Sex-Specific Effects of Early Life Stress on Brain Mitochondrial Function, Monoamine Levels and Neuroinflammation

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.

Biological Connection of Psychological Stress and Polytrauma under Intensive Care: The Role of Oxytocin and Hydrogen Sulfide

“…In this regard, the effect of ELS/ACE on longterm morbidity after TBI is similar to that of comparable experiences in adulthood [35]. These clinical-epidemiological data are supported by experimental data in rats: ELS/ACE induce chronic neuro-inflammation [39,40] and oxidative stress concomitant with reduced mitochondrial activity [41]. Acute TBI in addition to pre-traumatic ELS/ACE amplifies microglial activation, neuro-inflammation [42,43], and cortical atrophy [44].…”

Early-Life Stress Modulates Gut Microbiota and Peripheral and Central Inflammation in a Sex-Dependent Manner

“…In clinical studies, these inconsistencies may be due to a number of confounding factors that could affect cytokine levels including the duration and recurrence frequency of depression, aging, BMI, smoking, alcohol consumption and medication [ 57 , 58 ]. Even though there may be various confounding factors, such as the duration of MS and aging, in experimental studies, relatively more severe inflammatory responses have been exhibited in males subjected to MS than females [ 28 , 29 ]. In the hippocampi, prefrontal cortices and/or striatums of MS rats, the elevations of proinflammatory cytokines such as IL-6 and/or TNF-α have been revealed in both males and females, being more pronounced in males [ 29 ].…”

“…Even though there may be various confounding factors, such as the duration of MS and aging, in experimental studies, relatively more severe inflammatory responses have been exhibited in males subjected to MS than females [ 28 , 29 ]. In the hippocampi, prefrontal cortices and/or striatums of MS rats, the elevations of proinflammatory cytokines such as IL-6 and/or TNF-α have been revealed in both males and females, being more pronounced in males [ 29 ]. MS has also been shown to enhance the mRNA levels of TNF-α and TNF receptor-1 in the prefrontal cortices and nucleus accumbens of males, but not females [ 28 ].…”

“…Considering these previous reports, we speculated that ELS would alter gut microbiota composition in a sex-specific manner, leading to the sex-specific pathophysiology of psychiatric disorders via distinct inflammation processes in males and females. In previous studies, sex-specific inflammatory responses have been reported in ELS rodents subjected to MS [ 28 , 29 ]; however, to the best of our knowledge, there is not any report on sex-specific alterations in gut microbiota composition or associations of those with sex-specific inflammatory responses in ELS models, yet. In order to determine the sex-specific pathophysiology of psychiatric disorders induced by ELS, we investigated the alterations of gut microbiota composition, inflammatory cytokine levels and TRP-KYN metabolism in rats subjected to MS during postnatal days (PNDs) 1–21 and assessed the differences between males and females.…”

Western Diet: Implications for Brain Function and Behavior

“…In addition, sex and gender differences on programming of behavior, brain development, and metabolism by diet during early life should be addressed in future studies. In this regard, exposure to a high-fat and -sugar diet prenatally and during early life, together with early life psychosocial stress, induce sex-dependent effects on adult metabolism, neuroinflammation, altered brain energy metabolism, and monoaminergic activity as recently reported by us and other research groups (Dearden et al, 2018;González-Pardo et al, 2020).…”