Conclusion and outlook

Converging lines of evidence suggest that variation in the transcriptional regulation of 5-HT signalling-related genes and in the activity of their respective gene products, i.e. proteins, plays a critical role in synaptic plasticity of a multitude of neuronal networks, thus setting the stage for expression of complex traits and their associated behaviours throughout development and adult life. Moreover, genetic variation in genes moderating 5-HT system function, in conjunction with other rare and common variants of the genetic background and with inadequate adaptive responses to environmental stressors, is also likely to contribute to inappropriate impulsivity and aggression-related behaviour emerging from compromised brain development and from highly efficient neuroadaptive processes across the life cycle.

Negative emotionality, increased impulsivity and hostility, resulting in aggressive, violent and antisocial behaviour, are not infrequent, the expression of which must be carefully controlled to ensure the success of individuals, small groups and large societies, especially within the evolutionarily recent framework extending from the development of agriculture, to urbanization/ industrialization, to rapid population growth and globalization.

Genetic mechanisms are not the only pathway that leads to individual differences in personality dimensions, behaviour and psychopathology. Complex traits are most likely to be generated by a complicated interaction of environmental and experiential factors with a large number of genes. Even pivotal regulatory proteins of neurotransmission, such as receptors, transporters and modifying enzymes, will individually have only modest impact, while noise from epigenetic as well as non-genetic mechanisms genuinely obstruct identification of relevant genes. Although methods for the detection of G × E interaction in the behavioural genetics of aggression and violence are still in the process of attaining sophistication, the most relevant consequence of gene identification for personality and behavioural traits may be that it will provide the tools required to systematically clarify the effects of epigenetic programming [76,157–162].

On the basis of the remarkable progress in technologies that allow the alteration or elimination of individual genes to create unique animal models, gene modification strategies are likely to continue to increase our knowledge about which gene products are involved in emotion- and aggression-related traits. However, because a missing or dysfunctional gene might affect many developmental processes throughout ontogeny, and compensatory mechanisms may be activated in KO mice, behavioural data from mice with targeted gene deletions should be interpreted with caution. It is evident that many neurotransmitters and their receptors are expressed at early periods of neural development, and it is widely appreciated that they participate in the structural organization of the brain. The increasing versatility of conditional KO strategies, in which a gene-of-interest can be inactivated tissue-specifically any time during ontogeny, are therefore likely to avoid these imperfections associated with phenotypic data from constitutive KOs.

Despite the usefulness of the gene targeting strategy in identifying specific pathways that may be involved in aggression, this approach is limited to known candidate genes. Owing to the complexity in the expression of aggressive behaviour, it is impossible to predict which genes contribute to the variability of this trait in different populations. The current state-of-the-art of this field illustrates how progress in behavioural genetics might be accelerated by closer integration of neuroscience and genetic approaches and a dimensional, quantitative approach to behavioural phenotypes.

In the present epigenomic era, modest advances in behavioural genetics are contrasted by giant leaps in genome-wide screening approaches, leading to the identification of a remarkable number of intriguingly complicated genetic and epigenetic mechanisms. Novel conceptual paradigms and technical progress have facilitated investigations into the connection between genes of the 5-HT signalling pathway, (social) cognition and emotionality: (i) generation of mouse models allowing time- and cell-specific alteration of gene function in different subdivisions of the brain 5-HT system which project to neural units fine-tuning the cognitive–emotional interface, (ii) validation of G × E models in non-human primates and rodents, (iii) functional neuroimaging of 5-HT-specific neurocircuits in humans, (iv) rapidly evolving sequencing technologies in the quest for low-frequent and rare genetic variants with high effect size but variable penetrance, and (v) inclusion of a more extensive phenotypic spectrum (e.g. sex-specific differences, higher cognitive functions, social skills, resilience, etc.). These elaborations continue to enable a more profound understanding of the integration of physiological responses to environmental adversity and the pathophysiology of disorders of emotion regulation.

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