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Circulating vitamin B12 concentrations during pregnancy are associated with offspring health. Foetal DNA methylation changes could underlie these associations. Within the Pregnancy And Childhood Epigenetics Consortium, we meta-analysed epigenome-wide associations of circulating vitamin B12 concentrations in mothers during pregnancy (n = 2,420) or cord blood (n = 1,029), with cord blood DNA methylation. Maternal and newborn vitamin B12 concentrations were associated with DNA methylation at 109 and 7 CpGs, respectively (False Discovery Rate P-value <0.05). Persistent associations with DNA methylation in the peripheral blood of up to 482 children aged 4-10 y were observed for 40.7% of CpGs associated with maternal vitamin B12 and 57.1% of CpGs associated with newborn vitamin B12. Of the CpGs identified in the maternal meta-analyses, 4.6% were associated with either birth weight or gestational age in a previous work. For the newborn meta-analysis, this was the case for 14.3% of the identified CpGs. Also, of the CpGs identified in the newborn meta-analysis, 14.3% and 28.6%, respectively, were associated with childhood cognitive skills and nonverbal IQ. Of the 109 CpGs associated with maternal vitamin B12, 18.3% were associated with nearby gene expression. In this study, we showed that maternal and newborn vitamin B12 concentrations are associated with DNA methylation at multiple CpGs in offspring blood (PFDR<0.05). Whether this differential DNA methylation underlies associations of vitamin B12 concentrations with child health outcomes, such as birth weight, gestational age, and childhood cognition, should be further examined in future studies. [ABSTRACT FROM AUTHOR]

Altered maternal haemoglobin levels during pregnancy are associated with pre-clinical and clinical conditions affecting the fetus. Evidence from animal models suggests that these associations may be partially explained by differential DNA methylation in the newborn with possible long-term consequences. To test this in humans, we meta-analyzed the epigenome-wide associations of maternal haemoglobin levels during pregnancy with offspring DNA methylation in 3,967 newborn cord blood and 1,534 children and 1,962 adolescent whole-blood samples derived from 10 cohorts. DNA methylation was measured using Illumina Infinium Methylation 450K or MethylationEPIC arrays covering 450,000 and 850,000 methylation sites, respectively. There was no statistical support for the association of maternal haemoglobin levels with offspring DNA methylation either at individual methylation sites or clustered in regions. For most participants, maternal haemoglobin levels were within the normal range in the current study, whereas adverse perinatal outcomes often arise at the extremes. Thus, this study does not rule out the possibility that associations with offspring DNA methylation might be seen in studies with more extreme maternal haemoglobin levels. [ABSTRACT FROM AUTHOR]

