Brain white matter microstructure alterations in adolescent rhesus monkeys exposed to early life stress: associations with high cortisol during infancy

Abstract

BackgroundEarly adverse experiences, especially those involving disruption of the mother-infant relationship, are detrimental for proper socioemotional development in primates. Humans with histories of childhood maltreatment are at high risk for developing psychopathologies including depression, anxiety, substance abuse, and behavioral disorders. However, the underlying neurodevelopmental alterations are not well understood. Here we used a nonhuman primate animal model of infant maltreatment to study the long-term effects of this early life stress on brain white matter integrity during adolescence, its behavioral correlates, and the relationship with early levels of stress hormones.MethodsDiffusion tensor imaging and tract based spatial statistics were used to investigate white matter integrity in 9 maltreated and 10 control animals during adolescence. Basal plasma cortisol levels collected at one month of age (when abuse rates were highest) were correlated with white matter integrity in regions with group differences. Total aggression was also measured and correlated with white matter integrity.ResultsWe found significant reductions in white matter structural integrity (measured as fractional anisotropy) in the corpus callosum, occipital white matter, external medullary lamina, as well as in the brainstem of adolescent rhesus monkeys that experienced maternal infant maltreatment. In most regions showing fractional anisotropy reductions, opposite effects were detected in radial diffusivity, without changes in axial diffusivity, suggesting that the alterations in tract integrity likely involve reduced myelin. Moreover, in most regions showing reduced white matter integrity, this was associated with elevated plasma cortisol levels early in life, which was significantly higher in maltreated than in control infants. Reduced fractional anisotropy in occipital white matter was also associated with increased social aggression.ConclusionsThese findings highlight the long-term impact of infant maltreatment on brain white matter structural integrity, particularly in tracts involved in visual processing, emotional regulation, and somatosensory and motor integration. They also suggest a relationship between elevations in stress hormones detected in maltreated animals during infancy and long-term brain white matter structural effects.

Early deprivation, atypical brain development, and internalizing symptoms in late childhood

“…If significant associations between MD values and internalizing symptoms and institutional rearing were observed, on a post hoc basis, we explored whether these associations were due to variability in AD or RD values. Consistent with prior work (Howell et al, 2013), we expected that RD values, but not AD values, would account for the associations between MD values, institutional rearing, and internalizing symptoms, reflecting maturational delays in early experience-driven myelination rates in institutionally reared children.…”

Enhanced Aggressive Behaviour in a Mouse Model of Depression

“…The findings of increased aggressive behaviours in depressed mice are consistent with previous reports examining the effects of stress on aggression in adult rodents, primates and human (Carnevali et al 2013;Crombach and Elbert 2014;Howell et al 2013). The tube test may reveal significant differences in mice with altered motor function or impulsivity, or under conditions of social stress (Kalueff et al 2007), and was originally developed as a test of social hierarchy/dominance.…”

Early-Life Experience, Epigenetics, and the Developing Brain

“…In colonies of macaques, maternal abuse (ie, dragging and stepping-on infants) occurs at a frequency of 2-10% and is associated with a delay in the onset of social play and heightened aggression in novel environments . Abusive mothers also engage in high levels of maternal rejection, which is predictive of HPA disruption, brain morphology, and serotonergic function in offspring (Howell et al, 2013;Koch et al, 2014;Maestripieri et al, 2006;Sanchez et al, 2010). Non-human primates have also been observed to vary in their frequency of mother-infant contact (ie, an over-protective parenting style), and high levels of contact predicts decreased exploration of a novel environment (Fairbanks and McGuire, 1988).…”