Estrogen Receptor α Agonist is Beneficial for Young Female Rats Against Chronic Unpredicted Mild Stress-Induced Depressive Behavior and Cognitive Deficits

Abstract

Background: Women are reported more likely to develop depression and dementia. However, the involved mechanism is poorly understood. Objective: Here, we clarified the role of estrogen receptor α (ERα) in depression and cognitive deficit in young female rats. Methods: After being exposed to 7-weeks’ chronic unpredicted mild stress (CUMS), the depression resilient rats (Res rats) and depressed rats (Dep rats) were selected according to their records in sucrose preference test, forced swimming test, and open field test. Their cognition abilities were tested by Morris water maze. Proteomic assay, immunoprecipitation, western blotting, immunohistochemical, and Nissl staining were also used to understand the involved mechanism. Results: Compared with control rats and Res rats, Dep rats showed cognitive deficits and hippocampal impairments revealed by proteomic data, neuron losses, increased cleaved caspase-3, β-catenin phosphorylation, and glycogen synthase kinase3β (GSK3β) activation. As ERα, but not ERβ, was found declined in hippocampi of Dep rats, 4,4k,4a-(4-propyl-[1H]-pyrazole-1,3,5-triyl) trisphenol (PPT, an ERα agonist, 1 mg/kg/day), was used to treat Dep rats (Dep + PPT). Twenty days later, the depressive behaviors, cognition deficits, and hippocampal neuron loss were rescued in Dep + PPT rats. Furthermore, Res and Dep + PPT rats had higher levels of β-catenin combined with ERα and lower levels of β-catenin combined with GSK3β than Dep rats in hippocampi. Conclusion: These results demonstrated hippocampal ERα is an important pro-resilient factor in CUMS-induced depressive behaviors and cognitive deficits. It was also given that the neuroprotection afforded by hippocampal ERα/Wnt interactions have significant implications for cognition and emotion in young females.