Microglia are emerging as critical regulators of neuronal function and behavior in nearly every area of neuroscience. Initial reports focused on classical immune functions of microglia in pathological contexts, however, immunological concepts from these studies have been applied to describe neuro-immune interactions in the absence of disease, injury, or infection. Indeed, terms such as 'microglia activation' or 'neuroinflammation' are used ubiquitously to describe changes in neuro-immune function in disparate contexts; particularly in stress research, where these terms prompt undue comparisons to pathological conditions. This creates a barrier for investigators new to neuro-immunology and ultimately hinders our understanding of stress effects on microglia. As more studies seek to understand the role of microglia in neurobiology and behavior, it is increasingly important to develop standard methods to study and define microglial phenotype and function. In this review, we summarize primary research on the role of microglia in pathological and physiological contexts. Further, we propose a framework to better describe changes in microglia1 phenotype and function in chronic stress. This approach will enable more precise characterization of microglia in different contexts, which should facilitate development of microglia-directed therapeutics in psychiatric and neurological disease.

The semantics of microglia activation: neuroinflammation, homeostasis, and stress.

The emerging tale of microglia in psychiatric disorders.

Orofacial musculoskeletal pain: An evidence-based bio-psycho-social matrix model

Major depressive disorder (MDD) is a debilitating neuropsychological disorder, which has caused serious health and socio-economic burdens worldwide. A growing body of evidence indicates that inflated neuroinflammation and aberrant microglial activity are associated with depressive-like symptoms. In the central nervous system (CNS), microglia constantly survey the internal environment, playing crucial roles in injury response and pathogen defense. From developmental stage through the whole adult life, microglia dynamically sculpt neural circuits by modulation of synaptic plasticity or engulfment of redundant synapses. Dysregulated microglia may impact these fundamental biophysiological processes and contribute to the pathogenesis of depressive disorder. In this review, we discuss candidate mechanisms by which stress induces microglia to deviate from its fine-tuned homeostasis in clinical and preclinical studies. These triggering factors include the neuroendocrine system, the noradrenergic system, gut-brain axis, and unbalanced pro- v.s. anti-inflammatory milieu composed of diversified cytokines and neurotransmitters. We argue that functional changes in microglia can strongly influence neuronal network activity due to dysregulated secretion of cytokines and elevated release of neurotoxic metabolites, therefore contributing to the pathological outcomes in stress. Understanding the role that microglia play in the etiology of depression may provide a tantalizing therapeutic target and help with the development of novel intervention strategies against this devastating mental health problem. 

Stress induced microglial activation contributes to depression.

Increasing evidence supports the notion that neuroinflammation plays a critical role in the etiology of major depressive disorder (MDD), at least in a subset of patients. By virtue of their capacity to transform into reactive states in response to inflammatory insults, microglia, the brain’s resident immune cells, play a pivotal role in the induction of neuroinflammation. Experimental studies have demonstrated the ability of microglia to recognize pathogens or damaged cells, leading to the activation of a cytotoxic response that exacerbates damage to brain cells. However, microglia display a wide range of responses to injury and may also promote resolution stages of inflammation and tissue regeneration. MDD has been associated with chronic priming of microglia. Recent studies suggest that altered microglial morphology and function, caused either by intense inflammatory activation or by senescence, may contribute to depression and associated impairments in neuroplasticity. In this context, modifying microglia phenotype by tuning inflammatory pathways might have important translational relevance to harness neuroinflammation in MDD. Interestingly, it was recently shown that different microglial phenotypes are associated with distinct metabolic pathways and analysis of the underlying molecular mechanisms points to an instrumental role for energy metabolism in shaping microglial functions. Here, we review various canonical pro-inflammatory, anti-inflammatory and metabolic pathways in microglia that may provide new therapeutic opportunities to control neuroinflammation in brain disorders, with a strong focus on MDD.

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Microglial Inflammatory-Metabolic Pathways and Their Potential Therapeutic Implication in Major Depressive Disorder

Synaptic and behavioral effects of chronic stress are linked to dynamic and sex-specific changes in microglia function and astrocyte dystrophy.

Recent studies demonstrate that chronic unpredictable stress (CUS) drives microglia-mediated neuronal remodeling, contributing to synapse loss in the prefrontal cortex (PFC) and cognitive-behavioral dysfunction. Nonetheless, it remains unclear what mechanisms guide microglia-neuron interactions in stress. Evidence indicates that neuronal activity-dependent purinergic signaling directs microglial processes and microglia-synapse interaction via P2Y12, a purinergic receptor exclusively expressed by microglia in the brain. Stress exposure alters excitatory neurotransmission in the PFC, thus we aimed to determine if P2Y12 signaling promotes functional changes in microglia in the context of chronic stress. Using an activating DREADD, our initial studies showed that PFC microglia adopt a CUS-associated phenotype after repeated pyramidal neuronal activation. To further investigate the role of purinergic signaling, we used genetic (P2ry12-/-) or pharmacological (clopidogrel, ticagrelor) approaches to block P2Y12 in the context of CUS. Various behavioral, physiological, and cytometric endpoints were analyzed. Both P2Y12-deletion and treatment with clopidogrel prevented increases in forced swim test immobility and attenuated deficits in temporal object recognition following CUS. Flow cytometry of PFC microglia revealed that both P2ry12-/- mice and those treated with clopidogrel have significantly different phenotypes (independent of CUS); with diminished P2Y12 expression and altered surface levels of CX3CR1, CSF1R, and CD11b. Immunohistology in Thy1-GFP(M) mice demonstrated that pharmacological blockade of P2Y12 prevented stress-induced increases in the proportion of microglia with GFP+ neuronal inclusions and limited dendritic spine loss in the PFC. Together, these findings indicate that microglial P2Y12 is a critical mediator of stress-induced neuronal remodeling in the PFC and subsequent behavioral deficits.

Samuel C. Woodburn

Papers

The semantics of microglia activation: neuroinflammation, homeostasis, and stress.

Synaptic and behavioral effects of chronic stress are linked to dynamic and sex-specific changes in microglia function and astrocyte dystrophy.

Microglial P2Y12 mediates chronic stress-induced synapse loss in the prefrontal cortex and associated behavioral consequences in male mice

Timing is key for behavioural benefits of psychedelics