proving to be valuable tools to investigate the neurobiological mechanisms underlying antisocial and aggressive behavior. Here, we provide a comprehensive overview of the current state of the knowledge on the involvement of MAOA in aggression, as defined by preclinical and clinical evidence. In particular, we show how the convergence of human and animal research is proving helpful to our understanding of how MAOA influences antisocial and violent behavior and how it may assist in the development of preventative and therapeutic strategies for aggressive manifestations.
... Still, it was not displayed in the female members of that family [13]. Some molecular genetic studies also reiterated the role played by the MAOA gene in various psychopathologies in both adults and children, including antisocial & psychiatric spectral behavior disorders and autism spectrum disorder [14]. The MAOA-L carriers of the MAOA-uVNTR polymorphism have been studied more frequently to be associated with a broad spectrum of antisocial behavioral traits that exhibit higher levels of aggression with violent and delinquent behavior patterns. ...
... MAOA gene polymorphisms broadly divide into tandem repeats and Single Nucleotide Polymorphism (SNP) [14]. ...
... The MAOA gene exhibits a series of mini-satellite genetic variations that have been studied to be responsible for a broad range of altered behavioral impacts. There are two variable number tandem repeats (VNTRs) in the MAOA gene within its promoter region: upstream variable number tandem repeat and distal variable number tandem repeat [14]. The locus of the upstream variable number tandem repeat (uVNTR) is about 1000 bp ahead of the gene transcription origin site, while the locus of the distal variable number tandem repeat (dVNTR) is approximately 700bp upstream from the uVNTR and about 1700bp upstream from the transcriptional origin site. ...
The Monoamine Oxidase A (MAOA) gene has acquired significant attention across the field of behavioral genetics over time due to its association with different adverse impacts it has had on altering human behavior. Research suggests that specific genetic variations of the MAOA gene, particularly the MAOA low allelic variants (MAOA-L alleles), are linked to increased susceptibility to aggression. Due to this association, the low-activity variations of the MAOA gene's upstream Variable Number Tandem Repeat (uVNTR) promoter region have conferred the name "warrior gene." A plethora of neurobiological investigations have revealed that the MAOA gene plays a significant role in the metabolism of neurotransmitters, such as dopamine, serotonin, and norepinephrine, that are implicated in regulating mood, impulse control, and emotional processing. Further, a wealth of research highlights that any form of dysregulation of these neurotransmitter systems, stemming from the genetic variants of the MAOA gene, can contribute to aberrant behavior and lead to aggressive tendencies. However, a negative association between the MAOA low allelic variant (MAOA-L) and aggressive behavior has recently been presented. Hence, a critical evaluation of available literature is important to retreat the relationship between the MAOA variants and human aggression and violence. A comprehensive review was conducted by utilizing Google Scholar, PubMed, and Scopus databases to explore the association of MAOA gene polymorphism with aggressive and violent behaviours. This review will be centered on peer-reviewed literature, evaluating the caliber of the studies and highlighting their profound outcomes. Therefore, this narrative review primarily focuses on the MAOA-uVNTR polymorphism and its influence on antisocial spectrum behaviors like aggression and violence. It also emphasizes the moral, legal, and societal issues that genetically influence human behavior. This comprehensive review conducted by utilizing 33 studies, where 19 studies revealed that the MAOA-L allelic variants are consistently associated with aggression. A total number of 14 studies supported the notion that MAOA-L allelic variants to show a positive correlation with violence and criminal violence. It was also disclosed that the MAOA-L variants are influenced by both genetic and environmental factors, underscoring the intricacy of its role in behavioral outcomes. Nevertheless, it is anticipated that the literature compiled herein would provide a critical justification for MAOA-L as a genetic risk factor for humans' aggressive and violent behavioral traits.
... The appellate court stated that jurors should consider expert testimony regarding the MAO-A evidence, but the high court unanimously ruled that it was within the court's discretion not to include the MAO-A evidence. The court concluded that "the mere showing of genetic predisposition as the cause of a certain mental state is not related to the defendant's intentional behavior" [7]. ...
... In a study examining 11 criminal cases between 1995 and 2016, the majority of cases were from the United States and Italy. In 8 of these cases, the MAO-A-L genotypes of the defendants were detected, and it was stated that this genotype was presented as a defense against the crime of first-degree murder in two cases [7], [19]. However, the study has some limitations; Due to limited access to court documents, published opinions and summaries from standard legal databases were used as literature. ...
... The MAO-A-L genotype has been associated with aggressive reactive impulsivity and may influence sentencing in cases of delinquency. However, there is no consensus on the inclusion of evidence regarding the MAO-A-L genotype in criminal proceedings [7]. ...
Monoamine oxidase (MAO-A) is an enzyme found in the nervous system and plays an important role in the breakdown of monoamine neurotransmitters. This enzyme varies among individuals depending on genetic factors. The monoamine oxidase-A (MAO-A) gene has been studied by various researchers to understand behavioral differences between individuals and evaluate crime propensity. However, serious ethical and legal problems may arise regarding the use of genetic factors alone in the judicial process. In this context, considering environmental factors as well as the MAO-A gene may contribute to the development of a more comprehensive approach. The role of the MAO-A gene in the judgment process has created an area of research that allows us to understand behavioral differences. The MAO-A gene has been associated with various behavioral traits. It has particular effects on aggressive behavior, antisocial behavior, and emotional reactions. In this context, the MAO-A gene may be an important factor in determining how individuals respond to environmental factors and guide their judgment processes. Some studies show that individuals with low MAO-A activity may be prone to antisocial behavior and crime. Thus, the MAO-A gene can be taken into consideration in determining guilt in legal processes. Assessing individuals' criminal propensity based on genetic factors can make the justice system more effective and fair. For example, harsh childhood conditions or traumatic experiences can trigger genetic predispositions and increase criminal propensity. In this case, it is important to take environmental factors into account when evaluating the genetic profile of the individual during the judicial process. Many ethical and legal issues need to be carefully considered on how to integrate the MAO-A gene into the judicial system. Therefore, research on the usability of the MAO-A gene in the judicial process should be continued.
... , consists of 15 exons 14 . Variants in the MAOA gene have been associated with altered enzymatic activity and various clinical outcomes [15][16][17] . Similarly, UGT2B7, an isoform of UDPglucuronosyltransferases encoded by a gene located on chromosome 4q13, catalyzes the glucuronidation of a wide range of endogenous and exogenous compounds. ...
... Genotypes and alleles of MAOA and UGT2B7 were inferred using Microsoft Office Excel v16. 16.1, without evaluating the phenotype, since there are no guidelines for predicting enzymatic activity. CYP2D6 haplotypes were inferred using the HaploStats package (version 1.7.7) ...
The biotransformation of primaquine is mediated by cytochrome P-450 (CYP) enzymes and monoamine oxygenase A (MAO-A). Polymorphisms in the genes that encode these enzymes can alter the clinical response of patients with Plasmodium vivax malaria, leading to therapeutic failure and recurrences. This study aimed to investigate the influence of variations in CYP2D6, MAOA, and UGT2B7 genes on recurrences of vivax malaria. In this case-control study, 72 individuals with vivax malaria were divided into two groups: 18 recurrences and 54 non-recurrences cases. Genotyping of CYP2D6, MAOA, and UGT2B7 was performed using a TaqMan assay and Real-time PCR. The frequency of CYP2D6 alleles was similar between the groups, except for the reduced-function allele *4, which was more frequent in the recurrence group (p = 0.019). Furthermore, the CYP2D6 normal metabolizers (gNM) phenotype had a higher frequency in individuals without recurrence (p = 0.039). An association was found between mutated MAOA genotypes (CC + CT) and a shorter time to recurrence compared to the wild-type (p = 0.0437). However, no association was found between UGT2B7 genotypes and recurrence. These findings suggest that genetic variations in both CYP2D6 and MAOA may contribute to the therapeutic failure of primaquine, reinforcing the importance of pharmacogenetics in monitoring antimalarial therapies.
Supplementary Information
The online version contains supplementary material available at 10.1038/s41598-025-94679-7.
... Molecular methodologies are being applied to the study of ASPD. Research points to the influence of the monoamine oxidase A (MAOA) gene in mediating aggression, antisocial behavior, and violence [25]. Perhaps one of the most interesting findings is that the low-activity variant of the gene has been found in antisocial persons who had been severely abused as children [26]. ...
... Possibly, the presence of serotonin helps curb impulsive and aggressive behaviors. Likewise, low levels of monoamine oxidase A (MAOA) in the brain have been associated with aggression and antisocial behavior [25]. (MAOA is an enzyme that breaks down monoamines thereby serving to regulate neurotransmitter levels.) ...
Purpose of Review
Antisocial personality disorder (ASPD) is a characterized by lifelong or recurrent behavioral problems that begin in childhood or early adolescence. This communication provides an overview on ASPD including findings from recent reviews and new research.
Recent Findings
With regard to DSM-5’s Section III Alternative Model of Personality Disorder criteria for ASPD, advocates point to the broader symptom coverage and harmonization with ICD-11; yet critics point to the lack of evidence for improved outcomes. A new report shows that antisocial individuals age faster than non-antisocial peers. ASPD has high heritability and newer molecular studies have found intriguing linkages to genes associated with crucial brain regions. A mentalization-based therapy model has been developed and early work shows promise.
Summary
ASPD is common, widespread, and disruptive to individuals, families, and society. Chronic and lifelong, ASPD typically lessens in severity with advancing age. Assessment rests on the individual’s history because there are no diagnostic tests. ASPD likely results from an interplay of genetic and environmental factors. Brain imaging studies have linked cortical dysfunction to antisocial behavior in crucial brain regions. Medication is sometimes targeted at the individual’s aggression and irritability, but a more rational approach is to target co-occurring disorders. Cognitive-behavioral therapy and mentalization-based therapy models have been developed and are being studied.
... Few have been connected to a useful role in regulating MAOA expression. Initially, rs6323 G>T and rs1137070 T>C, two synonymous polymorphisms that could be separated based on the activity of the FnuHI and EcoRV restriction endonucleases, respectively, were found (Kolla & Bortolato, 2020). The thymine (T) variant of rs1137070 is associated with higher levels of activity than the cytosine (C) allele, whereas the guanine (G) allele of rs6323 encodes an enzyme that is more active than the thymine (T) variant (Hwang, Lim, Kwon, & Jin, 2018). ...
... Previous research revealed that the rs1137070 variant, specifically the thymine (T) allele, has been found to be associated with increased enzymatic activity compared to the cytosine (C) allele. Similarly, the guanine (G) allele of rs6323 has been observed to encode an enzyme with higher activity than its thymine (T) variant (Kolla & Bortolato, 2020). However, it should be emphasized that these results are in contrast to those in a study conducted on individuals with gout, it was observed that there was a marginal inclination towards heightened monoamine oxidase (MAO) activity in samples obtained from carriers of the C-allele, in comparison to their counterparts who carried the T-allele (Tu et al., 2010). ...
... When MAO activity is reduced, neurotransmitter levels-particularly dopamine and serotonin-increase, which may contribute to improved mood and cognitive function. Notably, the involvement of dopaminergic and serotonergic pathways has been associated with positive affective and neurocognitive outcomes [135] . However, the extent to which these psychological effects depend on dietary intake of coumarins or the efficiency of their absorption remains unclear. ...
Coumarins, a diverse family of naturally occurring compounds, offer a remarkable window into the deep and dynamic relationship between humans and the natural world. Found in plants, fungi, and even insects, these benzopyrone derivatives are not only known for their pharmacological versatility but also for their cultural, psychological, and ecological resonance. This review journeys through the multifaceted narrative of coumarins-from their ancient medicinal uses and spiritual significance to their contemporary relevance in environmental sustainability and mental health. Historically used in embalming rituals and herbal remedies, coumarins have been quietly shaping human experience for centuries. Their fragrant presence in essential oils and plant-based incense once framed sacred spaces and contemplative practices, hinting at their subtle but lasting psychological impact. Today, coumarins are gaining renewed interest not only for their anti-inflammatory, antimicrobial, and antioxidant properties but also for their potential role in mood regulation, cognitive enhancement, and neuroprotection. Their influence on monoamine pathways suggests applications in stress relief and emotional well-being-key concerns in the modern, often nature-deprived lifestyle. Environmentally, coumarins act as plant defense agents and ecological messengers, influencing biodiversity, herbivore behavior, and even soil microbiota. Their allelopathic and biocidal properties position them as vital tools in green chemistry and sustainable agriculture. Furthermore, interdisciplinary collaborations now explore coumarins in fields ranging from biomedicine and biotechnology to aromatherapy and environmental psychology. This review highlights coumarins not just as biochemical agents but as symbolic links in the human-nature nexus-agents of healing, communication, and balance. Understanding their roles across ecosystems, cultures, and psychological dimensions is essential for developing sustainable strategies that respect both biodiversity and human well-being. In an era of ecological uncertainty and emotional fragmentation, coumarins offer a fragrant reminder that nature and humanity are deeply, chemically, and spiritually entwined.
... While there are many genetic, epigenetic, and environmental factors that contribute to socialisation, we noted that the gene MAOA was altered in the hippocampus of injured mice at the acute timepoint and a trend for increased expression at the intermediate time point. As MAOA has been linked to antisocial personality disorder and aggression [4,54], it is possible that this change may be linked to the social deficits produced in this model. However, further tests are required to examine if this link is causal or if MAOA changes of this magnitude would result in increased aggression in adulthood. ...
