Abstract
Sex differences have been reported in the susceptibility to early life stress and its neurobiological correlates in humans and experimental animals. However, most of the current research with animal models of early stress has been performed mainly in males. In the present study, prolonged maternal separation (MS) paradigm was applied as an animal model to resemble the effects of adverse early experiences in male and female rats. Regional brain mitochondrial function, monoaminergic activity, and neuroinflammation were evaluated as adults. Mitochondrial energy metabolism was greatly decreased in MS females as compared with MS males in the prefrontal cortex, dorsal hippocampus, and the nucleus accumbens shell. In addition, MS males had lower serotonin levels and increased serotonin turnover in the prefrontal cortex and the hippocampus. However, MS females showed increased dopamine turnover in the prefrontal cortex and increased norepinephrine turnover in the striatum, but decreased dopamine turnover in the hippocampus. Sex differences were also found for pro-inflammatory cytokine levels, with increased levels of TNF-α and IL-6 in the prefrontal cortex and hippocampus of MS males, and increased IL-6 levels in the striatum of MS females. These results evidence the complex sex- and brain region-specific long-term consequences of early life stress.
Highlights
There is compelling evidence supporting the hypothesis that early exposure to adverse or stressful life experiences (ELS) like childhood abuse or neglect increases the vulnerability to develop during adulthood the most prevalent mental disorders like depression, anxiety, and substance use disorders, and common physical health problems like obesity, cardiovascular diseases, cancer, diabetes, neurodegenerative diseases, among others [1,2,3,4]
Brain Sci. 2020, 10, 447 in rodents have been shown to alter adult brain monoamine levels in several brain regions related with abnormal behavior, like dopamine, serotonin, and norepinephrine [12,13,14,15]
Given the paucity of studies about sex differences in the long-term effects of ELS on brain mitochondrial function, neurochemistry, and neuroinflammation, the present study aimed to evaluate these effects after prolonged maternal separation (MS) in male and female rats over the entire weaning period (PND 1-21, 4 h/day) [34,35,36,37,38,39]
Summary
There is compelling evidence supporting the hypothesis that early exposure to adverse or stressful life experiences (ELS) like childhood abuse or neglect increases the vulnerability to develop during adulthood the most prevalent mental disorders like depression, anxiety, and substance use disorders, and common physical health problems like obesity, cardiovascular diseases, cancer, diabetes, neurodegenerative diseases, among others [1,2,3,4]. Childhood abuse and parental neglect increase adult inflammatory responses and alters neuroendocrine stress responses mediated by the hypothalamic-pituitary-adrenal (HPA). ELS can modulate mitochondrial function because stress response mediators like cortisol and catecholamines are both synthesized and metabolized by mitochondria [16] and the stress response essentially involves energy production and increased availability of energy substrates like glucose in the brain, one of main energy-demanding organs in the body [21]. Prolonged exposure to psychosocial stress has been linked to mitochondrial dysfunction by increased oxidative stress that can lead to increased neuroinflammatory response mediated by cytokine release and pro-inflammatory gene expression, together with increased glucocorticoid production by mitochondria [22]. Chronic psychological stress and ELS are mainly associated with altered mitochondrial metabolic capacity mediated by respiratory chain enzymes of brain cells in human and animal studies [17,23,24,25]
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