Abstract
Major depression is a serious and chronic mental illness. However, its etiology is poorly understood. Although glial cells have been increasingly implicated in the pathogenesis of depression, the specific role of microglia and astrocytes in stress-induced depression remains unclear. Translocator protein (TSPO) has long been considered a marker of neuroinflammation and microglial activation. However, this protein is also present on astrocytes. Thus, it is necessary to explore the relationships between TSPO, microglia, and astrocytes in the context of depression. In this study, C57BL/6J male mice were subjected to chronic unpredictable stress (CUS) for 5 weeks. Subsequently, sucrose preference and tail suspension tests (TSTs) were performed to assess anhedonia and despair in these mice. [18F]DPA-714 positron emission tomography (PET) was adopted to dynamically assess the changes in glial cells before and 2, 4, or 5 weeks after CUS exposure. The numbers of TSPO+ cells, ionized calcium-binding adaptor molecule (Iba)-1+ microglial cells, TSPO+/Iba-1+ cells, glial fibrillary acidic protein (GFAP)+ astrocytes, TSPO+/GFAP+ cells, and TUNEL-stained microglia were quantified using immunofluorescence staining. Real-time PCR was used to evaluate interleukin (IL)-1β, IL-4, and IL-18 expression in the hippocampus. We observed that hippocampal [18F]DPA-714 uptake significantly increased after 2 weeks of CUS. However, the signal significantly decreased after 5 weeks of CUS. CUS significantly reduced the number of Iba-1+, TSPO+, and TSPO+/Iba-1+ cells in the hippocampus, especially in the CA1 and dentate gyrus (DG) subregions. However, this intervention increased the number of GFAP+ astrocytes in the CA2/CA3 subregions of the hippocampus. In addition, microglial apoptosis in the early stage of CUS appeared to be involved in microglia loss. Further, the expression of pro-inflammatory cytokines (IL-1β and IL-18) was significantly decreased after CUS. In contrast, the expression of the anti-inflammatory cytokine IL-4 was significantly increased after 2 weeks of CUS. These results suggested that the CUS-induced dynamic changes in hippocampal [18F]DPA-714 uptake and several cytokines may be due to combined microglial and astrocyte action. These findings provide a theoretical reference for the future clinical applications of TSPO PET.
Highlights
Major depression is a serious and chronic mental illness, affecting approximately 350 million people worldwide (Malhi and Mann, 2018)
Hippocampal astrocytes mediate the depressive behavior induced by chronic stress (Hisaoka-Nakashima et al, 2020; Du Preez et al, 2021). These findings indicate that dynamic changes in glia and their interactions contribute to the inflammatory processes involved in depression
Translocator protein (TSPO) positron emission tomography (PET) is a valid method for evaluating the status of glia in vivo
Summary
Major depression is a serious and chronic mental illness, affecting approximately 350 million people worldwide (Malhi and Mann, 2018). Antidepressants are effective in only 60– 70% of cases, and the treatment outcomes in patients with depression remain unsatisfactory (Rush et al, 2006). Such outcomes severely impact patient quality of life and create a heavy social burden (GBD 2016 Disease and Injury Incidence and Prevalence Collaborators, 2017). The etiology of depression and relevant antidepressant mechanisms are poorly understood (Otte et al, 2016). Previous studies on depression have largely focused on neuronal mechanisms and neural loops (Fang et al, 2021; Malberg et al, 2021). In recent years, growing evidence has shown that glial cells are involved in the pathogenesis of depression (Rial et al, 2015; Czéh and Nagy, 2018; Durkee et al, 2021) and could hold the key for its diagnosis and prevention
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