Abusive head trauma (AHT) resulting from violent shaking and whiplash-induced brain injury by a caregiver, is the leading cause of abusive mortality and morbidity in children. Cerebral oedema is common in survivors of AHT. While many children may initially appear behaviourally asymptomatic or present with non-specific symptoms following the AHT, deficits often emerge later in childhood. Additionally, AHTs are frequently repetitive, with a single child likely to experience multiple AHTs. Despite the prevalence of AHT, the mechanisms that lead to brain pathology and the latent emergence of behavioural deficits are poorly understood, and there is a paucity of preclinical, small animal models to investigate the biology and cumulative effects of repetitive injuries. This study aimed to develop a preclinical model of repetitive AHT and subsequently examine alterations in gene expression, cell types, and early adolescent behaviour. Mice were placed on a 400 rpm shaking device for 60s. This was repeated one, three, or five times throughout the neonatal development period (postnatal days (P)8–12). Injured mice initially displayed no overt behavioural changes compared to uninjured controls; however, in adolescence (P40-45) they later developed deficits in socialisation and thermal nociception. Further, alterations in the expression of genes involved in growth, cell damage, and development were observed in the brains of injured mice, along with an increase in white matter cells and evidence of blood-brain barrier leakage. This novel preclinical model of AHT provides a valuable platform for exploring diagnostic biomarkers and potential therapeutic interventions for children with an AHT.
Supplementary Information
The online version contains supplementary material available at 10.1186/s40478-025-02029-5.
... По мнению исследователей, спектр социально приемлемых агрессивных проявлений у человека ограничен социально-культурными нормами. Учитывая многообразие мотивов, лежащих в основе агрессивного поведения, классификация, направленная на выделение различных подтипов агрессии, может быть особенно полезной для исследования биологических и эволюционных аспектов этого феномена [11]. ...
Background : aggression is one of the most complex and relevant clinical challenges faced by clinicians working with the mentally ill. Despite the significance of this problem, the mechanisms of occurrence and risk factors of aggression are still not fully understood. The aim of review is to analyse modern research studying aggression and aggressive behavior in psychiatric patients, as well as the possibility of predicting aggressive behavior using modern diagnostic methods. Material and Methods: sources were searched in Elibrary.ru, PubMed, Scopus, PsychINFO, MedLine and Google Scholar databases using the keywords: ‘aggression’, ‘psychiatric disorders’, ‘mechanisms of aggression’, ‘aggression factors’. The selection included articles published in Russian and English in the last 20 years. Discussion : various approaches to the definition and classification of aggressive behavior are considered and the main hypotheses explaining its mechanisms discussed. Most of studies demonstrates a strong association between psychiatric disorders and increased risk of aggressive behavior. Aggression in psychiatric patients considered due to the interaction of a complex set of factors. Researchers assign a significant role to genetic predisposition to aggression, but its manifestation closely related to environmental influences. The important role of genetic determinants in the formation of aggression is shown, including the analysis of individual genes, genomic associations and intergenerational transmission. It also shown that aggressive behavior closely related to neurophysiological processes in the brain. Nevertheless, it requires furtherresearch for a detailed study of aggressive behavior mechanisms on the molecular, neurochemical and neuronal levels. Conclusion : the study of the mechanisms of formation and implementation of aggressive behavior is crucial in the creation of systems for the prevention of socially dangerous actions on the part of patients in relation to their environment. Further research in the field of genetics, biology and neurobiology of aggressive behavior considered as the most perspective.
... Another gene of note is MAOA (monoamine oxidase A), which encodes an enzyme involved in the metabolism of neurotransmitters such as serotonin, dopamine, and norepinephrine and is primarily localized in the catecholaminergic cells of the central nervous system. Monoamine oxidase A (MAOA) plays a pivotal role in regulating the levels of these monoamines by breaking them down, thereby controlling their concentration in the central nervous system (CNS) (64). MAOA plays a pivotal role in maintaining neurochemical equilibrium, which is essential for optimal brain function. ...
... Other reports found a higher activity of the AChE in the saliva of Parkinson's patients [47]. The MAO has a role in regulating many neurological and psychological disorders‚ since an increase in the enzyme's activity may result in damage to the nervous system and a decline in cognitive awareness [48,49]. MAO inhibitors work as antidepression and anti-anxiety agents and additional nervous system disorders such as panic disorder, and social phobia‚ as a study indicated that MAO inhibitors are one of the main classes of medications prescribed to treat depression [50]. ...
... y dopamina. Un estudio que cubre la genómica comparativa entre especies, utilizando un enfoque de asociación de todo el genoma, reveló que MAOA presentaba un número considerable de ocurrencias y clasificaciones ponderadas para la agresión(Kolla, & Bortolato, 2020).En los trastornos debilitantes del neurodesarrollo, como el trastorno del espectro autista, con deterioro de la interacción social, ya está bien establecido que se trata de un trastorno poligénico de origen multifactorial, que involucra variables en el número de copias de los genes de la sinaptogénesis y sus vías de señalización con modificaciones moleculares relacionadas con la adhesión celular, canales iónicos y vías de señalización (PTEN -fosfatasa homóloga a la tensina y mTOR -Mammalian target of rapamycin)(Thomas et al., 2023).Además, en el fenotipo actual están implicadas modificaciones epigenéticas impuestas por la exposición prenatal y posnatal. Todos estos factores involucrados responden a la desregulación de la señalización de la vía glutamatérgica, lo que resulta en la activación de las células gliales y la liberación de factores inflamatorios que complican el comportamiento social del individuo(Bhandari et al., 2020). ...
La comprensión del comportamiento humano se basa en conceptos patogénicos, terapias empíricas y enfoques neuropsicofarmacológicos, involucrando neurotransmisores como noradrenalina, dopamina, serotonina y el tratamiento de patologías subyacentes incluye psicofármacos, antipsicóticos e inhibidores selectivos, cuya efectividad ha sido limitada, lo que denota la participación de otras vías en el proceso patogénico. Estudios basados en ciencias ómicas (biología molecular, metabolismo, factores transcripcionales, genética y epigenética) demuestran varios genes y procesos genéticos de metilación y reparación del ADN implicados en la patogénesis de estas enfermedades. El objetivo de este artículo es presentar un estudio de revisión sistemática sobre los principales aspectos de las ciencias ómicas que pueden contribuir a la comprensión de los mecanismos moleculares del comportamiento agresivo humano, dada su presencia en la mayoría de los trastornos psiquiátricos. El conocimiento molecular de estos procesos revela una superposición de fundamentos genéticos y epigenéticos que pueden proporcionar información útil para el estudio, diagnóstico, predicción u investigación terapéutica de los mecanismos del comportamiento agresivo humano.
... • Enzymes such as monoamine oxidase (MAO), which metabolizes neurotransmitters like dopamine and serotonin, generate hydrogen peroxide as a byproduct. This process can increase vulnerability to oxidative stress and trigger migraine attacks in predisposed individuals [44]. ...
Migraine with aura (MA) affects one-third of people who suffer from it and is characterized by the presence of transient neurological symptoms, such as visual, sensory, or language disturbances, that precede or accompany the headache. Various studies have highlighted the relationship between migraine with aura and mutations in the MTHFR gene, which encodes the enzyme methylenetetrahydrofolate reductase, responsible for folate metabolism and the regulation of homocysteine levels. Two main mutations, C677T and A1298C, have been implicated in the risk of developing migraine with aura. The C677T mutation in the MTHFR gene can reduce enzymatic activity by up to 30% in homozygous individuals, which increases homocysteine levels, especially in those with low folate intake. Elevated homocysteine has been associated with endothelial dysfunction and inflammatory processes, both factors involved in the pathophysiology of migraine. Additionally, the A1298C mutation has also been linked to a decrease in enzymatic activity, although its impact on homocysteine levels is less significant. Genetic studies have linked these mutations to a higher susceptibility to migraine with aura. For instance, individuals with the TT genotype of the C677T mutation have a significantly higher risk of suffering from MA compared to those without the mutation. This review article discusses the pathophysiological implications of these mutations, the relationship between hyperhomocysteinemia and migraine with aura, and the possible underlying mechanisms, including oxidative stress and mitochondrial dysfunction, which may contribute to the development and severity of migraine with aura.
... These findings are of scientific and practical interest, as in a significant number of publications, polymorphisms of this gene are more strongly associated with aggression and antisocial behaviour (Kolla & Bortolato, 2020). ...
Objective
Atypical depression (AD) is a clinical subtype of depression characterised by mood reactivity and at least two of the following features: significant weight gain/increased appetite, hypersomnia, leaden paralysis, and/or interpersonal rejection sensitivity. The role of genetics in the development of depression remains a considerable level of interest among individuals. Due to the large number of breakthrough studies in genetics, there is currently a wealth of heterogeneous data on the existence of genetic markers for depression, including AD. However, it appears that there is a gap in the literature, as we were unable to identify any systematic reviews or meta-analyses that comprehensively describe these data. Therefore, our research aims to provide high-quality, solid evidence for further studies in this area.
Method
Electronic bibliographic databases (Scopus, MEDLINE) were systematically searched from inception to September 2023. We searched for any specific genetic markers that could be retrieved associated with AD. The quality of studies has been assessed by means of the Q-genie tool.
Results
Nine studies meeting the inclusion criteria were selected, which appeared to link genetic polymorphisms to atypical depression. Four studies examined genetic polymorphisms associated with the serotonin transporter gene (5-HTT), three studies examined genetic polymorphisms associated with endocrine regulation, two studies considered genetic polymorphisms associated with immune and/or cellular regulation, specifically the melanin-concentrating hormone receptor 2 (MCHR2), mineralocorticoid receptor (MR), and fat mass and obesity-associated protein (FTO) genes involved in the regulation of energy balance.
Conclusions
The extracted data confirm that the atypical type of major depressive disorder is heritable to a certain extent. Individual risk markers for developing this type of depression may be identified in the future.
... MAOA increases with aging [29]. Reports were published in which MAO variations in the human brain during aging were studied using approaches different from the measurement of enzymatic activity using high-resolution enzyme radioautography to quantify MAOA [30]. ...
It is thought that the monoamine oxidase-A (MAOA) enzyme, which catalyzes key brain signaling chemicals like serotonin, noradrenaline, and dopamine, indirectly influences antisocial behavior by disrupting the neurotransmitter balance in brain regions and neural networks. This study aims to assess the MAOA enzyme level in serum and serotonin linked to antisocial behavior in cases in the prison of Baghdad City, Iraq. Blood samples were collected from (63) prisoners and (27) control groups, ages 18 years to 65 years, with a mean ± SD of 37.8 ± 8.8, all males, with different prison terms and different crimes for prisoners in the prison at Baghdad City, Iraq. MAOA and serotonin levels were measured in serum in prisoners and healthy men, and the results showed the serum levels of MAOA enzyme and serotonin were decreased in prisoners compared to the healthy (11.5 IU/ml vs. 19.5 IU/ml) and (79 IU/ml vs. 439 IU/ml), respectively, with the observed difference being significant (P < 0.001(. The results of the relationship between education and social violence were: illiterate 11.1%, primary school 27%, secondary 52.4%, and university 9.5%. The median serum level of MAOA and serotonin in the age group 18–39 years was (11.3 IU/ml, 68.3 ng/ml), respectively, and in the age group 40–65 years was (13 IU/ml, 139 ng/ml), respectively.
... 30 Males are also typically more impulsive, irritable, and have difficulty controlling their emotions, which makes them more likely to engage in violent or antisocial behaviors in the face of conflict. 31 Similar to the effect of gender on antisocial behavior, the risk of ASPD in males is typically 3-5 times greater than in females. 11,32 Being an only child is an independent risk factor for the emergence of antisocial behavior. ...
Objective: Antisocial behavior and antisocial personality disorder (ASPD) cause serious harm to society and families. Ethnicity may have an impact on an individual’s antisocial behavior and the incidence of ASPD. Therefore, this study aimed to investigate the current status of antisocial behavior and ASPD among youth and its correlation with ethnicity in ethnic minority areas in China. Methods: A total of 2475 Chinese youth (1794 under 18 and 681 greater than or equal to 18) were recruited from December 1 to 30, 2021, in Yunnan, China. All participants com-pleted a General Information Questionnaire and the Personality Diagnostic Questionnaire Fourth Edition Plus (PDQ-4+). Associations between antisocial behavior and ASPD and sociodemographic factors such as ethnicity were examined using binary logistic regres-sion analysis. Results: The positive rate of antisocial behavior screening in youth was 5.4% (95% CI (con-fidence interval): 4.3-6.4), with a positive rate of ASPD screening of 4.4% (95% CI: 2.9-6.0). Male, single-child and maternal education level at senior high school and above were risk factors for positive antisocial behavior screening, while senior high school grade and medium subjective family economic status were protective factors for positive antisocial behavior screening. Being male and paternal educational background were risk factors for positive ASPD screening. Conclusion: This study found high rates of positive screening for antisocial behavior and ASPD in youth and no significant differences in ethnicity. These results can be used to inform personality development.
... These monoamines are considered pivotal neurotransmitters in the pathophysiology of conditions like schizophrenia (Sun et al., 2012). MAOA has been consistently associated with conditions such as addiction, depression, autism, and antisocial behavior (Byrd and Manuck, 2014;Kolla and Bortolato, 2020). Additionally, MAOA plays a critical role in regulating neurotransmitters in the brain that are closely linked to emotions, including depression, reward, and aggression (Cases et al., 1995). ...
The Monoamine Oxidase-A ( MAOA ) EcoRV polymorphism (rs1137070) is a unique synonymous mutation (c.1409 T > C) within the MAOA gene, which plays a crucial role in Maoa gene expression and function. This study aimed to explore the relationship between the mouse Maoa rs1137070 genotype and differences in MAOA gene expression. Mice carrying the CC genotype of rs1137070 exhibited a significantly lower Maoa expression level, with an odds ratio of 2.44 compared to the T carriers. Moreover, the wild-type TT genotype of MAOA demonstrated elevated mRNA expression and a longer half-life. We also delved into the significant expression and structural disparities among genotypes. Furthermore, it was evident that different aspartic acid synonymous codons within Maoa influenced both MAOA expression and enzyme activity, highlighting the association between rs1137070 and MAOA. To substantiate these findings, a dual-luciferase reporter assay confirmed that GAC was more efficient than GAT binding. Conversely, the synonymous mutation altered Maoa gene expression in individual mice. An RNA pull-down assay suggested that this alteration could impact the interaction with RNA-binding proteins. In summary, our results illustrate that synonymous mutations can indeed regulate the downregulation of gene expression, leading to changes in MAOA function and their potential association with neurological-related diseases.
