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Gene-environment interactions in antisocial behavior are mediated by early-life 5-HT2A receptor activation.

ABSTRACT: 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'.

SUBMITTER: Godar SC

PROVIDER: S-EPMC7578912 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Gene-environment interactions in antisocial behavior are mediated by early-life 5-HT<sub>2A</sub> receptor activation.

Godar Sean C SC Mosher Laura J LJ Scheggi Simona S Devoto Paola P Moench Kelly M KM Strathman Hunter J HJ Jones Cori M CM Frau Roberto R Melis Miriam M Gambarana Carla C Wilkinson Brent B DeMontis M Graziella MG Fowler Stephen C SC Coba Marcelo P MP Wellman Cara L CL Shih Jean C JC Bortolato Marco M

Neuropharmacology 20190201

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 hypomorph ...[more]

PMID: 30716416

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Project description:This study aimed to identify whether early-life conditions in broiler chickens could affect their behavior and welfare, and whether or not this was associated with an altered gut microbiome composition or diversity. Broilers were tested in a 2 x 2 factorial design with hatching conditions [home pen (OH) or at the hatchery (HH)] and enrichment (dark brooder (EE) or no brooder (NE) until 14 days of age) as factors (N = 6 per treatment combination). Microbiota composition was measured in the jejunum on days (d) 7, 14, and 35 and in pooled fecal samples on day 14. A novel environment test (NET) was performed on days 1 and 11, and the behavior was observed on days 6, 13, and 33. On day 35, composite asymmetry was determined and footpad dermatitis and hock burn were scored. In their home pen, HH showed more locomotion than OH (P = 0.05), and NE were sitting more and showed more comfort behavior than EE at all ages (P <0.001 and P = 0.001, respectively). On days 6 and 13 NE showed more eating and litter pecking while sitting, but on day 33 the opposite was found (age*enrichment: P = 0.05 and P <0.01, respectively). On days 1 and 11, HH showed more social reinstatement in the NET than OH, and EE showed more social reinstatement than NE (P <0.05). Composite asymmetry scores were lower for EE than NE (P <0.05). EE also had less footpad dermatitis and hock burn than NE (P <0.001). Within OH, NE had a more diverse fecal and jejunal microbiome compared to EE on day 14 (feces: observed richness: P = 0.052; jejunum: observed richness and Shannon: P <0.05); the principal component analysis (PCA) showed differences between NE and EE within both HH and OH in fecal samples on day 14, as well as significant differences in bacterial genera such as Lactobacillus and Lachnospiraceae (P <0.05). On day 35, PCA in jejunal samples only showed a trend (P = 0.068) for differences between NE vs. EE within the OH. In conclusion, these results suggest that especially the dark brooder affected the behavior and had a positive effect on welfare as well as affected the composition and diversity of the microbiome. Whether or not the behavior was modulated by the microbiome or vice versa remains to be investigated.

Project description:Prior research shows that individuals who have exhibited antisocial behavior are in poorer health than their same-aged peers. A major driver of poor health is aging itself, yet research has not investigated relationships between offending trajectories and biological aging. We tested the hypothesis that individuals following a life-course persistent (LCP) antisocial trajectory show accelerated aging in midlife. Trajectories of antisocial behavior from age 7 to 26 years were studied in the Dunedin Multidisciplinary Health and Development Study, a population-representative birth cohort (N = 1037). Signs of aging were assessed at age 45 years using previously validated measures including biomarkers, clinical tests, and self-reports. First, we tested whether the association between antisocial behavior trajectories and midlife signs of faster aging represented a decline from initial childhood health. We then tested whether decline was attributable to tobacco smoking, antipsychotic medication use, debilitating illnesses in adulthood, adverse exposures in childhood (maltreatment, socioeconomic disadvantage) and adulthood (incarceration), and to childhood self-control difficulties. Study members with a history of antisocial behavior had a significantly faster pace of biological aging by midlife, and this was most evident among individuals following the LCP trajectory (β, 0.22, 95%CI, 0.14, 0.28, p ≤ 0.001). This amounted to 4.3 extra years of biological aging between ages 25-45 years for Study members following the LCP trajectory compared to low-antisocial trajectory individuals. LCP offenders also experienced more midlife difficulties with hearing (β, -0.14, 95%CI, -0.21, -0.08, p ≤ 0.001), balance (β, -0.13, 95%CI, -0.18, -0.06, p ≤ 0.001), gait speed (β, -0.18, 95%CI, -0.24, -0.10, p ≤ 0.001), and cognitive functioning (β, -0.25, 95%CI, -0.31, -0.18, p ≤ 0.001). Associations represented a decline from childhood health. Associations persisted after controlling individually for tobacco smoking, antipsychotic medication use, midlife illnesses, maltreatment, socioeconomic status, incarceration, and childhood self-control difficulties. However, the cumulative effect of these lifestyle characteristics together explained why LCP offenders have a faster Pace of Aging than their peers. While older adults typically age-out of crime, LCP offenders will likely age-into the healthcare system earlier than their chronologically same-aged peers. Preventing young people from offending is likely to have substantial benefits for health, and people engaging in a LCP trajectory of antisocial behaviors might be the most in need of health promotion programs. We offer prevention and intervention strategies to reduce the financial burden of offenders on healthcare systems and improve their wellbeing.

Dataset Information

Gene-environment interactions in antisocial behavior are mediated by early-life 5-HT2A receptor activation.

Publications

Gene-environment interactions in antisocial behavior are mediated by early-life 5-HT<sub>2A</sub> receptor activation.

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