Microglia Loss Contributes to the Development of Major Depression Induced by Different Types of Chronic Stresses

Abstract

Recently, the loss and dystrophy of hippocampal microglia induced by chronic unpredictable stress (CUS) has been reported to mediate the development of major depression in mice whose microglial cells were labeled with enhanced green fluorescent protein-conjuncted-CX3C receptor type 1. However, whether this happens in endogenous microglia with no genetic intervention remains unclear. Here, we addressed this issue in mice treated with different types of chronic stresses, including the CUS, chronic restraint stress (CRS) and chronic social defeat stress (CSDS). Results showed that the cellular numbers, process lengths, soma areas and activation markers of endogenous hippocampal but not cortical microglia, were markedly reduced by CUS, CRS and CSDS treatment. Administration of mice with two classical stimulators of microglia, lipopolysaccharide (LPS) or macrophage colony-stimulating factor (M-CSF), reversed the CUS-, CRS- and CSDS-induced reductions in endogenous hippocampal microglial numbers, and also improved the CUS-, CRS- or CSDS-induced behavioral abnormalities, including the increases in the immobile time in the forced swimming test and tail suspension test, the inhibition of sucrose preference, and the decrease in the time spent in the center of open field. Furthermore, inhibition of the initial activation of hippocampal microglia by minocycline pretreatment also reversed the reduction in hippocampal microglial numbers as well as the behavioral abnormalities induced by CUS, CRS and CSDS treatment. These results provide compelling evidences to show that different types of chronic stresses can trigger the loss of endogenous hippocampal microglia and restoration of microglial numbers may have therapeutic values in major depression.

Microglia: An Interface between the Loss of Neuroplasticity and Depression

“…Overexpression of proinflammatory cytokines in microglia is one of the primary factors responsible for the development of depression in diverse situations (Volpato et al, 2001 ; Avitsur et al, 2005 ; Il'yasova et al, 2005 ; De Rekeneire et al, 2006 ; Dunn, 2006 ; Kumagai et al, 2007 ; You et al, 2011 ; Stannus et al, 2013 ; Fenn et al, 2014 ). The related underlying factors include inflammation of neurons (Kumagai et al, 2007 ), neurodegeneration and apoptosis (Cacci et al, 2005 ; Kumagai et al, 2007 ), impaired neurogenesis (Kempermann and Neumann, 2003 ; Sierra et al, 2014 ), production of stress proteins (Goshen et al, 2008 ; Berry et al, 2012 ; Ramirez et al, 2016 ; Tong et al, 2017 ), alteration in brain tryptophan (Bosnyák et al, 2015 ; Dantzer, 2016 ; Parrott et al, 2016 ; Liu et al, 2017 ), and neurotrophins metabolisms (Zhang et al, 2008 ; Ye et al, 2011 ; Ferrini and De Koninck, 2013 ), as well as morphological and functional changes in microglia itself (Fenn et al, 2014 ), all leading to depression. Also, instead of acting directly, microglia may first activate the inflammasomes in more glial cells, in turn releasing an IL-1 family of cytokines, causing neuroinflammation and depression (Arend et al, 2008 ; Chakraborty et al, 2010 ; Alcocer-Gómez et al, 2013 ; Zhang Y. et al, 2014 ), and this could be an ongoing process in psychiatric patients (Hohmann et al, 2014 ).…”

“…Recent studies have established a causal relationship between the stress-related life events/chronic stress and depressive-like behavior in mice (Goshen et al, 2008 ; Berry et al, 2012 ). Indeed, chronic unpredictable mild stress (CUMS) has been shown to cause neuroinflammation and subsequently depression in several studies (Farooq et al, 2012 ; Ramirez et al, 2016 ; Tong et al, 2017 ). Microglial dysfunction has been implicated in chronic unpredictable stress-induced neuroinflammation and depression-like condition in rodents (Kreisel et al, 2014a ).…”

“…While over expressed microglia trigger the onset of depression through the neuroinflammatory pathway as mentioned before, under expressed microglia could result in depression through hippocampal degeneration pathway. Chronic form of stressors, for example chronic unpredictable stress, chronic restraint stress, and chronic social defeat stress have all lead to depression through reduction in the number of hippocampal microglia (Tong et al, 2017 ). On the other hand, rats exposed to learned helplessness showed increase in the number of activated microglia in the granule cell layer, hilus, CA1, and CA3 regions of the hippocampus (Iwata et al, 2016 ).…”

Human Interleukin-34 facilitates microglia-like cell differentiation and persistent HIV-1 infection in humanized mice

“…Although both are the ligands for CSF1 receptor (CSF1R), differentiation of bone marrow (BM)-derived progenitor cells from monocytes to tissue macrophages and dendritic cells require CSF-1. IL-34, in contrast is required specifically for the development of microglia and Langerhans cells [15][16][17]. The existing immunodeficient transgenic mouse strains that express human CSF-1 [18,19] do not support human microglial development following human HSPC reconstitution (our unpublished observation).…”

Social defeat stress: Mechanisms underlying the increase in rewarding effects of drugs of abuse

“…), which when stimulated, induce proliferation, recruitment of monocytes from the peripheral blood, release of pro‐inflammatory cytokines and expression of several cell surface antigens (e.g., Iba1; Kettenmann et al., ; Wohleb, Powell, Godbout, & Sheridan, ). The well‐known stress‐induced depression effect induced through microglial activation (Tong et al., ) is hypothesized to involve inflammation of neurons, neurodegeneration and apoptosis, impaired neurogenesis, production of stress proteins, or alteration in neurotrophin metabolisms (see Singhal and Baune, ).…”