Study Question: Is cord blood DNA methylation associated with having been conceived by medically assisted reproduction?Summary Answer: This study does not provide strong evidence of an association of conception by medically assisted reproduction with variation in infant blood cell DNA methylation.What Is Known Already: Medically assisted reproduction consists of procedures used to help infertile/subfertile couples conceive, including ART. Due to its importance in gene regulation during early development programming, DNA methylation and its perturbations associated with medically assisted reproduction could reveal new insights into the biological effects of assisted reproductive technologies and potential adverse offspring outcomes.Study Design, Size, Duration: We investigated the association of DNA methylation and medically assisted reproduction using a case-control study design (N = 205 medically assisted reproduction cases and N = 2439 naturally conceived controls in discovery cohorts; N = 149 ART cases and N = 58 non-ART controls in replication cohort).Participants/materials, Settings, Methods: We assessed the association between medically assisted reproduction and DNA methylation at birth in cord blood (205 medically assisted conceptions and 2439 naturally conceived controls) at >450 000 CpG sites across the genome in two sub-samples of the UK Avon Longitudinal Study of Parents and Children (ALSPAC) and two sub-samples of the Norwegian Mother, Father and Child Cohort Study (MoBa) by meta-analysis. We explored replication of findings in the Australian Clinical review of the Health of adults conceived following Assisted Reproductive Technologies (CHART) study (N = 149 ART conceptions and N = 58 controls).Main Results and the Role Of Chance: The ALSPAC and MoBa meta-analysis revealed evidence of association between conception by medically assisted reproduction and DNA methylation (false-discovery-rate-corrected P-value < 0.05) at five CpG sites which are annotated to two genes (percentage difference in methylation per CpG, cg24051276: Beta = 0.23 (95% CI 0.15,0.31); cg00012522: Beta = 0.47 (95% CI 0.31, 0.63); cg17855264: Beta = 0.31 (95% CI 0.20, 0.43); cg17132421: Beta = 0.30 (95% CI 0.18, 0.42); cg18529845: Beta = 0.41 (95% CI 0.25, 0.57)). Methylation at three of these sites has been previously linked to cancer, aging, HIV infection and neurological diseases. None of these associations replicated in the CHART cohort. There was evidence of a functional role of medically assisted reproduction-induced hypermethylation at CpG sites located within regulatory regions as shown by putative transcription factor binding and chromatin remodelling.Limitations, Reasons For Cautions: While insufficient power is likely, heterogeneity in types of medically assisted reproduction procedures and between populations may also contribute. Larger studies might identify replicable variation in DNA methylation at birth due to medically assisted reproduction.Wider Implications Of the Findings: Newborns conceived with medically assisted procedures present with divergent DNA methylation in cord blood white cells. If these associations are true and causal, they might have long-term consequences for offspring health.Study Funding/competing Interests(s): This study has been supported by the US National Institute of Health (R01 DK10324), the European Research Council under the European Union's Seventh Framework Programme (FP7/2007-2013)/ERC Grant agreement no. 669545, European Union's Horizon 2020 research and innovation programme under Grant agreement no. 733206 (LifeCycle) and the NIHR Biomedical Centre at the University Hospitals Bristol NHS Foundation Trust and the University of Bristol. The UK Medical Research Council and Wellcome (Grant ref: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. Methylation data in the ALSPAC cohort were generated as part of the UK BBSRC funded (BB/I025751/1 and BB/I025263/1) Accessible Resource for Integrated Epigenomic Studies (ARIES, http://www.ariesepigenomics.org.uk). D.C., J.J., C.L.R. D.A.L and H.R.E. work in a Unit that is supported by the University of Bristol and the UK Medical Research Council (Grant nos. MC_UU_00011/1, MC_UU_00011/5 and MC_UU_00011/6). B.N. is supported by an NHMRC (Australia) Investigator Grant (1173314). ALSPAC GWAS data were generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. The Norwegian Mother, Father and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research, NIH/NIEHS (Contract no. N01-ES-75558), NIH/NINDS (Grant nos. (i) UO1 NS 047537-01 and (ii) UO1 NS 047537-06A1). For this work, MoBa 1 and 2 were supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01-ES-49019) and the Norwegian Research Council/BIOBANK (Grant no. 221097). This work was partly supported by the Research Council of Norway through its Centres of Excellence funding scheme, Project no. 262700.D.A.L. has received support from national and international government and charity funders, as well as from Roche Diagnostics and Medtronic for research unrelated to this study. The other authors declare no conflicts of interest.Trial Registration Number: N/A. [ABSTRACT FROM AUTHOR]

Background: Breastfeeding is associated with short and long-term health benefits. Long-term effects might be mediated by epigenetic mechanisms, yet the literature on this topic is scarce. We performed the first epigenome-wide association study of infant feeding, comparing breastfed vs non-breastfed children. We measured DNA methylation in children from peripheral blood collected in childhood (age 7 years, N = 640) and adolescence (age 15–17 years, N = 709) within the Accessible Resource for Integrated Epigenomic Studies (ARIES) project, part of the larger Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Cord blood methylation (N = 702) was used as a negative control for potential pre-natal residual confounding. Results: Two differentially-methylated sites presented directionally-consistent associations with breastfeeding at ages 7 and 15–17 years, but not at birth. Twelve differentially-methylated regions in relation to breastfeeding were identified, and for three of them there was evidence of directional concordance between ages 7 and 15–17 years, but not between birth and age 7 years. Conclusions: Our findings indicate that DNA methylation in childhood and adolescence may be predicted by breastfeeding, but further studies with sufficiently large samples for replication are required to identify robust associations. [ABSTRACT FROM AUTHOR]

