Early Life Stress Alters Gene Expression and Cytoarchitecture in the Prefrontal Cortex Leading to Social Impairment and Increased Anxiety

Abstract

Early life stress (ELS), such as abuse, neglect, and maltreatment, exhibits a strong impact on the brain and mental development of children. However, it is not fully understood how ELS affects social behaviors and social-associated behaviors as well as developing prefrontal cortex (PFC). In this study, we performed social isolation on weaned pre-adolescent mice until adolescence and investigated these behaviors and PFC characteristics in adolescent mice. We found the ELS induced social impairments in social novelty, social interaction, and social preference in adolescent mice. We also observed increases of anxiety-like behaviors in ELS mice. In histological analysis, we found a reduced number of neurons and an increased number of microglia in the PFC of ELS mice. To identify the gene associated with behavioral and histological features, we analyzed transcriptome in the PFC of ELS mice and identified 15 differentially expressed genes involved in transcriptional regulation, stress, and synaptic signaling. Our study demonstrates that ELS influences social behaviors, anxiety-like behaviors through cytoarchitectural and transcriptomic alterations in the PFC of adolescent mice.

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.…”

S-Ketamine Pretreatment Alleviates Anxiety-Like Behaviors and Mechanical Allodynia and Blocks the Pro-inflammatory Response in Striatum and Periaqueductal Gray From a Post-traumatic Stress Disorder Model

“…Nevertheless, previous studies showed multivariate results of the cortex in PTSD models. In an early-life stress and herpes zoster pain model, microglia in the PFC is markedly activated ( Ma et al, 2021 ; Usui et al, 2021 ). Neuroinflammation originating from microglia in the medial PFC induced by chronic stress, leading to depressive-like behavior ( Kitaoka, 2022 ).…”

Social Communication of Maternal Immune Activation-Affected Offspring Is Improved by Si-Based Hydrogen-Producing Agent

“…Quantitative real-time PCR (qPCR) was performed as described previously ( 16 , 21 ). Total RNA was extracted from the mouse prefrontal cortex (PFC) using the miRNeasy Mini Kit (#217004; Qiagen, Hilden, Germany) according to the manufacturer's instructions.…”