... These products were also characterized by 1 HNMR and 13 CNMR analyses (Section 4.4). As these metabolites are produced as a result of demethylation and/or oxidative deamination, it can be hypothesized that sumatriptan will be metabolized in the liver and central nervous system where such transformations can occur, as reported for MAO A [17]. B. subtilis is commonly found in the bowel as part of the normal flora, Salmonella spp. is present during active infections, and S. aureus and P. aeruginosa are not typically found in the bowel under normal conditions but can be present in specific pathological situations, so the metabolization of sumatriptan by these organisms can occur in the bowel. ...
This study aimed at the biotransformation of sumatriptan by Staphylococcus aureus, Bacillus subtilis, Pseudomonas aeruginosa and Salmonella enterica subsp. enterica and the identification of the drug metabolites by liquid chromatography–mass spectrometry. The drug was incubated with the organisms in tryptic soya broth at 37 °C. The broth was filtered and subjected to liquid chromatography–mass spectrometry. The metabolites identified by the use of mass spectral (+ve ion mode) fragmentation patterns were (3-methylphenyl)methanethiol (Bacillus subtilis), 1-(4-amino-3-ethylphenyl)-N-methylmethanesulfonamide (Salmonella enterica subsp. enterica) and 1-{4-amino-3-[(1E)-3-(dimethylamino)prop-1-en-1-yl]phenyl}methanesulfinamide (Salmonella enterica subsp. enterica, Bacillus subtilis, Pseudomonas aeruginosa, Staphylococcus aureus). These metabolites exhibit high gastrointestinal absorption, no blood–brain barrier permeability (except (3-methylphenyl)methanethiol), a bioavailability score of 0.55 and no inhibitory effect on CYP2C19, CYP2C9, CYP2D6, CYP3A4 or cytochrome P450 1A2 (except (3-methylphenyl)methanethiol), as determined by SwissADME software ver. 2024. The metabolites appear to be more toxic than the parent drug, as suggested by their calculated median lethal dose values. All four organisms under investigation transformed sumatriptan to different chemical substances that were more toxic than the parent drug.
... While no alterations were observed in MsrA, COMT and AANAT. MAOA deficiency may result in aggressive feature in the behaviour of ASD patients compared to the control, in dystociarelated ASD children may refer to the increased sensitivity to this feature [47]. A significant number of autistic individuals had hyperserotonemia in serum and whole blood, but outside the brain and the possibility for used this biomarker for ASD diagnosis [48]. ...
... While no alterations were observed in MsrA, COMT and AANAT. MAOA deficiency may result in aggressive feature in the behaviour of ASD patients compared to the control, in dystociarelated ASD children may refer to the increased sensitivity to this feature [47]. A significant number of autistic individuals had hyperserotonemia in serum and whole blood, but outside the brain and the possibility for used this biomarker for ASD diagnosis [48]. ...
... Sex is a major factor that may modify the gene-behavior association. While males are three times more likely to exhibit aggressive behaviors than females due to both biological and cultural factors [137][138][139], the effects of genes on behavior may also be modified by sex-specific factors such as the levels of testosterone and Y-chromosome genes [140,141]. Therefore more studies focusing on females are necessary to understand the genetics underlying female youth aggressive behaviors. ...
Excessive and persistent aggressiveness is the most common behavioral problem that leads to psychiatric referrals among children. While half of the variance in childhood aggression is attributed to genetic factors, the biological mechanism and the interplay between genes and environment that results in aggression remains elusive. The purpose of this systematic review is to provide an overview of studies examining the genetics of childhood aggression irrespective of psychiatric diagnosis. PubMed, PsycINFO, and MEDLINE databases were searched using predefined search terms for aggression, genes and the specific age group. From the 652 initially yielded studies, eighty-seven studies were systematically extracted for full-text review and for further quality assessment analyses. Findings show that (i) investigation of candidate genes, especially of MAOA (17 studies), DRD4 (13 studies), and COMT (12 studies) continue to dominate the field, although studies using other research designs and methods including genome-wide association and epigenetic studies are increasing, (ii) the published articles tend to be moderate in sizes, with variable methods of assessing aggressive behavior and inconsistent categorizations of tandem repeat variants, resulting in inconclusive findings of genetic main effects, gene-gene, and gene-environment interactions, (iii) the majority of studies are conducted on European, male-only or male-female mixed, participants. To our knowledge, this is the first study to systematically review the effects of genes on youth aggression. To understand the genetic underpinnings of childhood aggression, more research is required with larger, more diverse sample sets, consistent and reliable assessments and standardized definition of the aggression phenotypes. The search for the biological mechanisms underlying child aggression will also benefit from more varied research methods, including epigenetic studies, transcriptomic studies, gene system and genome-wide studies, longitudinal studies that track changes in risk/ameliorating factors and aggression-related outcomes, and studies examining causal mechanisms.
... Regarding the bars, items that fell below the threshold are shown in blue, whereas items above the threshold are represented in pink intensity of incoordination resulting from mental instability, which likely influence master-servant relationship with a trainer. Moreover, MAOA is associated with aggression and antisocial behavior (Kolla and Bortolato 2020). In the present study, it was associated with PC2 (indifference or roughness to the external environment), suggesting the potential to identify horses that display disinterest in humans or other horses and tend to exhibit harmful behavior toward negative stimuli. ...
Retraining retired racehorses for various purposes can help correct behavioral issues. However, ensuring efficiency and preventing accidents present global challenges. Based on the hypothesis that a simple personality assessment could help address these challenges, the present study aimed to identify genetic markers associated with personality. Eight genes were selected from 18 personality-related candidate genes that are orthologs of human personality genes, and their association with personality was verified based on actual behavior. A total of 169 Thoroughbred horses were assessed for their tractability (questionnaire concerning tractability in 14 types of situations and 3 types of impressions) during the training process. Personality factors were extracted from the data using principal component analysis and analyzed for their association with single nucleotide variants as non-synonymous substitutions in the target genes. Three genes, CDH13, SLC6A4, and MAOA, demonstrated significant associations based on simple linear regression, marking the identification of these genes for the first time as contributors to temperament in Thoroughbred horses. All these genes, as well as the previously identified HTR1A, are involved in the serotonin neurotransmitter system, suggesting that the tractability of horses may be correlated with their social personality. Assessing the genotypes of these genes before retraining is expected to prevent problems in the development of a racehorse’s second career and shorten the training period through individual customization of training methods, thereby improving racehorse welfare.
... Among these, MAOA, which encodes the key enzyme for the 2 degradation of serotonin and catecholamines is the best-documented gene. Human genetic studies associated a higher risk for antisocial and violent behavior both with congenital MAOA deficiency and low-activity MAOA variants [13]. Moreover, a sexual dimorphic effect of MAOA in behavioral traits beyond an increase of its activity levels with age hasbeen detected [14]. ...
ADHD is a neurodevelopmental disorder that children and also adults can develop. A complex interplay of genetic and environmental factors may underlie interindividual variability in ADHD and potentially related aggressive behavior. Using high-resolution molecular biology techniques, we investigated the impact of some MAOA and SLC6A4 variations on ADHD and aggressive behavior in a group of 80 Italian children with ADHD and in 80 healthy controls.We found that homozygous genotypes of MAOA rs6323 and rs1137070 were associated with an increased risk of ADHD (p=0.02 and p=0.03, respectively), instead the heterozygous genotypes (GT of rs6323 and CT of rs1137030) (p=0.0002 and p=0.0006) were strongly linked to a lower risk of developing this disorder. In patients with aggressive behavior, we highligted only a weak negative association of both MAOA polymorphisms (heterozygous genotypes) with aggressiveness then, suggesting that these genotypes maybe protective towards specific changes in behavior (p=0.05). Interestingly, an increase of the GG genotype of rs6323 (p=0.01) and a decrease of GT genotype (p=0.0005) was also found in patients without aggressive behavior compared with controls. Regarding 5HTT gene genotyping, no allele and genotype differences have been detected among patients and controls. Our work shows that defining a genetic profile of ADHD may help to early detect those patients who are more vulnerable to ADHD and/or antisocial and aggressive behavior and to design precision-targeted therapies.
... Among these, MAOA, which encodes the key enzyme for the degradation of serotonin and catecholamines, is the bestdocumented gene. Human genetic studies associated a higher risk for antisocial and violent behavior both with congenital MAOA deficiency and low-activity MAOA variants [19]. Moreover, a sexual dimorphic effect of MAOA in behavioral traits beyond an increase in its activity levels with age has been detected [20]. ...
ADHD is a neurodevelopmental disorder that children and adults can develop. A complex interplay of genetic and environmental factors may underlie interindividual variability in ADHD and potentially related aggressive behavior. Using high-resolution molecular biology techniques, we investigated the impact of some MAOA and SLC6A4 variations on ADHD and aggressive behavior in a group of 80 Italian children with ADHD and in 80 healthy controls. We found that homozygous genotypes of MAOA rs6323 and rs1137070 were associated with an increased risk of ADHD (p = 0.02 and p = 0.03, respectively), whereas the heterozygous genotypes (GT of rs6323 and CT of rs1137030) (p = 0.0002 and p = 0.0006) were strongly linked to a lower risk of developing this disorder. In patients with aggressive behavior, we highlighted only a weak negative association of both MAOA polymorphisms (heterozygous genotypes) with aggressiveness, suggesting that these genotypes may be protective towards specific changes in behavior (p = 0.05). Interestingly, an increase in the GG genotype of rs6323 (p = 0.01) and a decrease in GT genotype (p = 0.0005) was also found in patients without aggressive behavior compared to controls. Regarding 5HTT gene genotyping, no allele and genotype differences have been detected among patients and controls. Our work shows that defining a genetic profile of ADHD may help in the early detection of patients who are more vulnerable to ADHD and/or antisocial and aggressive behavior and to design precision-targeted therapies.
... Although aggression has been observed to be hereditable in some humans (Tuvblad & Baker, 2011), several genome-wide association studies (GWAS) have failed to identify a sole gene responsible for aggression (Odintsova et al., 2019). Despite this, many genes have been reported as possible candidates for human aggressive behavior, such as RBFOX1 (essential for neuronal development) (Fernàndez-Castillo et al., 2020), the gene for monoamine oxidase A MAOA (an enzyme for the degradation of serotonin and catecholamines) (Kolla & Bortolato, 2020), and the mineralocorticoid receptor gene NR3C2 (involved in stress responses) (Qing et al., 2021), among others. A significant challenge for aggression research to address the factors above has been to develop a questionnaire or a scale to provide an adequate measurement of aggression in individuals. ...
The psychometric properties of the Buss and Perry AQ questionnaire of aggression, one of the most used questionnaires worldwide to measure aggressive behavior, were examined in a sample of adolescents (n=779 participants) from the cities of Barranquilla (n= 410) and Pereira (n= 369), in Colombia. In total, 752 participants (Mean age of 15.3 years, SD = 1.9; 57,4%. women and 42,6 men) completed the Buss and Perry AQ questionnaire. Subsequently, the univariate and multivariate normality of the items was evaluated, and a confirmatory factor analysis (CFA) was performed on the data set. Likewise, the fit of two models was evaluated, a multidimensional a priori model, and a model with a second-order factor (aggressive behavior), which could explain the variance of the items. Finally, the reliability indices of the questionnaire were identified. The results showed acceptable goodness-of-fit indices (X2/df = 2.29, CFI = .977, IFI = .977, GFI = .984, AGFI = .979, RNI = .984, NFI = .972, RMSEA of .047 [90% CI = .016 - .036] and SRMR = .059) for the second-order one-factor model, as well as acceptable reliability indices (α= .55 - .88). In conclusion, these results show that the scale can be applicable to Colombian preadolescents and adolescents, but warn of the limitations of its use for the non-aggression subscale. Nevertheless, the application of the scale in its original version is suggested to determine its psychometric behavior.
... MAOA regulates neurotransmitter homeostasis to engage with synaptic transmission processes in the central nervous system, which in turn affects central neuronal reactivity and peripheral neurophysiological functions [19]. MAOA catalyzes the oxidative deamination of several monoamine neurotransmitters-including serotonin, norepinephrine and dopamine into aldehydes-with the synthesis of ammonia and hydrogen peroxide as by-products [20]. The abnormally elevated levels of MAOA activity result in increased production of harmful by-products: hydrogen peroxide (H 2 O 2 ) and aldehydes [21]. ...
Monoamine oxidase A (MAOA) is a membrane-bound mitochondrial enzyme present in almost all vertebrate tissues that catalyzes the degradation of biogenic and dietary-derived monoamines. MAOA is known for regulating neurotransmitter metabolism and has been implicated in antitumor immune responses. In this review, we retrospect that MAOA inhibits the activities of various types of tumor-associated immune cells (such as CD8⁺ T cells and tumor-associated macrophages) by regulating their intracellular monoamines and metabolites. Developing novel MAOA inhibitor drugs and exploring multidrug combination strategies may enhance the efficacy of immune governance. Thus, MAOA may act as a novel immune checkpoint or immunomodulator by influencing the efficacy and effectiveness of immunotherapy. In conclusion, MAOA is a promising immune target that merits further in-depth exploration in preclinical and clinical settings.
Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder that affects 6-7% of people worldwide (Wilcutt, 2012). MAOA is a gene that encodes monoamine oxidase A, an enzyme responsible for the regulation and metabolism of monoamines thought to be associated with ADHD. This study investigates a leucine to serine swap at amino acid position 32 in FAD-binding domain of the enzyme monoamine oxidase A. Results from in silico prediction tools and molecular dynamics modeling provide evidence to support pathogenicity of the L32S missense variant of monoamine oxidase A.
Genetic research in the field of sports sciences offers new perspectives on various crucial aspects, including the determination of individual performance, predisposition to sports injuries, and the personalization of nutrition strategies. Sports Paradigms VIII (Genetic Research in Sports) comprehensively examines the impact of genetics on sports performance, presenting scientific findings aimed at maximizing athletes' physical and mental capacities. This book provides an in-depth exploration of key topics such as the importance of genetics in sports performance, genetic predisposition to sports injuries, muscle fiber types and genetics, genetics and nutrition, psychological resilience and genetics, as well as the effects of genetics on doping in sports. The chapters, prepared by expert researchers in the field, serve as a valuable resource for both the academic community and sports professionals. We hope that this book, which presents the latest scientific advancements in sports genetics, will contribute to research aimed at enhancing athlete health and performance.