Background: Stress experienced by mothers during pregnancy can have both immediate and long-term effects on child development, potentially mediated by breastfeeding. Aim: Using a UK birth cohort study, we asked how maternal stress relates to breastfeeding and consequences for growth and puberty onset. Subjects and methods: We analysed data from the Avon Longitudinal Study of Parents and Children, collected via questionnaires and clinic visits (N: 698–8,506). We used reports of prenatal anxiety, breastfeeding, early growth and age at menarche or first voice change. Confounding by maternal age, parity, smoking, education and body mass index (BMI) was considered. Results: Mothers with higher levels of reported anxiety were less likely to breastfeed (Odds ratio (OR): 0.83, 95% confidence interval (CI): 0.71, 0.97). Breastfed infants had slower growth before weaning, although growth differences were unclear thereafter. Being breastfed for more than six months was associated with later puberty onset in females (2.76 months later than non-breastfed; CI: 0.9, 4.63), although the association was attenuated by confounders and BMI (1.51 months, CI: −0.38, 3.40). No association between breastfeeding and puberty onset in males was found. Conclusion: Our studies fit results shown previously, and we consider these in light of evolutionary life history theory while discussing key challenges in such an approach. [ABSTRACT FROM AUTHOR]

Background: Animal and human studies suggest that inflammation is associated with behavioral disorders including aggression. We have recently shown that physical aggression of boys during childhood is strongly associated with reduced plasma levels of cytokines IL-1α, IL-4, IL-6, IL-8 and IL-10, later in early adulthood. This study tests the hypothesis that there is an association between differential DNA methylation regions in cytokine genes in T cells and monocytes DNA in adult subjects and a trajectory of physical aggression from childhood to adolescence. Methodology/Principal Findings: We compared the methylation profiles of the entire genomic loci encompassing the IL-1α, IL-6, IL-4, IL-10 and IL-8 and three of their regulatory transcription factors (TF) NFkB1, NFAT5 and STAT6 genes in adult males on a chronic physical aggression trajectory (CPA) and males with the same background who followed a normal physical aggression trajectory (control group) from childhood to adolescence. We used the method of methylated DNA immunoprecipitation with comprehensive cytokine gene loci and TF loci microarray hybridization, statistical analysis and false discovery rate correction. We found differentially methylated regions to associate with CPA in both the cytokine loci as well as in their transcription factors loci analyzed. Some of these differentially methylated regions were located in known regulatory regions whereas others, to our knowledge, were previously unknown as regulatory areas. However, using the ENCODE database, we were able to identify key regulatory elements in many of these regions that indicate that they might be involved in the regulation of cytokine expression. Conclusions: We provide here the first evidence for an association between differential DNA methylation in cytokines and their regulators in T cells and monocytes and male physical aggression. [ABSTRACT FROM AUTHOR]

