[The interplay between inflammation and metabolism in chronic stress pathophysiology]

Depression is among the most burdensome diseases worldwide, yet treatment resistance and frequent relapse after remission remain common, underscoring the need for therapies with novel mechanisms of action. Inflammation in both the central nervous system and the periphery has attracted attention as a key pathophysiological mechanism, and lipid mediators that promote or resolve inflammation have been implicated in its regulation. Studies using the chronic social defeat stress model have shown that microglial activation controls depression-related behaviors through pathways that differ across distinct brain regions. Because stress susceptibility varies markedly among individuals, resolving the underlying mechanisms requires stratification of animals based on quantitative, multidimensional behavioral analysis. These central inflammatory processes are closely linked to alterations in the peripheral immune system. Notably, the inflammatory responses of immune cells are finely regulated not only by lipid mediators but also by core intracellular metabolic pathways such as glycolysis and the TCA cycle. This immunometabolic perspective suggests that systemic and brain metabolic states constitute a fundamental basis governing the function of glia and neurons. Furthermore, disruption of brain energy-metabolic homeostasis associated with chronic stress and aging has been implicated in cognitive decline, making it a key future challenge to capture such metabolic alterations in a cell-type- and spatially specific manner, clarifying in which cell types and at what timing they occur. Focusing on inflammatory mechanisms and metabolic homeostasis across the brain and periphery as a unifying perspective on chronic stress, depression, and age-related cognitive decline, this review summarizes current knowledge and discusses future research directions.