Microglial Responses to Stress-Induced Depression: Causes and Consequences

Abstract

Chronic stress is a major risk factor for various psychiatric diseases, including depression; it triggers various cellular and structural changes, resulting in the alteration of neurocircuitry and subsequent development of depression. Accumulating evidence suggests that microglial cells orchestrate stress-induced depression. Preclinical studies of stress-induced depression revealed microglial inflammatory activation in regions of the brain that regulate mood. Although studies have identified several molecules that trigger inflammatory responses in microglia, the pathways that regulate stress-induced microglial activation remain unclear. Understanding the exact triggers that induce microglial inflammatory activation can help find therapeutic targets in order to treat depression. In the current review, we summarize the recent literature on possible sources of microglial inflammatory activation in animal models of chronic stress-induced depression. In addition, we describe how microglial inflammatory signaling affects neuronal health and causes depressive-like behavior in animal models. Finally, we propose ways to target the microglial inflammatory cascade to treat depressive disorders.

Keywords: chronic stress; depression; microglia; neuroinflammation; proinflammatory cytokines.

Figure 1

Triggers and role of microglial inflammatory activation in the pathogenesis of depression. Chronic psychosocial stress can increase hyperactivity of the hypothalamic-pituitary-adrenal axis, activation of peripheral immune cells, and release of damage-associated molecular patterns (DAMPs). Stress can also disturb communication between microglia and neurons that regulate microglial immune responses. Inflammatory signaling in microglia increases the expression of proinflammatory cytokines and the generation of reactive oxygen species (ROS). Inflammatory microglia also show decreased neurotrophic signaling, which hampers the release of brain-derived neurotrophic factor (BDNF) from microglia. These changes culminate in neuronal damage, including decreased neurogenesis, dendritic spine density, and impaired synaptic plasticity, leading to depression. ↓, decrease; ↑, increase; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; IL, interleukin; C1q, complement component 1q; TNF, tumor necrosis factor; MeCP2, methyl-CpG binding protein 2; CREB, cAMP response element binding protein; ERK, extracellular signal-regulated kinase; PPAR-γ, peroxisome proliferator-activated receptor gamma, NLRP3, nucleotide-binding domain, leucine-rich repeat, pyrin domain-containing protein 3.