Laboratory of Pharmacology and Brain Biostructure, Department of Pharmacology, Maj Institute of Pharmacology, Polish Academy of Sciences, Smętna Street 12, 31-343, Kraków, Poland.
Department of Chemistry and Biochemistry, Institute for Basics Sciences, Faculty of Physiotherapy, University of Physical Education, Jana Pawła II Av. 78, 31-571, Kraków, Poland.
Pharmacol Rep. 2023 Apr;75(2):293-319. doi: 10.1007/s43440-023-00456-6. Epub 2023 Feb 27.
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.
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.
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.
Modulation of ER stress and UPR processes may potentially underlie susceptibility or resilience to ELS.
早期生活应激（ELS）会影响大脑发育，并增加与内侧前额叶皮层（mPFC）功能障碍相关的精神障碍风险。ELS 作用的机制尚不清楚。内质网（ER）应激和未折叠蛋白反应（UPR）是通过调节生存或促凋亡过程参与大脑成熟的细胞过程。我们假设 mPFC 中的 ER 应激和 UPR 参与了 ELS 的神经生物学。
我们在大鼠出生后第 1 天至第 14 天进行了母婴分离（MS）程序。在每次 MS 之前，幼鼠被注射 ER 应激抑制剂 salubrinal 或载体。使用 RT-qPCR 和 Western blot 方法分别评估 mPFC 中 UPR 和凋亡标志物的 mRNA 和蛋白表达。我们还使用体视学方法估计神经元和神经胶质细胞的数量。此外，我们评估了与恐惧、快感缺失和对精神兴奋剂反应相关的行为表型。
MS 轻度增强了 UPR 在青少年中的激活，并调节了青少年和青春期前的凋亡标志物表达，但在成年期则没有。此外，MS 不会影响任何年龄的神经元和神经胶质细胞数量。Salubrinal 和载体都在幼鼠和青春期前 MS 大鼠中减弱了 UPR 标志物的表达，通常以特定于处理的方式。此外，salubrinal 和载体通常减轻了青春期前和成年大鼠 MS 的行为影响。
ER 应激和 UPR 过程的调节可能潜在地成为 ELS 易感性或弹性的基础。
