Ovariectomy Induces Microglial Cell Activation and Inflammatory Response in Rat Prefrontal Cortices to Accelerate the Chronic Unpredictable Stress-Mediated Anxiety and Depression

Abstract

Perimenopausal women are associated with increased risks of depression and anxiety, which may be potentially related to the lack of ovarian hormone with antidepression activity in the body. However, the precise mechanism remains unclear so far. This study first adopted the Sprague-Dawley (SD) female rats to construct the ovariectomy (OVX) combined with a chronic unpredictable stress (CUS) model. Then, a series of behavioral experimental results revealed that the ovariectomized rats receiving CUS had remarkably elevated anxiety and depression behaviors relative to those in sham group rats, and the sucrose preference rate in the sucrose preference test (SPT) was evidently reduced. In elevated plus maze test (EPM) experiment, the open arm entry time and open arm duration were decreased. In the open field test (OFT), the number of line crossings, rearing number, center square entries, and center square duration were reduced; the grooming time was extended; and the number of fecal particles in rats was increased. In the forced swimming test (FST), the rat immobility rate was increased, while the numbers of swimming and crawling were decreased. Afterwards, we discovered that OVX downregulated the serum levels of estradiol and corticosterone in rats. Thereafter, IF results suggested that OVX dramatically induced the increasing of the number of activated microglial cells in prefrontal cortices and the level of M1-type marker iNOS. Finally, PCR results demonstrated that, compared with the sham group, the proinflammatory and prooxidative genes, such as IL-1β, IL-6, TNF-α, iNOS, and CX3CR1, were upregulated in the prefrontal cortices of OVX rats after CUS stimulation, whereas the anti-inflammatory factor Arg1 and microglial cell negative regulatory factor CD200 were downregulated. To sum up, OVX enhances the CUS-mediated anxiety and depression phenomena in rats, and its mechanism may be related to inducing the activation and polarization of microglial cells in the prefrontal cortex of animal and to accelerating the inflammatory response.