Neonatal Maternal Separation Modifies Proteostasis Marker Expression in the Adult Hippocampus

Abstract

Exposure to early-life stress (ELS) can persistently modify neuronal circuits and functions, and contribute to the expression of misfolded and aggregated proteins that are hallmarks of several neurodegenerative diseases. The healthy brain is able to clear dysfunctional proteins through the ubiquitin-proteasome system (UPS) and the autophagy-lysosomal pathway (ALP). Accumulating evidence indicates that impairment of these pathways contributes to enhanced protein aggregation and neurodegeneration. While stress is a known precipitant of neurological decline, few specific mechanistic links underlying this relationship have been identified. We hypothesized that neonatal maternal separation (MatSep), a well-established model of ELS, has the ability to alter the levels of UPS and ALP components in the brain, and thus has the potential to disrupt proteostasis. The expression of proteostasis-associated protein markers was evaluated by immunoblotting in the hippocampus and cortex of adult Wistar rats that were previously subjected to MatSep. We observed multiple sex- and MatSep-specific changes in the expression of proteins in the ALP, mitophagy, and UPS pathways, particularly in the hippocampus of adult animals. In contrast, MatSep had limited influence on proteostasis marker expression in the cortex of adult animals. Our results indicate that MatSep can selectively modify the intracellular protein degradation machinery in ways that may impact the development and progression of neurodegenerative disease.

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

“…With an unbiased WGCNA analysis, we identified an ELS-associated gene module in P200 microglia specifically related to protein ubiquitination and degradation of ubiquitinylated proteins, consistent with reported alterations in the ubiquitin-proteasome system in the hippocampus and cortex of adult rats exposed to maternal separation (65). Ubiquitin is crucial for protein degradation processes and is also involved in pathways such as inflammation (66).…”

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

“…With an unbiased weighted gene co-expression network analysis (WGCNA) analysis, we identified an ELS-associated gene module in P200 microglia specifically related to protein ubiquitination and degradation of ubiquitinated proteins, consistent with reported alterations in the ubiquitin-proteasome system in the hippocampus and cortex of adult rats exposed to maternal separation [72]. Ubiquitin is crucial for protein degradation processes and is also involved in inflammatory pathways [73].…”

Maternal separation stress through triggering of the neuro‐immune response in the hippocampus induces autistic‐like behaviors in male mice

“…MS with its structural, developmental, neuroendocrine, and neurochemical changes in different areas of the brain such as the amygdala nucleus, prefrontal cortex, and hippocampus causes mood and behavioral disorders; These changes in the nervous system provide the basis for the occurrence of several neurodegenerative diseases in the adulthood including depression, Alzheimer's disease, etc. (Sierra‐Fonseca et al, 2021; Tanaka et al, 2021). Studies on ASD patients indicated defects in brain development as well as structural and endocrinal disturbances.…”