Convergent Microglial and Astrocytic Responses across Diverse Stress Paradigms: Integrating Inflammation, Metabolism,...

The central nervous system responds to diverse challenges through convergent glial mechanisms, yet most reviews examine single stressor paradigms in isolation. This review uniquely integrates current knowledge across five major stress categories (psychosocial, immune/inflammatory, infectious, injury/damage, and metabolic), revealing both shared pathways and stimulus-specific glial responses that have not been systematically compared. Because microglia and astrocytes are the principal immune-metabolic sensors mediating these responses, this review is centered on these two cell types, while acknowledging that oligodendrocytes, oligodendrocyte precursor cells, and ependymal cells also participate in stress-related glial pathology, particularly with respect to white matter and cerebrospinal fluid homeostasis. While all stressors activate common inflammatory cascades including NF-κB signaling, complement activation, and inflammasome assembly, they elicit distinguishable molecular signatures. For instance, psychosocial stress uniquely engages type I interferon responses driving microglial synapse elimination. Viral infections produce severe metabolic reprogramming, hijacking host metabolism to support viral replication while depleting cellular NAD+ and ATP. Autoimmune inflammation generates lipid-laden disease-associated microglia with upregulated cholesterol metabolism genes. Unlike previous reviews focusing solely on inflammation or metabolism, we emphasize their bidirectional integration as a unifying principle. Inflammatory signals trigger metabolic shifts toward aerobic glycolysis, generating lactate serving dual functions as neuronal fuel and inflammatory mediator. This metabolic reprogramming, orchestrated by pyruvate dehydrogenase kinase, hypoxia-inducible factor-1α, and mTOR, creates feedback loops linking glial dysfunction to neuronal alterations. Complement-mediated synaptic pruning, disrupted neuron-glia metabolic coupling, and impaired neurotrophic support converge to produce depression, cognitive impairment, and sickness behaviors. Individual variability reflects interactions among genetic factors, sex, age, and blood-brain barrier integrity. This cross-paradigm comparative approach identifies high-value therapeutic targets applicable across multiple conditions rather than single diseases. We propose integrated intervention strategies simultaneously targeting inflammatory and metabolic pathways, guided by single-cell profiling for personalized medicine tailored to individual patient molecular signatures. We further discuss the conceptual overlaps inherent to the five-category classification scheme adopted here and outline the limitations of extrapolating across heterogeneous stress paradigms, glial cell types, and species.