The main challenge in addressing the role of DNA methylation in human behaviour is the fact that the brain is inaccessible to epigenetic analysis in living humans. Using positron emission tomography (PET) measures of brain serotonin (5-HT) synthesis, we found in a longitudinal sample that adult males with high childhood-limited aggression (C-LHPA) had lower in vivo 5-HT synthesis in the orbitofrontal cortex (OBFC). Here we hypothesized that 5-HT alterations associated with childhood aggression were linked to differential DNA methylation of critical genes in the 5-HT pathway and these changes were also detectable in peripheral white blood cells. Using pyrosequencing, we determined the state of DNA methylation of SLC6A4 promoter in T cells and monocytes isolated from blood of cohort members (N = 25) who underwent a PET scan, and we examined whether methylation status in the blood is associated with in vivo brain 5-HT synthesis. Higher levels of methylation were observed in both T cells and monocytes at specific CpG sites in the C-LHPA group. DNA methylation of SLC6A4 in monocytes appears to be associated more reliably with group membership than T cells. In both cell types the methylation state of these CpGs was associated with lower in vivo measures of brain 5-HT synthesis in the left and right lateral OBFC (N = 20) where lower 5-HT synthesis in C-LHPA group was observed. Furthermore, in vitro methylation of the SLC6A4 promoter in a luciferase reporter construct suppresses its transcriptional activity supporting a functional role of DNA methylation in SLC6A4 promoter regulation. These findings indicate that state of SLC6A4 promoter methylation is altered in peripheral white blood cells of individuals with physical aggression during childhood. This supports the relevance of peripheral DNA methylation for brain function and suggests that peripheral SLC6A4 DNA methylation could be a marker of central 5-HT function. [ABSTRACT FROM AUTHOR]

In the past decade there has been a profusion of studies highlighting covariation between individual differences in stress physiology and behavioural profiles, here called personalities. Such individual differences in ways of coping with stress are relevant both in biomedicine, since different personalities may experience a different stress and disease vulnerability, and in behavioural ecology, since their adaptive value and evolutionary maintenance are the subject of debate. However, the precise way in which individual stress differences and personalities are linked is unclear. Here we provide an updated overview of this covariation across different species and taxa, consider its functional significance and present working hypotheses for how behavioural and physiological responses to stress might be causally linked, affecting life-history traits such as dispersal and life-span. [ABSTRACT FROM AUTHOR]

Abstract: Aggressiveness is often considered a life-long, persistent personality trait and is therefore expected to have a consistent neurobiological basis. Recent meta-analyses on physiological correlates of aggression and violence suggest that certain aggression-related psychopathologies are associated with low functioning of the hypothalamo-pituitary-adrenal (HPA) axis and autonomic nervous system (ANS). We tested this hypothesis in mice selected for high and low aggressiveness by measuring baseline plasma corticosterone levels and, via radiotelemetry, heart rate and core body temperature. The radiotelemetric recordings were made for 48 h under baseline undisturbed conditions and for 90 min after a handling stressor. Consistent with the hypoarousal hypothesis of violence, we found lower resting heart rates in two out of the three highly aggressive selection lines. In contrast, body temperature during the active phase, as another ANS-regulated physiological parameter, was higher in two out of three highly aggressive lines. The handling-induced tachycardiac and hyperthermic responses were similar across the six mouse lines except for the most docile and obese line, which showed a blunted reactivity. Besides significant differences between strains, no differences in plasma corticosterone levels were found between the high- and low-aggressive phenotypes. These results are discussed in relation to the different types of aggression (normal versus pathological) exhibited by the three highly aggressive lines. We conclude that while high trait-like aggressiveness is generally associated with a higher active phase core body temperature, only animals that express pathological forms of aggression are characterized by a low resting heart rate. [Copyright &y& Elsevier]