This chapter examines the relationship between disruptive, impulse-control, and conduct disorders and substance use during adolescence, focusing on diagnostic criteria, prevalence, neurobiological, and neuropsychological aspects as outlined in the DSM-5-TR. The etiology of these conditions is multifactorial, involving genetic predispositions, neurobiological characteristics, and social factors such as histories of neglect and physical or emotional adversity during development. Research indicates that these challenges significantly increase the risk of substance use, with behaviors such as conduct-related difficulties often preceding the onset of substance use and subsequent substance-related issues. On a neurobiological level, difficulties in processing punishment and rewards and impaired cognitive control are frequently observed. Individuals may exhibit reduced sensitivity to punishment, lower reactivity to rewards, and challenges in executive functioning. Neuropsychological studies have shown that adolescents with oppositional defiant behavior often display considerable difficulties in executive functioning and are frequently diagnosed with additional mental health conditions, including anxiety and depression, which complicate family and social dynamics. Substance use in these adolescents is often shaped by environmental and sociocultural factors that hinder the development of self-regulation and personal boundaries. These young people are particularly vulnerable to peer influence and may turn to substances as a coping strategy for managing emotions such as anger and frustration. The chapter concludes by stressing the importance of integrated psychosocial interventions that address both behavioral challenges and substance use, aiming to improve outcomes for adolescents facing these issues.
Numerous studies support the role of dopamine in modulating aggression1,2, but the exact neural mechanisms remain elusive. Here we show that dopaminergic cells in the ventral tegmental area (VTA) can bidirectionally modulate aggression in male mice in an experience-dependent manner. Although VTA dopaminergic cells strongly influence aggression in novice aggressors, they become ineffective in expert aggressors. Furthermore, eliminating dopamine synthesis in the VTA prevents the emergence of aggression in naive mice but leaves aggression intact in expert aggressors. VTA dopamine modulates aggression through the dorsal lateral septum (dLS), a region known for aggression control. Dopamine enables the flow of information from the hippocampus to the dLS by weakening local inhibition in novice aggressors. In expert aggressors, dLS local inhibition naturally weakens, and the ability of dopamine to modulate dLS cells diminishes. Overall, these results reveal a sophisticated role of dopamine in the rise of aggression in adult male mice.
Territorial aggression is widespread across the animal kingdom and is expressed in diverse ecological and social contexts. In addition, there are marked variations in the degree of male reproductive territoriality within and between species. These differences are often attributed to genetic components. However, the evolutionary genetic mechanisms in wild animals are poorly understood. This study explored the genetic basis of divergent male territorial aggressiveness between two Japanese freshwater populations, Gifu (GF) and Tomakomai (TM), in the threespine stickleback, which is a well‐known model system for both behavioral ecology and evolutionary genetics. First, our field survey indicated that the distribution of reproductive territories differed greatly across breeding habitats between the focal populations, and the density of reproductive territories was much greater in the GF population. Second, a one‐on‐one arena aquarium experiment on male–male combat using wild‐caught and common‐garden‐reared males revealed that GF males were genetically more aggressive than TM males. Finally, we performed quantitative trait loci (QTL) analysis using an F2 hybrid cross between the two populations to identify the causal genomic regions contributing to the divergence in male territorial aggressiveness. Our QTL analysis identified a single significant locus in an aggression‐related behavioral component, that is, the number of bites of focal F2 males toward a GF stimulus intruder. Two notable behavior‐related genes, HTR2A and MAO‐A, are found near this locus. These genes have often been suggested to influence of aggressive behavior in animals; therefore, they are regarded as important candidate genes for further functional analyses. Thus, we are the first to provide a QTL‐based genetic basis for population divergence in male territorial aggressiveness in the threespine stickleback.
Recent shifts in societal attitudes toward cannabis have led to a dramatic increase in consumption rates in many Western countries, particularly among young people. This trend has shed light on a significant link between cannabis use disorder (CUD) and pathological reactive aggression, a condition involving disproportionate aggressive and violent reactions to minor provocations. The discourse on the connection between cannabis use and aggression is frequently enmeshed in political and legal discussions, leading to a polarized understanding of the causative relationship between cannabis use and aggression. However, integrative analyses from both human and animal research indicate a complex, bidirectional interplay between cannabis misuse and pathological aggression. On the one hand, emerging research reveals a shared genetic and environmental predisposition for both cannabis use and aggression, suggesting a common underlying biological mechanism. On the other hand, there is evidence that cannabis consumption can lead to violent behaviors while also being used as a self-medication strategy to mitigate the negative emotions associated with pathological reactive aggression. This suggests that the coexistence of pathological aggression and CUD may result from overlapping vulnerabilities, potentially creating a self-perpetuating cycle where each condition exacerbates the other, escalating into externalizing and violent behaviors. This article aims to synthesize existing research on the intricate connections between these issues and propose a theoretical model to explain the neurobiological mechanisms underpinning this complex relationship.
The MAOA gene is widely known regulator of aggressive behavior among human and animals. Here, we analyzed the genetic variability of the MAOA gene and its promoter region in non-canonical behavioral model – American mink (Neogale vison). We didn’t observe any significant genetic variations among animals with aggressive behavior, that suggests the presence of genetic and/or epigenetic variations in other systems involved in regulation of aggression in this model.
Monoamine oxidase A (MAOA) catalyzes the degradation of norepinephrine, dopamine, and serotonin, i.e. neurotransmitters involved in the pathogenesis of pathological addictions, including internet addiction (IA). Gene MAOA has been actively studied in terms of genetic predisposition to the development of aggressive behavior potentially involved in the formation of IA. The study included 602 adolescents (9–18 years old, mean age = 14.6, SD 1.7) from the Angara-Yenisei macroregion (Russians n = 329, Tuvans n = 158, Khakasses n = 158). The type of IA was assessed according to the Chen scale (Chen Internet Addiction Scale, CIAS), gene polymorphism was detected using real-time PCR. The distribution of the TT genotype of MAOA rs1137070 polymorphism associated with low activity of the monoamine oxidase A enzyme and aggressive behavior affected by IA, was found to be significantly higher in Tuvan adolescents compared with Russians (31.1/21.2% p = = 0.02). Pathological internet addiction (more than 65 points by Chen scale) often observed among Khakass adolescents compared to Russian (26.4/15.5%, p = 0.03). Thus, the allelic variant T of MAOA rs1137070 polymorphism appears to be potential marker for dependent and aggressive behavior to form, Asian representatives being more susceptible to the development of pathological addictions than Caucasian populations.
Aggressive behavior is instinctively driven behavior that helps animals to survive and reproduce and is closely related to multiple behavioral and physiological processes. The dorsal raphe nucleus (DRN) is an evolutionarily conserved midbrain structure that regulates aggressive behavior by integrating diverse brain inputs. The DRN consists predominantly of serotonergic (5‐HT:5‐hydroxytryptamine) neurons and decreased 5‐HT activity was classically thought to increase aggression. However, recent studies challenge this 5‐HT deficiency model, revealing a more complex role for the DRN 5‐HT system in aggression. Furthermore, emerging evidence has shown that non‐5‐HT populations in the DRN and specific neural circuits contribute to the escalation of aggressive behavior. This review argues that the DRN serves as a multifaceted modulator of aggression, acting not only via 5‐HT but also via other neurotransmitters and neural pathways, as well as different subsets of 5‐HT neurons. In addition, we discuss the contribution of DRN neurons in the behavioral and physiological aspects implicated in aggressive behavior, such as arousal, reward, and impulsivity, to further our understanding of DRN‐mediated aggression modulation.
Early starting, lifetime criminal persistence has been called sociopathy, antisocial personality disorder, and psychopathy. There is, however, disagreement about its core features and which measure is best for identifying such individuals. In the 1st of 2 studies of male offenders (n = 74), we found a large association between scores on the Psychopathy Checklist—Revised (PCL–R; R. D. Hare, 1991) and the Diagnostic and Statistical Manual of Mental Disorders (4th ed. [DSM–IV]; American Psychiatric Association, 1994) antisocial personality disorder criteria scored as a scale. The second study (n = 684) replicated this finding and found that, as previously shown for PCL–R scores, a discrete class (or taxon) also underlies scores on items reflecting antisocial personality disorder. The high association among these sets of items and their similarity in predicting violence suggested that the same natural class underlies each. Results indicated that life-course-persistent antisociality can be assessed well by measures of psychopathy and antisocial personality disorder.
The Psychopathy Checklist (PCL) is a reliable and valid instrument for the assessment of psychopathy in criminal populations. Although it was designed to measure a unitary construct, the instrument has been shown to comprise several factors. To determine whether the PCL contains a factor structure that is stable and replicable, we factor-analyzed data from six samples of male prison inmates (N = 1,119) in Canada, the United States, and England. Split-half cross-validation and analysis of congruence coefficients indicated that a two-factor solution could be replicated in all six samples. Factor 1 was defined by core personality traits, including superficiality; habitual lying and manipulation; callousness; and lack of affect, guilt, remorse, and empathy. Factor 2 was defined by a chronically unstable and antisocial lifestyle.
Background:
Studies with behavioural and neuropsychological tests have supported the developmental taxonomy theory of antisocial behaviour, which specifies abnormal brain development as a fundamental aspect of life-course-persistent antisocial behaviour, but no study has characterised features of brain structure associated with life-course-persistent versus adolescence-limited trajectories, as defined by prospective data. We aimed to determine whether life-course-persistent antisocial behaviour is associated with neurocognitive abnormalities by testing the hypothesis that it is also associated with brain structure abnormalities.
Methods:
We used structural MRI data collected at 45 years of age from participants in the Dunedin Study, a population-representative longitudinal birth cohort of 1037 individuals born between April 1, 1972, and March 31, 1973, in Dunedin, New Zealand, who were resident in the province and who participated in the first assessment at 3 years of age. Participants underwent MRI, and mean global cortical surface area and cortical thickness were extracted for each participant. Participants had been previously subtyped as exhibiting life-course-persistent, adolescence-limited, or no history of persistent antisocial behaviour (ie, a low trajectory group) based on informant-reported and self-reported conduct problems from the ages of 7 years to 26 years. Study personnel who processed the MRI images were masked to antisocial group membership. We used linear estimated ordinary least squares regressions to compare each antisocial trajectory group (life-course persistent and adolescence limited) with the low trajectory group to examine whether antisocial behaviour was related to abnormalities in mean global surface area and mean cortical thickness. Next, we used parcel-wise linear regressions to identify antisocial trajectory group differences in surface area and cortical thickness. All results were controlled for sex and false discovery rate corrected.
Findings:
Data from 672 participants were analysed, and 80 (12%) were classified as having life-course-persistent antisocial behaviour, 151 (23%) as having adolescence-limited antisocial behaviour, and 441 (66%) as having low antisocial behaviour. Individuals on the life-course-persistent trajectory had a smaller mean surface area (standardised β=-0·18 [95% CI -0·24 to -0·11]; p<0·0001) and lower mean cortical thickness (standardised β=-0·10 [95% CI -0·19 to -0·02]; p=0·020) than did those in the low group. Compared with the low group, the life-course-persistent group had reduced surface area in 282 of 360 anatomically defined parcels and thinner cortex in 11 of 360 parcels encompassing circumscribed frontal and temporal regions associated with executive function, affect regulation, and motivation. Widespread differences in brain surface morphometry were not observed for the adolescence-limited group compared with either non-antisocial behaviour or life-course-persistent groups.
Interpretation:
These analyses provide initial evidence that differences in brain surface morphometry are associated with life-course-persistent, but not adolescence-limited, antisocial behaviour. As such, the analyses are consistent with the developmental taxonomy theory of antisocial behaviour and highlight the importance of using prospective longitudinal data to define different patterns of antisocial behaviour development.
Funding:
US National Institute on Aging, Health Research Council of New Zealand, New Zealand Ministry of Business, Innovation and Employment, UK Medical Research Council, Avielle Foundation, and Wellcome Trust.
Polysubstance use (PSU) is highly prevalent among college students. Recent evidence indicates that PSU is based on gene x environment (G×E) interactions, yet the specific biosocial factors underlying this problem remain elusive. We recently reported that lifetime use of tobacco and cannabis in college students is influenced by the interaction of the X-linked MAOA (monoamine oxidase A) gene and child maltreatment. Building on these premises, here we evaluated whether the same G×E interaction may also predict PSU in this population. Students of a large Midwestern university (n = 470; 50.9% females) took part in a computer survey for substance use, as well as childhood trauma exposure, using the Child Trauma Questionnaire (CTQ). DNA was extracted from their saliva samples and genotyped for MAOA variable-number of tandem repeat (VNTR) variants. Findings indicated that the highest number of substances were used by male students harboring low-activity MAOA alleles with a history of childhood emotional abuse. In contrast, female homozygous high-activity MAOA carriers with a history of emotional and physical abuse reported consumption of the greatest number of substances. Our results indicate that PSU among college students is influenced by the interaction of MAOA and child maltreatment in a sex-specific fashion. Further studies are warranted to understand the mechanisms of sex differences in the biosocial interplays underlying PSU in this at-risk group.
High impulsive and aggressive traits associate with poor behavioural self-control. Despite their importance in predicting behavioural negative outcomes including suicide, the molecular mechanisms underlying the expression of impulsive and aggressive traits remain poorly understood. Here, we identified and characterized a novel long noncoding RNA (lncRNA), acting as a regulator of the monoamine oxidase A (MAOA) gene in the brain, and named it MAOA-associated lncRNA (MAALIN). Our results show that in the brain of suicide completers, MAALIN is regulated by a combination of epigenetic mechanisms including DNA methylation and chromatin modifications. Elevated MAALIN in the dentate gyrus of impulsive-aggressive suicides was associated with lower MAOA expression. Viral overexpression of MAALIN in neuroprogenitor cells decreased MAOA expression while CRISPR-mediated knock out resulted in elevated MAOA expression. Using viral-mediated gene transfer, we confirmed that MAALIN in the hippocampus significantly decreases MAOA expression and exacerbates the expression of impulsive-aggressive behavioural traits in CD1 aggressive mice. Overall, our findings suggest that variations in DNA methylation mediate the differential expression of a novel lncRNA that acts on MAOA expression to regulate impulsive-aggressive behaviours.
