Modulation of the endoplasmic reticulum stress and unfolded protein response mitigates the behavioral effects of early-life stress

by Selleckchem | Apr 13 2023

Background: Early-life stress (ELS) affects brain development and increases the risk of mental disorders associated with the dysfunction of the medial prefrontal cortex (mPFC). The mechanisms of ELS action are not well understood. Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) are cellular processes involved in brain maturation through the regulation of pro-survival or proapoptotic processes. We hypothesized that ER stress and the UPR in the mPFC are involved in the neurobiology of ELS.

Methods: We performed a maternal separation (MS) procedure from postnatal days 1 to 14 in rats. Before each MS, pups were injected with an inhibitor of ER stress, salubrinal or a vehicle. The mRNA and protein expression of UPR and apoptotic markers were evaluated in the mPFC using RT-qPCR and Western blot methods, respectively. We also estimated the numbers of neurons and glial cells using stereological methods. Additionally, we assessed behavioral phenotypes related to fear, anhedonia and response to psychostimulants.

Results: MS slightly enhanced the activation of the UPR in juveniles and modulated the expression of apoptotic markers in juveniles and preadolescents but not in adults. Additionally, MS did not affect the numbers of neurons and glial cells at any age. Both salubrinal and vehicle blunted the expression of UPR markers in juvenile and preadolescent MS rats, often in a treatment-specific manner. Moreover, salubrinal and vehicle generally alleviated the behavioral effects of MS in preadolescent and adult rats.

Conclusions: Modulation of ER stress and UPR processes may potentially underlie susceptibility or resilience to ELS.

Comments：

The study aimed to investigate the potential role of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in the neurobiology of early-life stress (ELS) in rats. The researchers used a maternal separation (MS) procedure from postnatal days 1 to 14 to induce ELS in the rats. Before each MS, the rats were injected with either an inhibitor of ER stress (salubrinal) or a vehicle. The researchers evaluated the mRNA and protein expression of UPR and apoptotic markers in the medial prefrontal cortex (mPFC) using RT-qPCR and Western blot methods, respectively. They also estimated the numbers of neurons and glial cells using stereological methods and assessed behavioral phenotypes related to fear, anhedonia, and response to psychostimulants.

The results showed that MS slightly enhanced the activation of the UPR in juveniles and modulated the expression of apoptotic markers in juveniles and preadolescents but not in adults. Additionally, MS did not affect the numbers of neurons and glial cells at any age. Both salubrinal and vehicle blunted the expression of UPR markers in juvenile and preadolescent MS rats, often in a treatment-specific manner. Moreover, both salubrinal and vehicle generally alleviated the behavioral effects of MS in preadolescent and adult rats.

Based on these findings, the researchers concluded that modulation of ER stress and UPR processes may potentially underlie susceptibility or resilience to ELS. However, further studies are needed to elucidate the precise mechanisms of ER stress and UPR in the neurobiology of ELS and to determine the potential therapeutic implications of these findings for mental health disorders associated with ELS.