Abstract: Differential role of the 5-HT1A receptor in aggressive and non-aggressive mice: an across-strain comparison. PHYSIOL BEHAV 00(0) 000-000, 2006. According to the serotonin (5-HT)-deficiency hypothesis of aggression, highly aggressive individuals are characterized by low brain 5-HT neurotransmission. Key regulatory mechanisms acting on the serotonergic neuron involve the activation of the somatodendritic inhibitory 5-HT1A autoreceptor (short feedback loop) and/or the activation of postsynaptic 5-HT1A receptors expressed on neurons in cortico-limbic areas (long feedback loop). In this study, we examined whether low serotonin neurotransmission is associated with enhanced 5-HT1A (auto)receptor activity in highly aggressive animals. Male mice (SAL-LAL, TA-TNA, NC900-NC100) obtained through different artificial-selection breeding programs for aggression were observed in a resident–intruder test. The prefrontal cortex level of 5-HT and its metabolite 5-HIAA were determined by means of HPLC. The activity of the 5-HT1A receptors was assessed by means of the hypothermic response to the selective 5-HT1A agonists S-15535 (preferential autoreceptor agonist) and 8-OHDPAT (full pre- and postsynaptic receptor agonist). Highly aggressive mice had lower serotonin levels in the prefrontal cortex and two out of three aggressive strains had higher 5-HT1A (auto)receptor sensitivity. The results strengthen the validity of the serotonin-deficiency hypothesis of aggression and suggest that chronic exaggerated activity of the 5-HT1A receptor may be a causative link in the neural cascade of events leading to 5-HT hypofunction in aggressive individuals. [Copyright &y& Elsevier]

Breastfeeding has long-term benefits for children that may be mediated via the epigenome. This pathway has been hypothesized, but the number of empirical studies in humans is small and mostly done by using peripheral blood as the DNA source. We performed an epigenome-wide association study (EWAS) in buccal cells collected around age nine (mean = 9.5) from 1006 twins recruited by the Netherlands Twin Register (NTR). An age-stratified analysis examined if effects attenuate with age (median split at 10 years; n<10 = 517, mean age = 7.9; n>10 = 489, mean age = 11.2). We performed replication analyses in two independent cohorts from the NTR (buccal cells) and the Avon Longitudinal Study of Parents and Children (ALSPAC) (peripheral blood), and we tested loci previously associated with breastfeeding in epigenetic studies. Genome-wide DNA methylation was assessed with the Illumina Infinium MethylationEPIC BeadChip (Illumina, San Diego, CA, USA) in the NTR and with the HumanMethylation450 Bead Chip in the ALSPAC. The duration of breastfeeding was dichotomized ('never' vs. 'ever'). In the total sample, no robustly associated epigenome-wide significant CpGs were identified (α = 6.34 × 10–8). In the sub-group of children younger than 10 years, four significant CpGs were associated with breastfeeding after adjusting for child and maternal characteristics. In children older than 10 years, methylation differences at these CpGs were smaller and non-significant. The findings did not replicate in the NTR sample (n = 98; mean age = 7.5 years), and no nearby sites were associated with breastfeeding in the ALSPAC study (n = 938; mean age = 7.4). Of the CpG sites previously reported in the literature, three were associated with breastfeeding in children younger than 10 years, thus showing that these CpGs are associated with breastfeeding in buccal and blood cells. Our study is the first to show that breastfeeding is associated with epigenetic variation in buccal cells in children. Further studies are needed to investigate if methylation differences at these loci are caused by breastfeeding or by other unmeasured confounders, as well as what mechanism drives changes in associations with age. [ABSTRACT FROM AUTHOR]

The recent focus on the role of epigenetic mechanisms in mental health has led to several studies examining the association of epigenetic processes with psychiatric conditions and neurodevelopmental traits. Some studies suggest that epigenetic changes might be causal in the development of the psychiatric condition under investigation. However, other scenarios are possible, e.g., statistical confounding or reverse causation, making it particularly challenging to derive conclusions on causality. In the present review, we examine the evidence from human population studies for a possible role of epigenetic mechanisms in neurodevelopment and mental health and discuss methodological approaches on how to strengthen causal inference, including the need for replication, (quasi-)experimental approaches and Mendelian randomization. We signpost openly accessible resources (e.g., "MR-Base" "EWAS catalog" as well as tissue-specific methylation and gene expression databases) to aid the application of these approaches. [ABSTRACT FROM AUTHOR]

