Repeated and single maternal separation specifically alter microglial morphology in the prefrontal cortex and neurogenesis in the hippocampus of 15-day-old male mice

Abstract

Early-life adversity impairs neuronal plasticity of the developing brain. In rodents, brain maturation processes, including neuro- and synaptogenesis, myelination, microglial maturation, and hypothalamic–pituitary–adrenal (HPA) axis development continue in the postnatal period. In our study, two models of early-life stress were used: repeated maternal separation (MS) from postnatal day (PND) 2 to PND14 for 3 h daily and single maternal deprivation (MD) on PND9 for 24 h. Effects of each type of early-life stress on neuron density, neurogenesis, microglial morphology, and HPA axis programming were studied in 15-day-old male mice. Neither early-life stress paradigm affected the expression of stress-related genes (Crh, Avp, Crhr1, Crhr2, Nr3c1, and Nr3c2) and the serum level of corticosterone on PND15. Immunohistochemical analysis was performed on slices of the hippocampus and prefrontal cortex (PFC) with antibodies against a marker of mature neurons (NeuN), of microglia (Iba1), proliferating cells (Ki67), and immature neurons (DCX). We found higher density of ameboid microglia and intermediate microglia in the PFC in groups MS and MD, respectively, than in a control group. In both stressed groups, a higher number of Ki67-positive cells was noted in the dentate gyrus. Thus, in mice, the process of transformation of ameboid microglia into ramified ones as well as a neurogenesis reduction take place during the second postnatal week, whereas early-life stress can disturb these processes in a stress- and region-dependent manner.

Early Life Adversity and Neuropsychiatric Disease: Differential Outcomes and Translational Relevance of Rodent Models

“…Along these lines, studies have shown that microglia are also more broadly impacted in rodent models of ELA. Maternal separation during the early postnatal period, as well as social isolation during adolescence, alters microglia morphology, activation, and number in the hippocampus and prefrontal cortex ( Delpech et al, 2016 ; Bachiller et al, 2020 ; Gildawie et al, 2020 ; Reshetnikov et al, 2020 ; Usui et al, 2021 ), and some evidence suggests that ELA-induced increases in microglial activation may be responsible for some of its effects on stress vulnerability, including reduced reward seeking and stress coping after subsequent stress exposure. Given the important role that microglia play in synaptogenesis, synapse elimination, and synaptic plasticity ( Wu et al, 2015 ; Wilton et al, 2019 ), it seems likely that microglial activation might be causally linked to ELA-induced behavioral phenotypes.…”

Glia-Driven Brain Circuit Refinement Is Altered by Early-Life Adversity: Behavioral Outcomes

“…Wei et al ( 2012 ) demonstrated that ELA exposure during the onset of synaptic pruning increases corticosterone levels and reduces LBP mRNA and protein expression in the HPC. Data from similar studies support this finding and suggest that aberrant microglia function early in life is correlated with a delay in synaptic pruning of connections in HPC during late childhood which leads to the emergence of redundant, less effective circuitry in adolescence (Wei et al, 2012 , 2015 ; Delpech et al, 2016 ; Reshetnikov et al, 2020 ; Zetter et al, 2021 ). However, the effect of ELA on the phagocytic activity of microglia is region-specific.…”

Early Adversity and Accelerated Brain Aging: A Mini-Review

“…Neuroinflammatory states evoked by early stress have been reviewed extensively, with evidence pointing to an induction of inflammatory cytokines, astrogliosis, and microglial activation ( Ganguly and Brenhouse, 2015 ; Desplats et al, 2020 ). Most studies examine consequences of early adversity in postnatal or adult life, and do not address the long-term consequences on neuroinflammation ( Delpech et al, 2016 ; Réus et al, 2019 ; Desplats et al, 2020 ; Dutcher et al, 2020 ; Reshetnikov et al, 2020 ; Kim et al, 2021 ). One of the reports indicates that MS increases microglial numbers/activation in 10 month old animals ( Criado-Marrero et al, 2020 ), but few studies have actually followed animals with a history of early adversity across the life-span, to address the temporal and circuit-specific emergence of neuroinflammatory signatures ( Ganguly and Brenhouse, 2015 ; Tay et al, 2018 ; Andersen, 2022 ).…”