Early-life stress elicits peripheral and brain immune activation differently in wild type and 5xFAD mice in a sex-specific manner

Abstract

Background The risk of developing Alzheimer’s disease (AD) is modulated by genetic and environmental factors. Early-life stress (ELS) exposure during critical periods of brain development can impact later brain function and health, including increasing the risk of developing AD. Microglial dysfunction and neuroinflammation have been implicated as playing a role in AD pathology and may be modulated by ELS. To complicate matters further, sex-specific effects have been noted in response to ELS and in the incidence and progression of AD. Methods Here, we subjected male and female mice with either a wild type or 5xFAD familial AD-model background to maternal separation (MS) from postnatal day 2 to 14 to induce ELS. Results We detected hippocampal neuroinflammatory alterations already at postnatal day 15. By 4 months of age, MS mice presented increased immobility time in the forced swim test and a lower discrimination index in the novel object recognition memory test compared to controls. We found altered Bdnf and Arc expression in the hippocampus and increased microglial activation in the prefrontal cortex due to MS in a sex-dependent manner. In 5xFAD mice specifically, MS exacerbated amyloid-beta deposition, particularly in females. In the periphery, the immune cell population was altered by MS exposure. Conclusion Overall, our results demonstrate that MS has both short- and long-term effects on brain regions related to memory and on the inflammatory system, both in the brain and periphery. These ELS-related effects that are detectable even in adulthood may exacerbate pathology and increase the risk of developing AD via sex-specific mechanisms.

Using SuperClomeleon to Measure Changes in Intracellular Chloride during Development and after Early Life Stress

“…Brain development is strongly influenced by external factors and early life experiences ( Hensch, 2004 ; Miguel et al, 2019 ). Here, we used ELS, an established model to interfere with early brain development with long-lasting consequences for psychopathological risks later in life ( Teicher et al, 2016 ; Joëls et al, 2018 ; Bachiller et al, 2022 ; Catale et al, 2022 ). We used SClm to detect possible alterations in chloride maturation in the mPFC.…”

Using SuperClomeleon to measure changes in intracellular chloride during development and after early life stress

“…Brain development is strongly influenced by external factors and early life experiences (Hensch, 2004; Miguel et al, 2019). Here we used ELS, an established model to interfere with early brain development with long-lasting consequences for psychopathological risks later in life (Bachiller et al, 2022; Catale et al, 2022; Joёls et al, 2018; Teicher et al, 2016). We used SClm to detect possible alterations in chloride maturation in the mPFC.…”

Sex-specific behavioral outcomes of early-life adversity and emerging microglia-dependent mechanisms

“…Intriguingly, this balance shifts to the opposite pattern by puberty, such that adolescent and adult females have more “activated” microglia in the same brain regions (Schwarz et al, 2012 ). In the context of ELA, work by Bachiller et al ( 2022 ) discovered that the extent of Iba1+ staining coverage is increased in the hippocampus of MS male, but not female, mice at P15. However, the same study found an increase in the percentage of microglia with an “activated” morphology in the PFC of MS females in comparison to male counterparts (Bachiller et al, 2022 ).…”

“…In the context of ELA, work by Bachiller et al ( 2022 ) discovered that the extent of Iba1+ staining coverage is increased in the hippocampus of MS male, but not female, mice at P15. However, the same study found an increase in the percentage of microglia with an “activated” morphology in the PFC of MS females in comparison to male counterparts (Bachiller et al, 2022 ). Thus, it is possible that experiencing adversity during a developmental period in which microglia show sex differences in number and morphology in certain brain regions could impact males and females differently, thereby resulting in sex-specific and region-specific ELA-induced changes in synaptic pruning and ultimately divergent behavioral outcomes.…”