There is evidence that corticotropin-releasing hormone receptor 1 (CRHR1) gene polymorphisms and indifferent impulsive personality traits play an important role in violent aggression in male adolescents. Genotyping for two tag single-nucleotide polymorphisms (SNP) (rs242924, rs17689966) was conducted using TaqMan SNP for 138 violent young male criminals, 98 nonviolent young male criminals, and 153 noncriminal adults. The general situation and personality traits (SSP) questionnaire was given to the young violent and nonviolent male criminal groups. The results showed that the frequency of the G allele in rs242924 of the CRHR1 gene in the violent aggression group was higher than that in the normal adult controls (P < 0.025, OR = 2.29, 95% CI = 1.13–4.62). The difference in genotype distribution was significant among the three groups (P < 0.05), and when the violent group was compared with the two control groups, no significant difference was found (P > 0.025). The impulsiveness, trait irritability, verbal trait aggression, and physical trait aggression scores in the violent group were significantly higher than those in the nonviolent group of adolescents. These findings suggest that the variance in CRHR1 gene polymorphisms and personality traits may play a role in violent aggression in male adolescents, and that the interaction of the CRHR1 gene and the impulsive personality trait may cause an increased susceptibility to violence towards others.
Previous studies have linked the low expression variant of a variable number of tandem repeat polymorphism in the monoamine oxidase A gene (MAOA‐L) to the risk for impulsivity and aggression, brain developmental abnormalities, altered cortico‐limbic circuit function, and an exaggerated neural serotonergic tone. However, the neurobiological effects of this variant on human brain network architecture are incompletely understood. We studied healthy individuals and used multimodal neuroimaging (sample size range: 219–284 across modalities) and network‐based statistics (NBS) to probe the specificity of MAOA‐L‐related connectomic alterations to cortical‐limbic circuits and the emotion processing domain. We assessed the spatial distribution of affected links across several neuroimaging tasks and data modalities to identify potential alterations in network architecture. Our results revealed a distributed network of node links with a significantly increased connectivity in MAOA‐L carriers compared to the carriers of the high expression (H) variant. The hyperconnectivity phenotype primarily consisted of between‐lobe (“anisocoupled”) network links and showed a pronounced involvement of frontal‐temporal connections. Hyperconnectivity was observed across functional magnetic resonance imaging (fMRI) of implicit emotion processing (pFWE = .037), resting‐state fMRI (pFWE = .022), and diffusion tensor imaging (pFWE = .044) data, while no effects were seen in fMRI data of another cognitive domain, that is, spatial working memory (pFWE = .540). These observations are in line with prior research on the MAOA‐L variant and complement these existing data by novel insights into the specificity and spatial distribution of the neurogenetic effects. Our work highlights the value of multimodal network connectomic approaches for imaging genetics.
Although considerable efforts have been made to understand the neural underpinnings of (state) reactive aggression, which is triggered by provocation or perceived threat, little is known about the neural correlates of proactive aggression, which is driven by instrumental motivations to obtain personal gains through aggressive means and which varies dramatically across individuals in terms of tendency of appealing to such means. Here, by combining structural (grey matter density, GMD) and functional (resting-state functional connection, RSFC) fMRI, we investigated brain structures and functional networks related to trait proactive aggression. We found that individual differences in trait proactive aggression were positively associated with GMD in bilateral dorsolateral prefrontal cortex (DLPFC) and negatively correlated with GMD in posterior cingulate cortex (PCC); they were also negatively correlated with the strength of functional connectivity between left PCC and other brain regions, including right DLPFC, right IPL, right MPFC/ACC, and bilateral precuneus. These findings shed light on the differential brain bases of proactive and reactive aggressions and suggested the neural underpinnings of proactive aggression.
Purpose of Review
This paper aims to provide a comprehensive discussion of single-photon emission computed tomography (SPECT) and positron emission tomography (PET) studies of antisocial personality disorder (ASPD) and aggression.
Recent Findings
Among ASPD males with high impulsivity, the density of brainstem serotonin (5-HT) transporters shows a relationship with impulsivity, aggression, and ratings of childhood trauma. 5-HT1B receptor (R) binding in the striatum, anterior cingulate cortex, and orbitofrontal cortex (OFC) correlated with anger, aggression, and psychopathic traits in another study of violent offenders, most of whom were diagnosed with ASPD. Finally, the density of monoamine oxidase-A (MAO-A), a mitochondrial enzyme that degrades 5-HT, norepinephrine, and dopamine (DA), was reported as lower in the OFC and ventral striatum of ASPD. Among non-clinical populations, 5-HT4R binding, as an index of low cerebral 5-HT levels, has been associated with high trait aggression, but only in males. Furthermore, evidence suggests that individuals with high-activity MAO-A genetic variants compared with low-activity MAO-A allelic variants release more DA in the ventral caudate and putamen when exposed to violent imagery.
Summary
There are very few PET or SPECT studies that exclusively sample individuals with ASPD. However, among ASPD samples, there is evidence of regional serotonergic abnormalities in the brain and alteration of neural MAO-A levels. Future studies should consider employing additional molecular probes that could target alternative neurotransmitter systems to investigate ASPD. Furthermore, examining different typologies of aggression in clinical and non-clinical populations using SPECT/PET is another important area to pursue and could shed light on the neurochemical origins of these traits in ASPD.
Among the genetic variations in the monoamine oxidase A (MAOA) gene, upstream variable number tandem repeats (uVNTRs) of the promoter have been associated with individual differences in human physiology and aggressive behaviour. However, the evidence for a molecular or neural link between MAOA uVNTRs and aggression remains ambiguous. Additionally, the use of inconsistent promoter constructs in previous studies has added to the confusion. Therefore, it is necessary to demonstrate the genetic function of MAOA uVNTR and its effects on multiple aspects of aggression. Here, we identified three MAOA alleles in Koreans: the predominant 3.5R and 4.5R alleles, as well as the rare 2.5R allele. There was a minor difference in transcriptional efficiency between the 3.5R and 4.5R alleles, with the greatest value for the 2.5R allele, in contrast to existing research. Psychological indices of aggression did not differ among MAOA genotypes. However, our electroencephalogram and electrocardiogram results obtained under aggression-related stimulation revealed oscillatory changes as novel phenotypes that vary with the MAOA genotype. In particular, we observed prominent changes in frontal γ power and heart rate in 4.5R carriers of men. Our findings provide genetic insights into MAOA function and offer a neurobiological basis for various socio-emotional mechanisms in healthy individuals.
We investigated gene–environment (G × E) interactions related to childhood antisocial behavior between polymorphisms implicated by recent genome-wide association studies (GWASs) and two key environmental adversities (maltreatment and smoking during pregnancy) in a large population cohort (ALSPAC). We also studied the MAOA candidate gene and addressed comorbid attention-deficit/hyperactivity disorder (ADHD). ALSPAC is a large, prospective, ethnically homogeneous British cohort. Our outcome consisted of mother-rated conduct disorder symptom scores at age 7;9 years. G × E interactions were tested in a sex-stratified way (α = 0.0031) for four GWAS-implicated variants (for males, rs4714329 and rs9471290; for females, rs2764450 and rs11215217), and a length polymorphism near the MAOA-promoter region. We found that males with rs4714329-GG (P = 0.0015) and rs9471290-AA (P = 0.0001) genotypes were significantly more susceptible to effects of smoking during pregnancy in relation to childhood antisocial behavior. Females with the rs11215217-TC genotype (P = 0.0018) were significantly less susceptible to effects of maltreatment, whereas females with the MAOA-HL genotype (P = 0.0002) were more susceptible to maltreatment effects related to antisocial behavior. After adjustment for comorbid ADHD symptomatology, aforementioned G × E’s remained significant, except for rs11215217 × maltreatment, which retained only nominal significance. Genetic variants implicated by recent GWASs of antisocial behavior moderated associations of smoking during pregnancy and maltreatment with childhood antisocial behavior in the general population. While we also found a G × E interaction between the candidate gene MAOA and maltreatment, we were mostly unable to replicate the previous results regarding MAOA–G × E’s. Future studies should, in addition to genome-wide implicated variants, consider polygenic and/or multimarker analyses and take into account potential sex stratification.
Epigenetic mechanisms have been proposed to mediate fear extinction in animal models. Here, MAOA methylation was analyzed via direct sequencing of sodium bisulfite-treated DNA extracted from blood cells before and after a 2-week exposure therapy in a sample of n = 28 female patients with acrophobia as well as in n = 28 matched healthy female controls. Clinical response was measured using the Acrophobia Questionnaire and the Attitude Towards Heights Questionnaire. The functional relevance of altered MAOA methylation was investigated by luciferase-based reporter gene assays. MAOA methylation was found to be significantly decreased in patients with acrophobia compared with healthy controls. Furthermore, MAOA methylation levels were shown to significantly increase after treatment and correlate with treatment response as reflected by decreasing Acrophobia Questionnaire/Attitude Towards Heights Questionnaire scores. Functional analyses revealed decreased reporter gene activity in presence of methylated compared with unmethylated pCpGfree_MAOA reporter gene vector constructs. The present proof-of-concept psychotherapy-epigenetic study for the first time suggests functional MAOA methylation changes as a potential epigenetic correlate of treatment response in acrophobia and fosters further investigation into the notion of epigenetic mechanisms underlying fear extinction.
Background:
Oppositional defiant disorder (ODD) is a behavioral disorder that mainly refers to a recurrent pattern of disobedient, defiant, negativistic and hostile behaviors toward authority figures. Previous studies have showed associations of serotonin transporter (5-HTT) and monoamine oxidase A (MAOA) with behavioral and psychiatric disorders. The purposes of this study were to investigate the potential association of 5-HTT gene promoter polymorphism (5-HTTLPR) and MAOA gene polymorphism with susceptibility to ODD in a Han Chinese school population.
Methods:
The 5-HTTLPR gene polymorphism and the MAOA gene polymorphism were genotyped in a case-control study of 257 Han Chinese children (123 ODD and 134 healthy controls).
Results:
There was significant difference in the allele distribution of 5-HTTLPR (χ2 = 7.849, P = 0.005) between the ODD and control groups. Further, there were significant differences in genotype (χ2 = 5.168, P = 0.023) and allele distributions (χ2 = 10.336, P = 0.001) of the MAOA gene polymorphism that is variable-number tandem repeat (MAOA-uVNTR) between two groups. Moreover, there were significant differences in genotype (χ2 = 4.624, P = 0.032) and allele distributions (χ2 = 9.248, P = 0.002) of MAOA-uVNTR only in the male ODD and healthy groups.
Conclusions:
Our results suggest that 5-HTTLPR and MAOA-uVNTR gene variants may contribute to susceptibility to ODD. Further, MAOA-uVNTR gene polymorphism may play a role in susceptibility to ODD only in male children.
Early-life adversity is associated with increased risk for substance abuse in later life, with women more likely to report past and current stress as a mediating factor in their substance use and relapse as compared to men. Preclinical models of neonatal and peri-adolescent (early through late adolescence) stress all support a direct relationship between experiences of early-life adversity and adult substance-related behaviors, and provide valuable information regarding the underlying neurobiology. This review will provide an overview of these animal models and how these paradigms alter drug and alcohol consumption and/or seeking in male and female adults. An introduction to the corticotropin-releasing factor (CRF) and serotonin systems, their development and their interactions at the level of the dorsal raphe will be provided, illustrating how this particular stress system is sexually dimorphic, and is well positioned to be affected by stressors early in development and throughout maturation. A model for CRF-serotonin interactions in the dorsal raphe and how these influence dopaminergic activity within the nucleus accumbens and subsequent reward-associated behaviors will be provided, and alterations to the activity of this system following early-life adversity will be identified. Overall, converging findings suggest that early-life adversity has long-term effects on the functioning of the CRF-serotonin system, highlighting a potentially important and targetable mediator linking stress to addiction. Future work should focus on identifying the exact mechanisms that promote long-term changes to the expression and activity of CRF receptors in the dorsal raphe. Moreover, it is important to clarify whether similar neurobiological mechanisms exist for males and females, given the sexual dimorphism both in CRF receptors and serotonin indices in the dorsal raphe and in the behavioral outcomes of early-life adversity.
The provision of environmental enrichment to numerous species of laboratory animals is generally considered routine husbandry. However, mouse enrichment has proven to be very complex due to the often contradictory outcomes (animal health and welfare, variability in scientific data, etc.) associated with strain, age of the animal when enrichment is provided, gender of the animal, scientific use of the animal, and other housing attributes. While this has led to some suggesting that mice should not be provided enrichment, more recently opinion is trending toward acknowledging that enrichment actually normalizes the animal and data obtained from a mouse living in a barren environment are likely not to be representative or even reliable. This article offers an overview of the types of impact enrichment can have on various strains of mice and demonstrates that enrichment not only has a role in mouse husbandry, but also can lead to new areas of scientific enquiry in a number of different fields.
Background
Postsecondary students in Western countries exhibit a high prevalence of cannabis and tobacco use disorders. The etiology of these problems is contributed by several psychosocial factors, including childhood adversity and trauma; however, the mechanisms whereby these environmental determinants predispose to the use of these substances remain elusive, due to our poor knowledge of genetic and biological moderators. Converging evidence points to the monoamine oxidase A (MAOA) gene as a moderator of the effects of lifetime stress on the initiation of substance use.
Aims
Building on these premises, in this study, we analyzed whether MAOA upstream variable number tandem repeat (uVNTR) alleles interact with child maltreatment history to predict for lifetime cannabis and tobacco consumption.
