The comparison of sex differences in depression-like behaviors and neuroinflammatory changes in a rat model of depression induced by chronic stress

Juan Xia; Haoyin Wang; Cai Zhang; Baiping Liu; Yuyu Li; Kangwei Li; Peng Li; Cai Song

doi:10.3389/fnbeh.2022.1059594

The comparison of sex differences in depression-like behaviors and neuroinflammatory changes in a rat model of depression induced by chronic stress

Front Behav Neurosci. 2023 Jan 4:16:1059594. doi: 10.3389/fnbeh.2022.1059594. eCollection 2022.

Authors

Juan Xia^{1

2}, Haoyin Wang¹, Cai Zhang¹, Baiping Liu¹, Yuyu Li¹, Kangwei Li¹, Peng Li^{1

3}, Cai Song^{1

4}

Affiliations

¹ Research Institute for Marine Drugs and Nutrition, College of Food Science and Technology, Guangdong Ocean University, Zhanjiang, China.
² Laboratory of Hematologic Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China.
³ Stem Cell Research and Cellular Therapy Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China.
⁴ Marine Medicine Research and Development Center of Shenzhen Institutes, Guangdong Ocean University, Shenzhen, China.

Abstract

Background: Clinical prevalence of major depression is higher in women than men, while the psychoneuroimmunological mechanisms underlying the differences between the two sexes are not fully understood.

Methods: The present study explored sex differences in the behaviors and depressive pathological mechanisms induced by chronic unpredictable mild stress (CUMS). Depression- and anxiety-like behaviors were assessed by the sucrose preference test (SPT), force swimming test (FST), open field test (OFT), and elevated plus-maze (EPM). The enzyme-linked immunosorbent assay (ELISA) was used to measure cytokine concentrations, high-performance liquid chromatography (HPLC) was used to measure monoamine neurotransmitters and metabolite contents, and real-time quantitative PCR (qPCR) and western blotting (WB) were used to measure glial parameters in the hippocampus.

Results: Under control conditions, female rats exhibited shorter immobility times in the FST, lower interferon (IFN)-γ, and interleukin (IL)-4 levels in the hippocampus, lower norepinephrine (NE) and homovanillic acid (HVA), and higher p75 and glial-derived neurotrophic factor (GDNF) expression than male rats. CUMS markedly reduced rat body weight gain, sucrose preference, locomotor activity, number of entries into the central zone and rearing in the OFT, as well as the number of entries into and time spent in open arms of the EPM; however, CUMS increased the immobility times of the rats of both sexes in the FST. Interestingly, more pronounced changes in sucrose preference and locomotor activity were observed in female rats than in males. Consistently, CUMS-increased glucocorticoid concentration, M1 microglial marker CD11b, and peripheral IL-1β and IL-4, while decreased hippocampal IL-10, serotonin (5-HT), dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC), and norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) were more significant in females than in males.

Conclusion: These data revealed possible mechanisms by which females suffer more depression than males at least in a stressful environment.

Keywords: chronic stress; depression; inflammation; neurotrophic factors; sex difference.

Grants and funding

This study was supported by Guangdong Provincial Natural Science Fund Project (2021A1515011579), Shenzhen Science and Technology Plan (International Cooperation Research) Project (GJHZ20190823111414825), and Zhanjiang Science and Technology Project (2021A05046).