Early-life stress lastingly impacts microglial transcriptome and function under basal and immune-challenged conditions

Abstract

Early-life stress (ELS) leads to increased vulnerability to psychiatric disorders including depression later in life. Neuroinflammatory processes have been implicated in ELS-induced negative health outcomes, but how ELS impacts microglia, the main tissue-resident macrophages of the central nervous system, is unknown. Here, we determined the effects of ELS-induced by limited bedding and nesting material during the first week of life (postnatal days [P]2–9) on microglial (i) morphology; (ii) hippocampal gene expression; and (iii) synaptosome phagocytic capacity in male pups (P9) and adult (P200) mice. The hippocampus of ELS-exposed adult mice displayed altered proportions of morphological subtypes of microglia, as well as microglial transcriptomic changes related to the tumor necrosis factor response and protein ubiquitination. ELS exposure leads to distinct gene expression profiles during microglial development from P9 to P200 and in response to an LPS challenge at P200. Functionally, synaptosomes from ELS-exposed mice were phagocytosed less by age-matched microglia. At P200, but not P9, ELS microglia showed reduced synaptosome phagocytic capacity when compared to control microglia. Lastly, we confirmed the ELS-induced increased expression of the phagocytosis-related gene GAS6 that we observed in mice, in the dentate gyrus of individuals with a history of child abuse using in situ hybridization. These findings reveal persistent effects of ELS on microglial function and suggest that altered microglial phagocytic capacity is a key contributor to ELS-induced phenotypes.

Evidence of microglial involvement in the childhood abuse-associated increase in perineuronal nets in the ventromedial prefrontal cortex

“…These effects were found to persist for up to 6 months after exposure to the stress paradigm. In an in vitro assay, this study further revealed that microglia exposed to ELS exhibit a reduced capacity for synaptosome phagocytosis in comparison to control microglia (Reemst et al, 2022). Intriguingly, the ELISA findings in the current study also indicate that the phagocytic capacity of microglia is attenuated by having experienced childhood adversity, as evidenced by lower expression of CX3CR1 and IL33R in the DS-CA group.…”

“…A recent study by the Korosi lab, in collaboration with our group, has shown an enduring effect of early-life stress, induced by limited bedding and nesting, on the microglial transcriptome and function under basal and immune-challenged conditions in mice (Reemst et al, 2022). These effects were found to persist for up to 6 months after exposure to the stress paradigm.…”

Resilience to Early Life Adversity Effects on Stress Reactivity by Postnatal Knockdown of 5-HT1AAutoreceptors

“…Previous studies have shown that ELA increases inflammatory processes in the rodent hippocampus. 46,47 Inflammation also decreases hippocampal neurogenesis and increases behavioral and neuroendocrine responses to stress – effects that we see specifically in female mice exposed to ELA. To test if ELA and 5HT 1A autoreceptor knockdown cause sex-specific effects on neuroinflammation following an acute stressor in adulthood, we used immunohistochemistry for the microglia-specific calcium binding protein, Iba1, and for the transmembrane glycoprotein, CD68, which increases in phagocytic microglia following their activation in response to neuroinflammatory processes ( Fig.…”

“…43 Such increased inflammation has been suggested to mediate an association between ELA and neurobiological correlates of mental illness. 44,45 Inflammatory effects of ELA on the brain are supported by studies showing higher numbers of activated microglia in the mouse and human hippocampus, 46,47 as well as disrupted microglia function in the developing PVN ,which promotes HPA axis hyperactivity following an acute stressor in adulthood. 17 ELA-dependent alterations in the function of microglia may thus contribute to heightened stress reactivity in adulthood.…”

Chondroitin sulfate glycan sulfation patterns influence histochemical labeling of perineuronal nets: a comparative study of interregional distribution in human and mouse brain

“…Using an ELS mouse model of limited bedding and nesting from P2-9 (Reemst et al, 2022), we found that WFL+ PNNs are increased in the mPFC of P70 male and female mice compared to controls (Figure 6). Moreover, our findings elucidate that PNN sulfation code and labeling pattern are undisturbed in adult human and mouse brains that have experienced early-life adversity.…”