Cognitive impairment effects of early life stress in adolescents can be predicted with early biomarkers: Impacts of sex, experience, and cytokines

Abstract

Childhood adversity increases vulnerability to psychiatric disorders that emerge in adolescence, in a sex-dependent manner. Early adversity modeled in rodents with maternal separation (MS) affects cognition and medial prefrontal cortex (mPFC) circuitry. Humans and animals exposed to early life adversity also display heightened circulating inflammatory cytokines, however the predictive relationship of these early measures with later behavioral deficits is unknown. Here, male and female rats were exposed to MS or control rearing during the postnatal period (P2–21). Blood samples were taken at distinct developmental time points for analysis of the pro-inflammatory cytokine IL-1β and the anti-inflammatory cytokines IL-4, and IL-10, followed by win-shift cognitive testing and analysis of mPFC parvalbumin (PVB) immunofluorescent interneurons in adolescence. Regression analyses were conducted to explore the relationship between early cytokines and adolescent behavioral measures. We observed sex- and age-dependent effects of MS on circulating cytokines. MS also yielded adolescent decreases in mPFC PVB and cognitive deficits, which were predicted by early cytokine expression in a sex- and experience-dependent manner. Taken together, the present data reveals that circulating cytokines and PVB levels are predictive of adolescent cognitive deficits, and therefore provide compelling evidence for a putative role of early biomarkers in mediating MS-induced behavioral dysfunction. Importantly, predictive relationships often depended on sex and on MS history, suggesting that early life experiences may yield individualistic mechanisms of vulnerability compared to the general population.

An overview of maternal separation effects on behavioural outcomes in mice: Evidence from a four-stage methodological systematic review

“…In line with that, we also found more evidences pointing to a decrease mRNA GR and MR expression within brain tissues of maternal separated animals. Another emergent hypothesis corroborated by our findings is related to the imbalance of the immune system because of stressful conditions, corroborating reported findings from rats (Grassi-Oliveira et al, 2016) and human ELS studies (Black, 2002;Coelho et al, 2014).…”

Does puberty mark a transition in sensitive periods for plasticity in the associative neocortex?

“…Stressors occurring during sensitive periods may have profound effects on development of brain, cognition, and behavior by altering the organization of neural circuits, which in turn may lead to increased risk for psychopathology and negative health outcomes (Gilbert et al, 2009; Heim and Nemeroff, 2001; Sánchez et al, 2001). Further, early life stress can induce early vaginal opening in female rats (Grassi-Oliveira et al, 2016) and may interact with puberty to exacerbate the rise in psychopathology during early puberty (Fig. 5; Silberg et al, 1999).…”

“…These structural changes are accompanied by changes to cognition supported by frontal circuits (Lovic and Fleming, 2004; Thomas et al, 2015; Yang et al, 2015). Interestingly, early life adversity may accelerate brain development (Callaghan et al, 2014; Hostinar and Gunnar, 2013), puberty onset (Belsky et al, 1991; Ellis et al, 1999; Grassi-Oliveira et al, 2016), maturation of fear extinction/recovery behavior (Callaghan and Richardson, 2011), attachment and avoidance learning (Moriceau et al, 2009), reversal learning (Thomas et al, 2015), and maturation of frontal-amygdala connectivity (Gee et al, 2013). This accelerated brain development following early life stress may be an adaptive mechanism that coordinates the development of neural circuits to meet the demands of an adverse environment (Callaghan et al, 2014; Hostinar and Gunnar, 2013).…”

Immunoadolescence: Neuroimmune development and adolescent behavior

“…For example, we recently observed that postnatal stress in rats caused by maternal separation from postnatal day (P) 2-20 yields a decrease in circulating levels of the anti-inflammatory cytokine IL-10 at P35, but not P25 nor P55 (Figure 2). This transient decrease occurred in adolescent males, but not females (Grassi-Oliveira et al, in press). In support of the idea that adolescent changes in circulating cytokines can predict altered behavioral outcomes, we found that lower levels of circulating peripheral IL-10 at P35 predicted poor performance in the win-shift cognitive behavioral task two weeks later, only in maternally separated male rats (Grassi-Oliveira et al, in press).…”

“…This transient decrease occurred in adolescent males, but not females (Grassi-Oliveira et al, in press). In support of the idea that adolescent changes in circulating cytokines can predict altered behavioral outcomes, we found that lower levels of circulating peripheral IL-10 at P35 predicted poor performance in the win-shift cognitive behavioral task two weeks later, only in maternally separated male rats (Grassi-Oliveira et al, in press). Adolescence may therefore be a period during which early-life stressors or events that “derail” development can manifest in immune dysfunction, with consequences for the brain and long-term behavioral outcomes.…”