Background: Breastfeeding is associated with short and long-term health benefits. Long-term effects might be mediated by epigenetic mechanisms, yet the literature on this topic is scarce. We performed the first epigenome-wide association study of infant feeding, comparing breastfed vs non-breastfed children. We measured DNA methylation in children from peripheral blood collected in childhood (age 7 years, N = 640) and adolescence (age 15-17 years, N = 709) within the Accessible Resource for Integrated Epigenomic Studies (ARIES) project, part of the larger Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Cord blood methylation (N = 702) was used as a negative control for potential pre-natal residual confounding., Results: Two differentially-methylated sites presented directionally-consistent associations with breastfeeding at ages 7 and 15-17 years, but not at birth. Twelve differentially-methylated regions in relation to breastfeeding were identified, and for three of them there was evidence of directional concordance between ages 7 and 15-17 years, but not between birth and age 7 years., Conclusions: Our findings indicate that DNA methylation in childhood and adolescence may be predicted by breastfeeding, but further studies with sufficiently large samples for replication are required to identify robust associations.

The main challenge in addressing the role of DNA methylation in human behaviour is the fact that the brain is inaccessible to epigenetic analysis in living humans. Using positron emission tomography (PET) measures of brain serotonin (5-HT) synthesis, we found in a longitudinal sample that adult males with high childhood-limited aggression (C-LHPA) had lower in vivo 5-HT synthesis in the orbitofrontal cortex (OBFC). Here we hypothesized that 5-HT alterations associated with childhood aggression were linked to differential DNA methylation of critical genes in the 5-HT pathway and these changes were also detectable in peripheral white blood cells. Using pyrosequencing, we determined the state of DNA methylation of SLC6A4 promoter in T cells and monocytes isolated from blood of cohort members (N = 25) who underwent a PET scan, and we examined whether methylation status in the blood is associated with in vivo brain 5-HT synthesis. Higher levels of methylation were observed in both T cells and monocytes at specific CpG sites in the C-LHPA group. DNA methylation of SLC6A4 in monocytes appears to be associated more reliably with group membership than T cells. In both cell types the methylation state of these CpGs was associated with lower in vivo measures of brain 5-HT synthesis in the left and right lateral OBFC (N = 20) where lower 5-HT synthesis in C-LHPA group was observed. Furthermore, in vitro methylation of the SLC6A4 promoter in a luciferase reporter construct suppresses its transcriptional activity supporting a functional role of DNA methylation in SLC6A4 promoter regulation. These findings indicate that state of SLC6A4 promoter methylation is altered in peripheral white blood cells of individuals with physical aggression during childhood. This supports the relevance of peripheral DNA methylation for brain function and suggests that peripheral SLC6A4 DNA methylation could be a marker of central 5-HT function.

Violence has been observed in humans and animals alike, indicating its evolutionary/biological significance. However, violence in animals has often been confounded with functional forms of aggressive behavior. Currently, violence in animals is identified primarily as either a quantitative behavior (an escalated, pathological and abnormal form of aggression characterized primarily by short attack latencies, and prolonged and frequent harm-oriented conflict behaviors) or a qualitative one (characterized by attack bites aimed at vulnerable parts of the opponent's body and context independent attacks regardless of the environment or the sex and type of the opponent). Identification of an operational definition for violence thus not only helps in understanding its potential differences from adaptive forms of aggression but also in the selection of appropriate animal models for both. We address this issue theoretically by drawing parallels from research on aggression and appeasement in humans and other animals. We also provide empirical evidences for violence in mice selected for high aggression by comparing our findings with other currently available potentially violent rodent models. The following violence-specific features namely (1) Display of low levels of pre-escalatory/ritualistic behaviors. (2) Immediate and escalated offense durations with low withdrawal rates despite the opponent's submissive supine and crouching/defeat postures. (3) Context independent indiscriminate attacks aimed at familiar/unfamiliar females, anaesthetized males and opponents and in neutral environments. (4) Orientation of attack-bites toward vulnerable body parts of the opponent resulting in severe wounding. (5) Low prefrontal serotonin (5-HT) levels upon repeated aggression. (6) Low basal heart rates and hyporesponsive hypothalamus-pituitary-adrenocortical (HPA) axis were identified uniquely in the short attack latency (SAL) mice suggesting a qualitative difference between violence and adaptive aggression in animals.

