Estrogen Receptor Alpha Agonist Is Beneficial For Young Female Rats Against Chronic Unpredicted Mild Stress-Induced Depressive Behavior And Cognitive Deficits

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 alpha (ER alpha) 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, beta-catenin phosphorylation, and glycogen synthase kinase3 beta (GSK3 beta) activation. As ER alpha, but not ER beta, was found declined in hippocampi of Dep rats, 4,4k,4a-(4-propyl-[1H]-pyrazole-1,3,5-triyl) trisphenol (PPT, an ER alpha 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 beta-catenin combined with ER alpha and lower levels of beta-catenin combined with GSK3 beta than Dep rats in hippocampi.Conclusion: These results demonstrated hippocampal ER alpha is an important pro-resilient factor in CUMS-induced depressive behaviors and cognitive deficits. It was also given that the neuroprotection afforded by hippocampal ER alpha/Wnt interactions have significant implications for cognition and emotion in young females.