Materials and methods
Five hundred college students (age: 18–25 years) from a large Midwestern University were surveyed for their child maltreatment history (encompassing emotional, physical, and sexual abuse, as well as emotional and physical neglect) and lifetime consumption of cannabis and tobacco. Saliva samples were obtained to determine the MAOA uVNTR genotype of each participant.
Results
In female students, lifetime tobacco and cannabis use was predicted by the interaction of physical and emotional abuse with high‐activity MAOA allelic variants; conversely, in males, the interaction of low‐activity MAOA alleles and physical abuse was associated with lifetime use of tobacco, but not cannabis.
Discussion
These findings collectively suggest that the vulnerability to smoke tobacco and cannabis is predicted by sex‐dimorphic interactions of MAOA gene with childhood abuse.
Conclusion
These biosocial underpinnings of tobacco and cannabis use may prove important in the development of novel personalized preventive strategies for substance use disorders in adolescents.
In addition to transmitter functions, many neuroamines have trophic or ontogenetic regulatory effects important to both normal and disordered brain development. In previous work (Mejia et al., 2002), we showed that pharmacologically inhibiting monoamine oxidase (MAO) activity during murine gestation increases the prevalence of behaviors thought to reflect impulsivity and aggression. The goal of the present study was to determine the extent to which this treatment influences dopamine and serotonin innervation of murine cortical and subcortical areas, as measured by regional density of dopamine (DAT) and serotonin transporters (SERT). We measured DAT and SERT densities at 3 developmental times (PND 14, 35 and 90) following inhibition of MAO A, or MAO B or both throughout murine gestation and early post-natal development. DAT binding was unaltered within the nigrostriatal pathway, but concurrent inhibition of MAO-A and MAO-B significantly and specifically reduced SERT binding by 10–25% in both the frontal cortex and raphe nuclei. Low levels of SERT binding persisted (PND 35, 90) after the termination (PND 21) of exposure to MAO inhibitors and was most marked in brain structures germane to the previously described behavioral changes. The relatively modest level of enzyme inhibition (25–40%) required to produce these effects mandates care in the use of any compound which might inhibit MAO activity during gestation.
Since the pioneering finding of Caspi and co-workers in 2002 that exposure to childhood maltreatment predicted later antisocial behaviour (ASB) in male carriers of the low-activity MAOA-uVNTR allele, frequent replication studies have been published. Two meta-analyses, one in 2006 and the other in 2014, confirmed the original findings by Caspi and co-workers. In the present paper, we review the literature, note some methodological aspects of candidate gene–environment interaction (cG×E) studies and suggest some future directions. Our conclusions are as follows. (1) The direction of the effect in a cG×E model may differ according to the positive and negative environmental background of the population. (2) There is a predictor-intersection problem such that when measuring one type of maltreatment in a person, other kinds of maltreatment often co-occur. Other forms of abuse are implicitly considered in statistical models; therefore, it is difficult to draw conclusions about the effects of timing and the severity of different forms of stressful life events in relation to ASB. (3) There is also an outcome-intersection problem because of the major intersection of ASB and other forms of mental health problems. It is likely that the G×E with MAOA is related to a common unmeasured factor. (4) For the G×E model, in which the effect of the gene on the outcome variable is dependent on other predictor variables, theoretically, hypothesis-driven statistical modelling is needed.
Human genome-wide association studies (GWAS), transcriptome analyses of animal models, and candidate gene studies have advanced our understanding of the genetic architecture of aggressive behaviors. However, each of these methods presents unique limitations. To generate a more confident and comprehensive view of the complex genetics underlying aggression, we undertook an integrated, cross-species approach. We focused on human and rodent models to derive eight gene lists from three main categories of genetic evidence: two sets of genes identified in GWAS studies, four sets implicated by transcriptome-wide studies of rodent models, and two sets of genes with causal evidence from online Mendelian inheritance in man (OMIM) and knockout (KO) mice reports. These gene sets were evaluated for overlap and pathway enrichment to extract their similarities and differences. We identified enriched common pathways such as the G-protein coupled receptor (GPCR) signaling pathway, axon guidance, reelin signaling in neurons, and ERK/MAPK signaling. Also, individual genes were ranked based on their cumulative weights to quantify their importance as risk factors for aggressive behavior, which resulted in 40 top-ranked and highly interconnected genes. The results of our cross-species and integrated approach provide insights into the genetic etiology of aggression.
Background:
The influence of genetic variation on resting-state neural networks represents a burgeoning line of inquiry in psychiatric research. Monoamine oxidase A, an X-linked gene, is one example of a molecular target linked to brain activity in psychiatric illness. Monoamine oxidase A genetic variants, including the high and low variable nucleotide tandem repeat polymorphisms, have been shown to differentially affect brain functional connectivity in healthy humans. However, it is currently unknown whether these same polymorphisms influence resting-state brain activity in clinical conditions. Given its high burden on society and strong connection to violent behavior, antisocial personality disorder is a logical condition to study, since in vivo markers of monoamine oxidase A brain enzyme are reduced in key affect-modulating regions, and striatal levels of monoamine oxidase A show a relation with the functional connectivity of this same region.
Methods:
We utilized monoamine oxidase A genotyping and seed-to-voxel-based functional connectivity to investigate the relationship between genotype and corticostriatal connectivity in 21 male participants with severe antisocial personality disorder and 19 male healthy controls.
Results:
Dorsal striatal connectivity to the frontal pole and anterior cingulate gyrus differentiated antisocial personality disorder subjects and healthy controls by monoamine oxidase A genotype. Furthermore, the linear relationship of proactive aggression to superior ventral striatal-angular gyrus functional connectivity differed by monoamine oxidase A genotype in the antisocial personality disorder groups.
Conclusions:
These results suggest that monoamine oxidase A genotype may affect corticostriatal connectivity in antisocial personality disorder and that these functional connections may also underlie use of proactive aggression in a genotype-specific manner.
The two monoamine oxidase (MAO) enzymes, A and B, catalyze the metabolism of monoamine neurotransmitters, such as serotonin, norepinephrine, and dopamine. The phenotypic outcomes of MAO congenital deficiency have been studied in humans and animal models, to explore the role of these enzymes in behavioral regulation. The clinical condition caused by MAOA deficiency, Brunner syndrome, was first described as a disorder characterized by overt antisocial and aggressive conduct. Building on this discovery, subsequent studies were focused on the characterization of the role of MAOA in the neurobiology of antisocial conduct. MAO A knockout mice were found to display high levels of intermale aggression; however, further analyses of these mutants unveiled additional behavioral abnormalities mimicking the core symptoms of autism-spectrum disorder. These findings were strikingly confirmed in newly reported cases of Brunner syndrome. The role of MAOB in behavioral regulation remains less well-understood, even though Maob-deficient mice have been found to exhibit greater behavioral disinhibition and risk-taking responses, supporting previous clinical studies showing associations between low MAO B activity and impulsivity. Furthermore, lack of MAOB was found to exacerbate the severity of psychopathological deficits induced by concurrent MAOA deficiency. Here, we summarize how the convergence of clinical reports and behavioral phenotyping in mutant mice has helped frame a complex picture of psychopathological features in MAO-deficient individuals, which encompass a broad spectrum of neurodevelopmental problems. This emerging knowledge poses novel conceptual challenges towards the identification of the endophenotypes shared by autism-spectrum disorder, antisocial behavior and impulse-control problems, as well as their monoaminergic underpinnings.
With the advent of new and more readily usable gene sequencing techniques, researchers have been able to examine the interactions between genes and the environment (G X E) within a multitude of scientific perspectives. One area that G X E interactions have been implicated in is the development of antisocial behavior (ASB). Antisocial behavior consists of a wide range of maladaptive behaviors and has been at the forefront of public health and mental health concerns for decades. One genetic polymorphism that has been associated with ASB is MAOA-uVNTR. Meta-analytic studies have found the low-activity MAOA-uVNTR polymorphism to be associated with ASB from early childhood through adulthood. Recently, studies have begun to examine the independent and interactive G X E relationship between MAOA-uVNTR and deviant peer affiliation on ASB. Inconsistent with the broader literature, these findings suggest an interaction between high-activity MAOA-uVNTR and deviant peer affiliation on ASB in a mixed sex sample. The current study re-examines the relationship between MAOA-uVNTR, peer delinquency, and ASB with a consideration of sex differences in 291 college participants. Findings indicate an interaction between the low-activity allele of the MAOA-uVNTR and peer delinquency in predicting ASB. Results are also specific to differences between the sexes. Implications and future research are discussed.
Appetitive aggression is a sub-category of instrumental aggression, characterised by the primary intrinsic enjoyment of aggressive activity. Aggression is heritable, and serotonergic and monoaminergic neurotransmitter systems have been found to contribute to the underlying molecular mechanisms. The aim of this study was to investigate the role that genetic variants in the serotonin transporter (SLC6A4) and monoamine oxidase A (MAOA) genes play in the aetiology of appetitive aggression in South African Xhosa males (n = 290). SLC6A4 5-HTTLPR, rs25531, and STin2 variants, as well as MAOA-uVNTR were investigated for their association with levels of appetitive aggression using Poisson regression analysis. The STin2 VNTR12 allele was found to be associated with increased levels of appetitive aggression (p = 0.003), but with decreased levels of reactive aggression (p = 7 × 10-5). This study is the first to investigate genetic underpinnings of appetitive aggression in a South African population, with preliminary evidence suggesting that SCL6A4 STin2 variants play a role in its aetiology, and may also be important in differentiating between appetitive and reactive aggression. Although the results require replication, they shed some preliminary light on the molecular dichotomy that may underlie the two forms of aggression.
Monoamine oxidase A and B (MAO A and B) play important roles in the metabolism of biogenic and dietary amines and are encoded by two genes derived from a common ancestral gene. The promoter regions for human MAO A and B genes have been characterized using a series of 5' flanking sequences linked to a human growth hormone reporter gene. When these constructs were transfected into NIH3T3, SHSY-5Y, and COS7 cells, the maximal promoter activity for MAO A was found in a 0.14 kilobase (kb) PvuII/DraII fragment (A0.14) and in a 0.15 kb PstI/NaeI fragment (B0.15) for MAO B. Both fragments are GC-rich, contain potential Sp1 binding sites, and are in the region where the MAO A and B 5' flanking sequences share the highest identity (approximately 60%). However, the organization of the transcription elements is distinctly different between these two promoters. Fragment A0.14 consists of three Sp1 elements, all in reversed orientations, and lacks a TATA box. Two of the Sp1 sites are located within the downstream 90 base pair (bp) direct repeat, and the third is located at the 3' end of the upstream 90 bp direct repeat. Fragment B0.15 contains an Sp1-CACCC-Sp1-TATA structure; deletion of any of these elements reduced promoter activity. Additional Sp1 sites, CACCC elements, CCAAT boxes, and direct repeats (four 30 bp direct repeats in MAO A and two 29 bp direct repeats in MAO B) are found in farther-upstream sequences of both genes (1.27 kb for MAO A and mostly in 0.2 kb for MAO B). Inclusion of these sequences decreased promoter activity. The different promoter organization of MAO A and B genes provides the basis for their different tissue- and cell-specific expression.
The monoamine oxidase A (MAOA) uVNTR (upstream variable number tandem repeat) is one of the most often cited examples of a gene by environment interaction (GxE) in relation to behavioral traits. However, MAOA possesses a second VNTR, 500 bp upstream of the uVNTR, which is termed d- or distal VNTR. Furthermore, genomic analysis indicates that there are a minimum of two transcriptional start sites (TSSs) for MAOA, one of which encompasses the uVNTR within the 5′ untranslated region of one of the isoforms. Through expression analysis in semi-haploid HAP1 cell lines genetically engineered in order to knockout (KO) either the uVNTR, dVNTR, or both VNTRs, we assessed the effect of the two MAOA VNTRs, either alone or in combination, on gene expression directed from the different TSSs. Complementing our functional analysis, we determined the haplotype variation of these VNTRs in the general population. The expression of the two MAOA isoforms was differentially modulated by the two VNTRs located in the promoter region. The most extensively studied uVNTR, previously considered a positive regulator of the MAOA gene, did not modulate the expression of what it is considered the canonical isoform, while we found that the dVNTR positively regulated this isoform in our model. In contrast, both the uVNTR and the dVNTR were found to act as negative regulators of the second less abundant MAOA isoform. The haplotype analysis for these two VNTRs demonstrated a bias against the presence of one of the potential variants. The uVNTR and dVNTR differentially affect expression of distinct MAOA isoforms, and thus, their combined profiling offers new insights into gene-regulation, GxE interaction, and ultimately MAOA-driven behavior.
Electronic supplementary material
The online version of this article (10.1007/s12031-018-1044-z) contains supplementary material, which is available to authorized users.
Neocortical regions are organized into columns and layers. Connections between layers run mostly perpendicular to the surface suggesting a columnar functional organization. Some layers have long-range excitatory lateral connections suggesting interactions between columns. Similar patterns of connectivity exist in all regions but their exact role remain a mystery. In this paper, we propose a network model composed of columns and layers that performs robust object learning and recognition. Each column integrates its changing input over time to learn complete predictive models of observed objects. Excitatory lateral connections across columns allow the network to more rapidly infer objects based on the partial knowledge of adjacent columns. Because columns integrate input over time and space, the network learns models of complex objects that extend well beyond the receptive field of individual cells. Our network model introduces a new feature to cortical columns. We propose that a representation of location relative to the object being sensed is calculated within the sub-granular layers of each column. The location signal is provided as an input to the network, where it is combined with sensory data. Our model contains two layers and one or more columns. Simulations show that using Hebbian-like learning rules small single-column networks can learn to recognize hundreds of objects, with each object containing tens of features. Multi-column networks recognize objects with significantly fewer movements of the sensory receptors. Given the ubiquity of columnar and laminar connectivity patterns throughout the neocortex, we propose that columns and regions have more powerful recognition and modeling capabilities than previously assumed.