Violence can be defined as a form of escalated aggressive behavior that is expressed out of context and out of inhibitory control, and apparently has lost its adaptive function in social communication. Little is known about the social and environmental factors as well as the underlying neurobiological mechanisms involved in the shift of normal adaptive aggression into violence. In an effort to model the harmful acts of aggression and violence in humans, we recently (re)developed an animal model that is focused on engendering uncontrolled forms of maladaptive aggressive behavior in laboratory-bred feral rats and mice. We show that certain (8-12%) constitutionally aggressive individuals gradually develop, over the course of repetitive exposures to victorious social conflicts, escalated (short-latency, high-frequency and ferocious attacks), persistent (lack of attack inhibition by defeat/submission signals and perseverance of the aggressive attack-biting bout), indiscriminating (attacking female and anesthetized male intruders) and injurious (enhanced vulnerable-body region attacks and inflicted wounding) forms of offensive aggression. Based on the neurobiological results obtained using this model, a revised view is presented on the key role of central serotonergic (auto)regulatory mechanisms in this transition of normal aggression into violence.

Mice selected for aggression and coping (long attack latency (LAL), reactive coping strategy; short attack latency (SAL), pro-active coping strategy) are a useful model for studying the physiological background of animal personalities. These mice also show a differential stress responsiveness, especially in terms of hypothalamic-pituitary-adrenal axis reactivity, to various challenges. Since the stress response can increase the production of reactive oxygen species, we predicted that the basic oxidative status of the lines could differ. We found that LAL showed higher serum antioxidant capacity (OXY) than SAL, while no differences emerged for reactive oxygen metabolites (ROMs) or the balance between ROMs and OXY, reflecting oxidative stress. Moreover, the lines showed inverse relationships between ROMs or OXY and body mass corrected for age. The results indicate that variation in oxidative status is heritable and linked to personality. This suggests that different animal personalities may be accompanied by differences in oxidative status, which may predict differences in longevity.

Differential role of the 5-HT(1A) receptor in aggressive and non-aggressive mice: an across-strain comparison. PHYSIOL BEHAV 00(0) 000-000, 2006. According to the serotonin (5-HT)-deficiency hypothesis of aggression, highly aggressive individuals are characterized by low brain 5-HT neurotransmission. Key regulatory mechanisms acting on the serotonergic neuron involve the activation of the somatodendritic inhibitory 5-HT(1A) autoreceptor (short feedback loop) and/or the activation of postsynaptic 5-HT(1A) receptors expressed on neurons in cortico-limbic areas (long feedback loop). In this study, we examined whether low serotonin neurotransmission is associated with enhanced 5-HT(1A) (auto)receptor activity in highly aggressive animals. Male mice (SAL-LAL, TA-TNA, NC900-NC100) obtained through different artificial-selection breeding programs for aggression were observed in a resident-intruder test. The prefrontal cortex level of 5-HT and its metabolite 5-HIAA were determined by means of HPLC. The activity of the 5-HT(1A) receptors was assessed by means of the hypothermic response to the selective 5-HT(1A) agonists S-15535 (preferential autoreceptor agonist) and 8-OHDPAT (full pre- and postsynaptic receptor agonist). Highly aggressive mice had lower serotonin levels in the prefrontal cortex and two out of three aggressive strains had higher 5-HT(1A) (auto)receptor sensitivity. The results strengthen the validity of the serotonin-deficiency hypothesis of aggression and suggest that chronic exaggerated activity of the 5-HT(1A) receptor may be a causative link in the neural cascade of events leading to 5-HT hypofunction in aggressive individuals.