Introduction. Negative emotionality, aggression and antisociality are complex temperamental traits and social behaviours that arise out of multiple causes involving
Negative emotionality, aggression and antisociality are complex temperamental traits and social behaviours that arise out of multiple causes involving biological and psychological dynamisms and social forces, and different forms of emotional behaviour may each result from different biopsychosocial pathways. The societal implications of aggressiveness, which results in numerous facets of aggressive behaviour and ranges from the establishment of hierarchies and dominance to antisocial behaviour and delinquency, have been examined with preclinical and clinical frameworks. Developmentally inappropriate conduct, aggressiveness and failure in social adjustment represent the most detrimental and harmful long-term outcome of a wide spectrum of neurodevelopmental disorders characterized by deficits in cognitive control and emotion regulation.
In both humans and animals, the term aggression comprises a variety of behaviours that are heterogeneous for clinical phenomenology and neurobiological features. While the impact of complex cultural variables on behaviour impedes simple extrapolation of animal phenotypes to human traits, clinical observation, experimental paradigms in the laboratory and cluster/factor-analytic statistics have been used in attempts to subdivide aggression. On the basis of different approaches, human aggression may be differentiated into several subtypes depending on the presence or absence of causes or motivation, nature of trigger, characteristics of mediators, form of manifestation, direction and function (for review, see ). The dichotomy between an impulsive–reactive–hostile–affective subtype and a controlled–proactive–instrumental–predatory subtype has emerged as the most promising construct of qualitatively distinct subtypes of human aggression . In animal models, violence is defined as a form of escalated aggressive behaviour that is expressed out of context and inhibitory control, with a loss of adaptive function in social communication [3,4]. Individual differences in the temperamental traits of impulsivity and aggressiveness, and the ultimate behavioural consequences (such as distinct types of aggression, violence and self-injurious behaviour, including suicidality and addiction) are relatively enduring and continuously distributed as well as substantially heritable, and therefore are likely to result from additive or non-additive interaction of multiple genetic variations with environmental influences. This possibility has encouraged many investigators to apply dimensional approaches to behavioural genetics .
The brain serotonin (5-hydroxytryptamine, 5-HT) system originates from the raphe of the mammalian brainstem, where serotonergic neurons are clustered into nine nuclei numbered B1–9 on a rostrocaudal axis [6,7]. These clusters are subdivided into a rostral and a caudal part, with the rostral subdivision comprising the caudal linear nucleus, the dorsal raphe nucleus (DR: B6, B7) and the median raphe nucleus (MnR: B9, B8 and B5). These groups of serotonergic neurons project primarily into the forebrain where they innervate virtually all regions (e.g. cerebral cortex, amygdala, hippocampus, basal ganglia, thalamus and hypothalamus), thus mediating perception, cognition, emotional states, circadian rhythms, food intake and reproduction. The caudal portion, which projects mainly to the spinal cord and cerebellum, consists of nuclei termed as raphe pallidus (B1), raphe obscurus (B2) and raphe magnus (B3). This subsystem is involved in motor activity, pain control and regulation of the autonomic nervous system.
Tph2 is the key enzyme in the synthesis of neuronal 5-HT [8–10] and catalyses the hydroxylation of tryptophan (Trp) to 5-hydroxytryptophan (5-HTP), which is directly transformed to 5-HT by the amino acid decarboxylase (AADC). Tph2 is specifically expressed in the serotonergic neurons of the brainstem raphe complex and is exclusively responsible for the 5-HT synthesis within the brain, whereas Tph1 is the peripheral isoform . The gene encoding TPH2 is located on human chromosome 12q21.1 and was mapped to chromosome 10D1 in the mouse, respectively.
A wide spectrum of different human behavioural traits as well as neurodevelopmental and neuropsychiatric disorders have been linked to TPH2 variation. Reduced TPH2 expression and function resulting from common variants in the gene's transcriptional control region is associated with anxiety-, depression- and aggression-related personality traits and moderates emotion-related neurocircuitry in various species ranging from humans to non-human primates and rodents (for review, see . Similarly, these regulatory and other structural variants (in the non-coding and coding regions, respectively) seem to have a role in neurodevelopmental and psychiatric conditions such as depression, bipolar disorder, suicide, anxiety disorders (especially obsessive–compulsive disorder), substance-use disorders and attention-deficit/hyperactivity disorder (ADHD). In addition, therapeutic responses and side effects following treatment with selective serotonin-reuptake inhibitors (SSRIs) and other compounds have been found to be associated with TPH2 variants . Although many of these findings have been replicated, uncertainties remain about the biological foundation for the associations.
To explore the question of what traits or neuropsychiatric disorders are attributable to TPH2 dysfunction across the lifespan, mice with targeted inactivation of Tph2 were generated , revealing a remarkable phenotypic pleiotropy (figures 1 and 2; table 1).
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