Low expressing alleles of the MAOA gene (MAOA-L) have been associated with an increased risk for developing an aggressive personality. This suggests an MAOA-L-specific neurobiological vulnerability associated with trait aggression. The neural networks underlying this vulnerability are unknown. The present study investigated genotype-specific associations between resting state brain networks and trait aggression (Buss-Perry Aggression Questionnaire) in 82 healthy Caucasian males. Genotype influences on aggression-related networks were studied for intrinsic and seed-based brain connectivity. Intrinsic connectivity was higher in the ventromedial prefrontal cortex (VMPFC) of MAOA-L compared to high expressing allele (MAOA-H) carriers. Seed-based connectivity analyses revealed genotype differences in the functional involvement of this region. MAOA genotype modulated the relationship between trait aggression and VMPFC connectivity with supramarginal gyrus (SMG) and areas of the default mode network (DMN). Separate analyses for the two groups were performed to better understand how the genotype modulated the relationship between aggression and brain networks. They revealed a positive correlation between VMPFC connectivity and aggression in right angular gyrus (AG) and a negative correlation in right SMG in the MAOA-L group. No such effect emerged in the MAOA-H carriers. The results indicate a particular relevance of VMPFC for aggression in MAOA-L carriers; in specific, a detachment from the DMN along with a strengthened coupling to the AG seems to go along with lower trait aggression. MAOA-L carriers may thus depend on a synchronization of emotion regulation systems (VMPFC) with core areas of empathy (SMG) to prevent aggression.
Violent offending is elevated among individuals with antisocial personality disorder (ASPD) and high psychopathic traits (PP). Morphological abnormalities of the amygdala and orbitofrontal cortex (OFC) are present in violent offenders, which may relate to the violence enacted by ASPD + PP. Among healthy males, monoamine oxidase-A (MAO-A) genetic variants linked to low in vitro transcription (MAOA-L) are associated with structural abnormalities of the amygdala and OFC. However, it is currently unknown whether amygdala and OFC morphology in ASPD relate to MAO-A genetic polymorphisms. We studied 18 ASPD males with a history of violent offending and 20 healthy male controls. Genomic DNA was extracted from peripheral leukocytes to determine MAO-A genetic polymorphisms. Subjects underwent a T1-weighted MRI anatomical brain scan that provided vertex-wise measures of amygdala shape and surface area and OFC cortical thickness. We found that ASPD + PP subjects with MAOA-L exhibited decreased surface area in the right basolateral amygdala nucleus and increased surface area in the right anterior cortical amygdaloid nucleus versus healthy MAOA-L carriers. This study is the first to describe genotype-related morphological differences of the amygdala in a population marked by high aggression. Deficits in emotional regulation that contribute to the violence of ASPD + PP may relate to morphological changes of the amygdala under genetic control.
Purpose of review:
Aggressive behavior has adaptive value in many natural environments; however, it places substantial burden and costs on human society. For this reason, there has long been interest in understanding the neurobiological basis of aggression. This interest, and the flourishing of neuroimaging research in general, has spurred the development of a large and growing scientific literature on the topic. As a result, a neural circuit model of aggressive behavior has emerged that implicates interconnected brain regions that are involved in emotional reactivity, emotion regulation, and cognitive control.
Recent findings:
Recently, behavioral paradigms that simulate provocative interactions have been adapted to neuroimaging protocols, providing an opportunity to directly probe the involvement of neural circuits in an aggressive interaction. Here we review neuroimaging studies of simulated aggressive interactions in research volunteers. We focus on studies that use a well-validated laboratory paradigm for reactive physical aggression and examine the neural correlates of provocation, retaliation, and evaluating punishment of an opponent.
Summary:
Overall, the studies reviewed support the involvement of neural circuits that support emotional reactivity, emotion regulation, and cognitive control in aggressive behavior. Based on a synthesis of this literature, future research directions are discussed.
Testosterone, a male sex hormone, has been suggested to partly explain mixed findings in males and females when investigating behavioral tendencies associated with the MAOA polymorphism. Prior studies indicated that the MAOA polymorphism represents a vulnerability factor for financial risk-taking and harm avoidance and that testosterone increases human risk-taking. We therefore assumed an interactive influence of the MAOA polymorphism and testosterone application on decision making and corresponding neural correlates in a risk and reward context. Stratified for the MAOA polymorphism (S =short, L =long), 103 healthy males were assigned to a placebo or testosterone group (double blind, randomized) receiving a topical gel containing 50 mg testosterone. During a functional MRI scan, the participants performed a sequential decision making task. Our results indicate that testosterone and the MAOA polymorphism jointly influence sequential decision making. The MAOA-S variant was associated with less automatic harm avoidance as reflected in response times on safe decisions. Moreover, after testosterone administration, MAOA-S carriers were more risk-taking. Overall activity in the anterior cingulate cortex, anterior insula and inferior frontal gyrus increased with growing risk for losses. In the anterior insula, testosterone administration mitigated this effect solely in MAOA-S carriers. This might be a reflection of an improved coping during risk-reward conflicts subsequently modulating risky decision making. While the molecular basis is not well defined so far, our results support the assumption of testosterone as a modulatory factor for previously reported sex differences of behavioral associations with the MAOA-S variant. Hum Brain Mapp, 2017. © 2017 Wiley Periodicals, Inc.
Antisocial Personality Disorder is an important personality disorder, in terms of both impact on society and complexity of psychological and legal issues. The antisocial personality presents a murky conflux of five axioms: an apparent rationality and social appropriateness; an apparent inability to process experience effectively under standard social controls and punishments; some evidence of behavior determining variables, such as genetic defect and brain dysfunction; an absence of evidence of mediating variables among these possible causes and eventual antisocial behavior; and a disinterest in changing oneself and a lack of positive response to imposed treatment methods. However pessimistic the picture regarding treatment potential may be, more psychopathic treatment and outcome studies are warranted, even if they focus on only the small improvements, which are made by that small percentage of psychopaths who would stay in treatment. Since psychopaths, as a relatively small percentage of the population, commit such a large percentage of violent and property crimes, even a 5–10% success rate may pay dividends in terms of overall reduction of the most severe offenses.
Background:
The association between childhood maltreatment and subsequent aggressive behaviour is modified by monoamine oxidase A (MAOA) functional polymorphism (MAOA-uVNTR) genotype, MAOA-Long (MAOA-L) in females, MAOA-Short (MAOA-S) in males. Childhood maltreatment is associated with differential DNA methylation in several genes. Consistent with recent proposals, we hypothesized that the association of the interaction of MAOA genotype and maltreatment with aggressive behaviour is further moderated by methylation of a region of interest (ROI) spanning the first exon and partial first intron of MAOA.
Method:
The sample included 117 women and 77 men who completed interviews and questionnaires to report maltreatment and aggressive behaviour towards others and provided saliva samples for DNA extraction. The MAOA-uVNTR polymorphism was genotyped, and methylation of the MAOA ROI was assessed.
Results:
Following adjustment for substance misuse, psychoactive medication use, and in males tobacco use, the highest levels of aggressive behaviour were found among maltreated male carriers of MAOA-S with high levels of exonic methylation.
Conclusion:
Methylation levels within the MAOA ROI further contributed to the interaction of MAOA risk genotypes and maltreatment on aggressive behaviours among men.
Disruptive behavior is associated with societally and personally problematic levels of aggression and has been linked to abnormal structure and function of fronto-amygdala-striatal regions. Abnormal glutamatergic signalling within this network may play a role in aggression. However, disruptive behavior does not represent a homogeneous construct, but can be fractionated across several dimensions. Of particular interest, callous-unemotional (CU) traits have been shown to modulate the severity, neural and behavioural characterisation, and therapeutic outcomes of disruptive behaviour disorders (DBDs) and aggression. Further, individuals showing disruptive behavior differ to the extent that they engage in subtypes of aggression (i.e., proactive [PA] and reactive aggression [RA]) which may also represent distinct therapeutic targets. Here we investigated how glutamate signalling within the fronto-amygdala-striatal circuitry was altered along these dimensions in youths showing disruptive behavior (n = 140) and typically developing controls (TD, n = 93) within the age-range of 8-18 years. We used proton magnetic resonance spectroscopy (1H-MRS) in the anterior cingulate cortex (ACC), striatum, amygdala and insula and associated glutamate concentrations with continuous measures of aggression and CU-traits using linear mixed-effects models. We found evidence of a dissociation for the different measures and glutamate concentrations. CU traits were associated with increased ACC glutamate ('callousness': b = .19, t (108) = 2.63, p = .01, r = .25; 'uncaring': b = .18, t (108) = 2.59, p = .011, r = .24) while PA was associated with decreased striatal glutamate concentration (b = -.23, t (28) = -3.02, p = .005, r = .50). These findings suggest dissociable correlates of CU traits and PA in DBDs, and indicate that the ACC and striatal glutamate may represent novel pharmacological targets in treating these different aspects.
The maladaptive form of aggressive behavior confers risk for violence and criminal incidences with profound impact on society. Although considerable research has been devoted to elucidate the etiology of aggression, molecular correlates of sex differences remains largely unexplored. Also, little attention has been given to whether males and females respond differently to similar causal factor of aggression. Here, we show the possible association of brain region specific neural activity (c-Fos expression) and monoamine oxidase A (MAOA) epigenetic state with sexual dimorphism in peripubertal stress (PPS) induced adulthood aggression. While PPS adult males exhibited escalated aggression, females spent maximal time in social exploration. c-Fos expression was brain region and sex specific. In the PPS adult cohort, only males showed elevated c-Fos expression in the prefrontal cortex, indicative of their hyper-responsive behavior. MAOA expression and enzyme activity was reduced in hypothalamus and increased in prefrontal cortex of hyper-aggressive male mice. Investigation into the underlying mechanisms revealed hypomethylation in prefrontal cortex and hypermethylation in hypothalamus of MAOA promoter negatively correlating with the expression pattern. On the other hand, binding of Sirt1 to MAOA promoter was diametrically opposite being increased in prefrontal cortex and reduced in hypothalamus. In females, neither expression nor epigenetic state of MAOA gene was significantly altered between control and PPS adult mice. Our study revealed novel epigenetic correlates of sexual dimorphism in stress induced aggressive psychopathology. However, given the multi-factorial nature with environmental influences, further studies are warranted to uncover the biological hub.
As the main excitatory neurotransmitter in the central nervous system, glutamate, as measured in combination with glutamine (Glx), is implicated in several psychopathologies when levels are aberrant. One illness that shows heightened Glx levels is bipolar disorder (BD), an illness characterized by high impulsivity. In addition, although animal studies have reported elevated levels of Glx in aggressive and impulsive phenotypes, no study, to our knowledge, has reported Glx in the human cortex in relation to aggression. Here, we addressed the question of whether elevated levels of Glx would be present in patients with BD and antisocial personality disorder (ASPD), a condition associated with aggression and, like BD, also presents high impulsivity. We recruited individuals with ASPD (n = 18), individuals with BD (n = 16), and a healthy control group (n = 24). We used proton magnetic resonance spectroscopy to measure relative neurometabolite concentrations in the left dorsolateral prefrontal cortex (dlPFC) and supra-genual anterior cingulate cortex (ACC), two brain regions associated with impulsivity and behavior control. We found significantly elevated levels of Glx in the ASPD group relative to the BD and healthy control groups in the dlPFC (p =.014), and a positive correlation between Glx levels and aggression in the dlPFC in the ASPD group alone (r =.59, p =.026). These findings suggest a link between aggression in ASPD and Glx levels.
Genetic analysis of population have benefit in behavior population and medical fields.However, genetic study and information on Iraqi population are limited, The gene of monoamine oxidase A (MAOA) was chosen because it has variable number tandem repeats (VNTR) in the promoter region of gene that are known to be correlated with social behavior. The analysis of (VNTR) polymorphism provide valuable information on behavioral disorders and traits in addition to providing information on population variation and differentiation. Methods: The present study, blood samples were randomly selected from 440 Iraqi volunteers. This study has been conducted in Biology department – collage of science –Babylon university and College of Pharmacy – Ahel AL-Bait University. DNA was extracted from the peripheral blood of all participants, and the VNTR-MAOA polymorphism were genotyped by using the polymerase chain reaction (PCR) and agarose gel electrophoresis, the different fragment sizes were determined by comparisons to molecular length standards. The results were confirmed by using sequencing PCR technique. Results: From the sequencing results 3.5R, 4.5R and 5.5R repeats were successfully identified instead of the 3R, 4R, 5R repeats which were identified by previous researchers In addition to the novel repeat 1.5R it first recorded in Iraqi population. The result of the MAOA – VNTR genotyping revealed that the two common genotype were 4.5/4.5 and 3.5/3.5 with percent about 47.7 % and 25.2% and the two common alleles were 4.5R and 3.5R with percent 54.3 % and 31.2 respectively. The result of our study compared with data of eleven populations, showed the significant difference between allele frequencies of Iraqi samples with other populations Hispanic (Latino), White (non-Hispanic), New Zealand (European origin), Italian (European origin), Chinese, Asian (Pacific Islander), African American and American populations (P ≤ 0.05).,while no significant difference was found with Afrikaner and German, European origin populations (p value= 0.06, 0.062 and 0.077) respectively. Conclusion: MAOA allele frequency were differ between racial groups. in addition to establish a new repeat (1.5 R), the Iraqi population had more 5.5R allele than other populations.
Aggressive behavior (AB) is a multifaceted disorder based on the interaction between genetic and environmental factors whose underlying mechanisms remain elusive. The best-characterized gene by environment (GxE) interaction for AB is the relationship between child neglect/abuse and low-activity alleles of the monoamine-oxidase A (MAOA) gene. MAOA oxidizes monoamines like serotonin and dopamine, whose aberrant signaling at discrete developmental ages plays a pivotal role in the ontogeny of AB. Here, we investigated the impact of this GxE on dopamine function at pre-adolescence by exposing hypomorphic MAOA (MAONeo) mice to early life stress (ES) and by performing behavioral and ex vivo electrophysiological analyses in the ventral tegmental area (VTA) and the prefrontal cortex (PFC). MAOANeo ES mouse dopamine neurons exhibited an enhanced post-synaptic responsiveness to excitatory inputs, aberrant plasticity in the PFC, and an AB. Systemic administration of the selective antagonist at dopamine D1 receptors SCH23390 fully restored PFC function and rescued AB. Collectively, these findings reveal that dysfunctional mesocortical dopamine signaling at pre-adolescence ties to AB in the MAOANeo ES mouse, and identify dopamine D1 receptor as a molecular target to be exploited for an age-tailored therapy.
