title: 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.
authors.affiliation: Developmental Cognitive Neuroscience Lab (DCNL), Pontifícia Universidade Católica do Rio Grande do Sul. Avenida Ipiranga, 6681, prédio 11, sala 928, Porto Alegre 90619-900, RS, Brazil.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Grassi-Oliveira
authors.affiliation: Psychology Department, Northeastern University, 125 Nightingale Hall, 360 Huntington Ave., Boston 02115, MA, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Honeycutt
authors.affiliation: Psychology Department, Northeastern University, 125 Nightingale Hall, 360 Huntington Ave., Boston 02115, MA, USA.
authors.forename: Freedom H
authors.initials: FH
authors.lastname: Holland
authors.affiliation: Psychology Department, Northeastern University, 125 Nightingale Hall, 360 Huntington Ave., Boston 02115, MA, USA.
authors.forename: Prabarna
authors.initials: P
authors.lastname: Ganguly
authors.affiliation: Psychology Department, Northeastern University, 125 Nightingale Hall, 360 Huntington Ave., Boston 02115, MA, USA. Electronic address: h.brenhouse@neu.edu.
authors.forename: Heather C
authors.initials: HC
authors.lastname: Brenhouse
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001010:Anxiety, Separation; D015415:Biomarkers / Q000032:analysis; D003072:Cognition Disorders / Q000503:physiopathology; D060825:Cognitive Dysfunction / Q000209:etiology* / Q000378:metabolism; D016207:Cytokines / Q000032:analysis* / Q000097:blood; D005260:Female; D005544:Forecasting; D016753:Interleukin-10 / Q000032:analysis / Q000097:blood; D053583:Interleukin-1beta / Q000032:analysis / Q000097:blood; D015847:Interleukin-4 / Q000032:analysis / Q000097:blood; D008297:Male; D008426:Maternal Deprivation; D017397:Prefrontal Cortex / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012737:Sex Factors; D013315:Stress, Psychological / Q000503:physiopathology
chemical_list: D015415:Biomarkers; D016207:Cytokines; D053583:Interleukin-1beta; D016753:Interleukin-10; D015847:Interleukin-4
keywords: Cytokines; Development; Early life stress; Interneurons; Maternal separation; Memory; Parvalbumin; Prefrontal cortex; Win-shift