Cognitive impairment effects of early life stress in adolescents can be predicted with early biomarkers: Impacts of sex, experience, and cytokines
Open accessAbstract
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.
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The reduction in PV+ interneuron densities observed in the MSEW hippocampus is likely due to decreased PV protein levels rather than loss of neurons.
“The reduction in PV+ interneuron densities we observed in the MSEW hippocampus is likely due to decreased PV protein levels rather than loss of neurons given our data on PV expression and GAD67+ cell densities, as well as previous studies showing reductions in PV protein levels due to early life adversity in the mPFC of juvenile mice (68; 69).”
From Perineuronal nets, inhibitory interneurons and anxiety-related ventral hippocampal neuronal oscillations are altered by early life adversity (2019) · cites this paper as [68]
Early life stress can induce early vaginal opening in female rats.
“Further, early life stress can induce early vaginal opening in female rats (Grassi-Oliveira et al., 2016)”
From Does puberty mark a transition in sensitive periods for plasticity in the associative neocortex? (2017) · cites this paper as Grassi-Oliveira et al., 2016
Early life adversity may accelerate puberty onset.
“puberty onset (Belsky et al., 1991; Ellis et al., 1999; Grassi-Oliveira et al., 2016)”
From Does puberty mark a transition in sensitive periods for plasticity in the associative neocortex? (2017) · cites this paper as Grassi-Oliveira et al., 2016
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Self-citation
- Authors
- Grassi-Oliveira, R., Honeycutt, J. A., Holland, F. H., Ganguly, P., & Brenhouse, H. C.
- Affiliations
- Northeastern University (US)
- Corresponding author
- Brenhouse, Heather C.
- Venue
- Psychoneuroendocrinology
- Publisher
- Elsevier BV
- Published
- 2016-09
- Volume
- 71
- Pages
- 19-30
- ISSN
- 0306-4530 (ISSN-L)
- PMC
- PMC5412140
- OpenAlex
- W2343099858
- Cited by
- 112
- References
- 64
- Citations by year
- 2026: 5 · 2025: 11 · 2024: 10 · 2023: 6 · 2022: 14 · 2021: 13 · 2020: 9 · 2019: 17 · 2018: 13 · 2017: 8 · 2016: 5
- FWCI
- 9.15
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Psychoneuroendocrinology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIMH (5R21MH097182-01)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Social Sciences › Psychology › Clinical Psychology › Child Abuse and Trauma
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- early life stress, maternal separation, childhood adversity, serum cytokines, IL-1β, IL-10, IL-4, sex differences, parvalbumin interneurons, medial prefrontal cortex, biomarkers, rodent models
- MeSH terms
- Age Factors, Animals, Animals, Newborn, Anxiety, Separation, Cognition Disorders, Female, Forecasting, Male, Maternal Deprivation, Sex Factors, Stress, Psychological, Biomarkers, Interleukin-4, Cytokines, Interleukin-10, Rats, Sprague-Dawley, Prefrontal Cortex, Rats, Interleukin-1beta, Cognitive Dysfunction
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