The ontogeny of antisocial behavior (ASB) is rooted in complex gene-environment (G×E) interactions. The best-characterized of these interplays occurs between: a) low-activity alleles of the gene encoding monoamine oxidase A (MAOA), the main serotonin-degrading enzyme; and b) child maltreatment. The purpose of this study was to develop the first animal model of this G×E interaction, to help understand the neurobiological mechanisms of ASB and identify novel targets for its therapy. Maoa hypomorphic transgenic mice were exposed to an early-life stress regimen consisting of maternal separation and daily intraperitoneal saline injections and were then compared with their wild-type and non-stressed controls for ASB-related neurobehavioral phenotypes. Maoa hypomorphic mice subjected to stress from postnatal day (PND) 1 through 7 – but not during the second postnatal week - developed overt aggression, social deficits and abnormal stress responses from the fourth week onwards. On PND 8, these mice exhibited low resting heart rate - a well-established premorbid sign of ASB – and a significant and selective up-regulation of serotonin 5-HT2A receptors in the prefrontal cortex. Notably, both aggression and neonatal bradycardia were rescued by the 5-HT2 receptor antagonist ketanserin (1–3 mg kg⁻¹, IP), as well as the selective 5-HT2A receptor blocker MDL-100,907 (volinanserin, 0.1–0.3 mg kg⁻¹, IP) throughout the first postnatal week. These findings provide the first evidence of a molecular basis of G×E interactions in ASB and point to early-life 5-HT2A receptor activation as a key mechanism for the ontogeny of this condition.
This article is part of the Special Issue entitled ‘The neuropharmacology of social behavior: from bench to bedside’.
Testosterone and the monoamine oxidase-A (MAOA) polymorphism are potential neuromodulators for aggression. By acting on similar brain circuits, they might interactively influence human behavior. The current study investigates the causal role of testosterone on aggression-related brain activity and the potential interaction with the MAOA polymorphism. In a double-blind process, 93 healthy males received a testosterone or placebo gel. In an fMRI session, participants performed a Taylor aggression paradigm in which they received provoking feedback and could afterwards decide how aggressively they would react. Testosterone and cortisol levels as well as subjective anger were assessed prior and after the task. Circulating testosterone levels were higher in carriers of the long compared to the short MAOA allele. An interaction of the MAOA polymorphism and testosterone administration was identified in the cuneus, where short allele carriers in the placebo group showed diminished activity in the decision period. Task-related anger was significantly higher in this group. Overall, a mesocorticolimbic network was implicated in processing of high versus low provoking feedback, and core hubs of the default mode network were implicated in the subsequent decision after high versus low provocation. Testosterone administration increased activation in this network. The data provides evidence for an interaction of the MAOA polymorphism and exogenous testosterone on anger and suggests that interactive effects on the brain signal could underlie differential emotional reactivity. The increased default mode activation in the testosterone group suggests an enhanced engagement of social cognition related regions possibly supporting responsivity towards social provocation. This article is part of the Special Issue entitled 'Current status of the neurobiology of aggression and impulsivity'.
Past research suggests an association between reactive aggression and alexithymia, but neural mechanisms underlying this association remain unknown. Furthermore, the relationship between proactive aggression and alexithymia remains untested. This study aimed to: (1) test whether alexithymia is more related to reactive than proactive aggression; and (2) determine whether amygdala, insula, and/or anterior cingulate cortical (ACC) volume could be neurobiological mechanisms for this association. One hundred and fifty-six community males completed the Reactive-Proactive Aggression Questionnaire and the Toronto Alexithymia Scale. Amygdala, insula, and ACC volumes were assessed using MRI. Alexithymia was positively associated with reactive but not proactive aggression. Alexithymia was positively and bilaterally associated with amygdala and anterior cingulate volumes. Reactive aggression was positively associated with right amygdala volume. Controlling for right amygdala volume rendered the alexithymia-reactive aggression relationship non-significant. Results suggest that increased right amygdala volume is a common neurobiological denominator for both alexithymia and reactive aggression. Findings suggest that greater right hemisphere activation may reflect a vulnerability to negative affect, which in turn predisposes to experiencing negative emotions leading to increased aggression. Findings are among the first to explicate the nature of the alexithymia-aggression relationship, with potential clinical implications.
There is ambiguity in how recurrent anger and aggression are accounted for by psychiatric nosology. One area of uncertainty is the extent to which Intermittent Explosive Disorder (IED) overlaps with and is distinct from Personality Disorder (PD). Accordingly, we conducted a study of individuals with IED and PD in order to understand the nature of comorbidity relationships seen across these two areas of psychopathology. One-thousand-five-hundred-twenty-one adults were studied (441 Healthy Controls (HC), 430 Psychiatric Controls (PC), and 650 IED subjects) and assessed for DSM-5 psychiatric disorders, life history of aggressive behavior, trait aggression, state and trait anger reactivity, and impulsivity. While nearly half of IED study participants had a comorbid PD diagnosis, nearly half with a Cluster B PD, almost as many had other personality disorders. IED predicted anger symptoms and history of aggressive behavior above and beyond a PD diagnosis. Comorbidity between IED and either Antisocial (AsPD) or Borderline (BPD) PD was associated with the highest levels of aggressive behavior. However, having IED comorbid with either AsPD and/or BPD PD was not associated with higher levels of impulsivity. Underlying personality traits related to anger, affect, and social behavior, but not identity disturbance, contribute to the shared symptom profile of IED and PD. IED is usually comorbid with PD, but does not have a unique relationship with any single PD. When comorbid with PD, a diagnosis of IED predicts more severe anger and aggression, but not necessarily increased impulsivity. These results suggest that IED and PD diagnoses retain clinical utility when made in cases meeting criteria for both.
Psychopathy is characterized by callous affect, interpersonal manipulation, a deviant lifestyle, and antisocial behavior. Previous research has linked psychopathic traits to childhood trauma, but also to the upstream variable number tandem repeat (uVNTR) polymorphism of the monoamine oxidase A (MAOA) gene. An interaction between childhood trauma and MAOA genotype has been associated with antisocial behavior, but so far little is known about interaction effects of childhood trauma and the MAOA uVNTR on psychopathy. In order to bridge this gap, we used data of 1531 male and 1265 female twins and their siblings from a Finnish community sample to estimate structural equation models. The psychopathy and childhood trauma constructs were conceptualized as bifactor models with one general and two orthogonal group factors. Data comprised self-reports on childhood trauma and psychopathic traits as well as MAOA uVNTR genotype. In both genders, childhood trauma was associated with the general factor that represents the overarching psychopathy construct, and with the group factor that captures social deviance, but not with the group factor capturing psychopathic core personality traits. Women with a low activity variant of the MAOA uVNTR reported slightly higher levels of psychopathy than those with a high activity allele, but only with respect to the general psychopathy factor. There was no evidence for an interaction effect between MAOA uVNTR genotype and childhood trauma on psychopathy in either gender. Our results suggest that psychopathy in general and social deviance in particular are associated with childhood trauma in men and women, and that psychopathic traits are subject to variation in the MAOA uVNTR genotype in women.
The placenta adapts to maternal environment and its alterations may have a lasting impact on child's temperament development. Prenatal stress has been linked to both a downregulation of monoamine oxidase A (MAOA) gene expression in the placenta and to difficult temperament. Capitalizing on an ongoing longitudinal study, we analysed data from 95 mother–child dyads to investigate whether MAOA mediates the association between prenatal stress and infant temperament. Prenatal stress was defined as exposure to Superstorm Sandy (Sandy) during pregnancy. Infant temperament was measured by Infant Behaviour Questionnaire‐Revised. MAOA gene expression was quantified in placenta tissue. The Smiling and Laughter subscale score was independently associated with Sandy exposure and MAOA placental gene expression. Mediation analysis confirmed that MAOA expression partially mediated the relationship between Sandy and Smiling and Laughter subscale, suggesting that in utero exposure to Sandy could induce lower frequency of smiling and laughter via downregulation of placental MAOA gene expression. These effects could compromise optimal temperamental trajectory and contribute to risk for psychological problems. Placental epigenetic markers can contribute to a multidimensional model of early intervention for high‐risk children.
Highlights
• The study examined whether placental MAOA gene expression operates as a biological mediator in the relationship between prenatal stress and infant temperament.
• Mediation analyses revealed a partial mediation between prenatal stress and Smiling and Laughter subscale.
• Stress in utero could change MAOA gene expression epigenetically, which could shape temperament development. Such placental gene expressions may become useful biomarkers for screening and intervention.
Background:
Child maltreatment is a pressing social problem in the USA and internationally. There are increasing calls for the use of a public health approach to child maltreatment, but the effective adoption of such an approach requires a sound foundation of epidemiological data. This study estimates for the first time, using national data, total and type-specific official maltreatment risks while simultaneously considering environmental poverty and race/ethnicity.
Methods:
National official maltreatment data (2009-13) were linked to census data. We used additive mixed models to estimate race/ethnicity-specific rates of official maltreatment (total and subtypes) as a function of county-level child poverty rates. The additive model coupled with the multilevel design provided empirically sound estimates while handling both curvilinearity and the nested data structure.
Results:
With increasing county child poverty rates, total and type-specific official maltreatment rates increased in all race/ethnicity groups. At similar poverty levels, White maltreatment rates trended higher than Blacks and Hispanics showed lower rates, especially where the data were most sufficient. For example, at the 25% poverty level, total maltreatment report rates were 6.91% [95% confidence interval (CI): 6.43%-7.40%] for Whites, 6.30% (5.50%-7.11%) for Blacks and 3.32% (2.88%-3.76%) for Hispanics.
Conclusions:
We find strong positive associations between official child maltreatment and environmental poverty in all race/ethnicity groups. Our data suggest that Black/White disproportionality in official maltreatment is largely driven by Black/White differences in poverty. Our findings also support the presence of a 'Hispanic paradox' in official maltreatment, where Hispanics have lower risks compared with similarly economically situated Whites and Blacks.
Two major types of aggression, proactive and reactive, are associated with contrasting expression, eliciting factors, neural pathways, development, and function. The distinction is useful for understanding the nature and evolution of human aggression. Compared with many primates, humans have a high propensity for proactive aggression, a trait shared with chimpanzees but not bonobos. By contrast, humans have a low propensity for reactive aggression compared with chimpanzees, and in this respect humans are more bonobo-like. The bimodal classification of human aggression helps solve two important puzzles. First, a long-standing debate about the significance of aggression in human nature is misconceived, because both positions are partly correct. The Hobbes-Huxley position rightly recognizes the high potential for proactive violence, while the Rousseau-Kropotkin position correctly notes the low frequency of reactive aggression. Second, the occurrence of two major types of human aggression solves the execution paradox, concerned with the hypothesized effects of capital punishment on self-domestication in the Pleistocene. The puzzle is that the propensity for aggressive behavior was supposedly reduced as a result of being selected against by capital punishment, but capital punishment is itself an aggressive behavior. Since the aggression used by executioners is proactive, the execution paradox is solved to the extent that the aggressive behavior of which victims were accused was frequently reactive, as has been reported. Both types of killing are important in humans, although proactive killing appears to be typically more frequent in war. The biology of proactive aggression is less well known and merits increased attention.
Physically healthy, adult, same-sexed twins (n = 287) from a population-based twin cohort underwent high-resolution magnetic resonance imaging (MRI) to identify fronto-limbic brain regions significantly associated with lifetime history of aggression. MRI scans used a 3D magnetization-prepared rapid acquisition gradient-echo (MP-RAGE) sequence, for voxel-based morphometry (VBM) and history of aggressive behavior was assessed using the Life History of Aggression measure. Aggression had modest, inverse associations with grey matter volume (GMV) in medial prefrontal cortex (mPFC, b = -0.20, se = 0.05, p < 0.001) and lateral prefrontal cortex (lPFC, b = -0.23, se = 0.06, p < 0.001). These associations were not confounded by other demographic, psychiatric, or personality factors. Biometrical twin analyses revealed significant heritabilities of 0.57 for GMV in the mPFC cluster and 0.36 for GMV in the lPFC cluster. Genetic factors accounted for the majority of the phenotypic correlations between aggression and mPFC GMV (85.3%) and between aggression and lPFC GMV (63.7%). Reduced GMV of prefrontal brain regions may be a neuronal characteristic of individuals with substantial histories of aggressive behavior regardless of psychiatric diagnosis. As such, these data suggest an anatomical correlate, with a possible genetic etiology, associated with functional deficits in social-emotional information processing.
Previous research showed that the disposition to react with disproportionate aggression in adults is influenced by an interaction between a variant in the X-chromosomal monoamine oxidase A gene (MAOA) and early traumatic events. Such studies have often focused on a single type of trauma, whereas we know that experiencing multiple trauma types is associated with more detrimental consequences. The differential susceptibility hypothesis suggests that individuals who are most susceptible to adversity, are also most likely to benefit from supportive experiences in childhood. Differences in susceptibility are thought to be partly genetically driven. In the present study we explored whether a genotype of MAOA linked to lower expression of the gene (MAOA-L) modified the effect of multiple types of trauma on aggression and/or altered responsiveness to treatment among adults with severe aggression. Forensic psychiatric outpatients (FPOs) (N=150) receiving treatment for aggression regulation problems were recruited. Traumatic events and aggression were measured using self-report. FPOs with multiple trauma types and those with the MAOA-L allele reported more severe levels of aggression. No interaction effects between MAOA genotype and trauma emerged. There were no differences in response to the intervention between FPOs with and without the MAOA-L variant, whereas FPOs with a single type of trauma showed the slowest reduction of aggression. FPOs with multiple types of trauma reported the highest levels of aggression over the course of treatment. Future research is needed to elucidate this association in further detail. The current study emphasized the importance of early recognition of early traumatic events.