**2. Microglia and stress**

Some studies have reported that stress promoted the production and release of cytokines by microglia, while others have reported that it suppressed them. It seems to depend on the type and intensity of stress and the brain region where microglia are present. Water immersion restraint stress is a stress paradigm in which mice are confined to a conical tube and then immersed in water to the chest level. Ohgidani et al. reported that a single water immersion restraint stress for 2 h increased the production of tumor necrosis α (TNF-α), an inflammatory mediator, from microglia in the mouse hippocampus [4]. Chronic unpredictable stress (CUS) is a stress paradigm in which multiple stressors are applied daily, including cage rotation, radio noise, food or water deprivation, light on or off all day, single breeding, overcrowding, no bedding, and wet bedding. Wholeb et al. reported that 14-day chronic unpredictable stress reduced the production of TNF-α and interleukin-1β (IL-1β) in microglia in the mouse prefrontal cortex [5].

Increased production of damage-associated molecular patterns (DAMPs) in the brain such as high-mobility group box 1 (HMGB1), heat-shock protein 72 (HSP72), and ATP is a pivotal molecular mechanism by which stress promotes cytokine release from microglia. These DAMPs bind to toll-like receptors (TLRs) on microglial cell membranes to induce nuclear factor-κB (NF-κB) and increase the production of pro-IL-1β, IL-6, and TNF-α. In addition, DAMPs activate nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain protein 3 (NLRP3) inflammasomes in microglia that act on pro-IL-1β processing to increase IL-1β production [6]. Stress activates the hypothalamus-pituitary-adrenal (HPA) axis and sympathetic nerves, then glucocorticoid and noradrenaline increase in the brain. It is proposed that both glucocorticoid and noradrenaline regulate cytokine release from microglia, but their effects on microglia are complex. Glucocorticoid is considered to suppress

*Stress, Microglial Activation, and Mental Disorders DOI: http://dx.doi.org/10.5772/intechopen.103784*

cytokine release from microglia through suppression of NF-κB. On the other hand, a few studies have shown that administration of glucocorticoid to the hippocampus after inducing inflammation by kainic acid increased inflammatory cytokines and the number of microglia in the hippocampus [7, 8]. CXCR1 and CD200R are receptors that are expressed in microglia and act in a direction that suppresses microglial inflammatory changes. Glucocorticoid promotes inflammatory responses in microglia to future stress by reducing CXCR1 and CD200R expression and increasing HMGB1 release, which is referred microglial priming [6]. Noradrenaline acts on the β-receptor of microglia to promote their activation and stimulate cAMP/protein kinase leading to the release of IL-1β. On the other hand, when noradrenaline acts on the α-receptor of microglia, it works in the direction of suppressing their activation [9].

Brain-derived neurotrophic factor (BDNF), which is released from neurons and microglia, is involved in neurogenesis and neurite branching. It has been reported

**Figure 1.** *Schematic of the proposed molecular mechanism by which stress influences microglia.*

that various stress paradigms such as repeated restraint stress and CUS reduce BDNF expression in the hippocampus and prefrontal cortex of rodents [10, 11]. A recent study reported that when CUS was loaded into a rat model of stroke, CUS reduced BDNF release from microglia in the amygdala [12]. One of the possible mechanisms of this microglial-derived BDNF decrease is the decrease in binding of the cAMP response element-binding protein to the promoter region of the BDNF gene due to overactivation of NF-κB [13].

It has recently been suggested that the phagocytic capacity of microglia is also affected by stress. Several studies have reported that 14-day CUS increased the uptake of neuronal structures, including synapses, by microglia in the hippocampus and medial prefrontal cortex [5, 14, 15]. A recent study in which male mice were loaded with CUS extended to 28 days observed no increase of uptake of neuronal structures by microglia at 28-day loading despite an increase at 14-day loading [16]. This result indicates that repeated stress exposure changes microglial function dynamically. In addition to CUS, the effects of restraint stress exposure on microglial phagocytosis have been investigated. Piirainen et al. found that 10-day restraint stress enhanced the phagocytosis of pre-glutamatergic synapses by CD206-positive microglia in the hippocampus and reduced microglial-synaptic contact in the amygdala [17]. In another study with 7-day restraint, stress loading showed increased rat microglial process branching and contacts between microglial processes and synapses, using two-photon microscopy [18]. As a molecular mechanism behind stress-enhanced microglial synaptic phagocytosis, a pathway in which an increase in glucocorticoid enhances phagocytosis via a colony-stimulating factor 1 (CSF1) signal has been reported [15]. Given that CX3CR1 knockout mice were shown to inhibit stress-enhanced microglial phagocytosis [14], CX3CL1/CX3CR1 signaling may also be one of the candidates of the mechanism. We summarize the molecular mechanisms above mentioned in **Figure 1**.
