Chronic glucocorticoid exposure disrupts lactate homeostasis and hippocampal neurogenesis by reducing cerebrovascular monocarboxylate transporter 1, leading to behavioral abnormalities in mice

Prolonged glucocorticoid elevation is strongly associated with brain dysfunction and the pathogenesis of stress-related disorders, including several psychiatric disorders. Elevated lactate levels have been reported in the brains of patients with psychiatric disorders and animal models of chronic stress and psychiatric disorders. Prolonged glucocorticoid elevation may disrupt brain lactate homeostasis, but the mechanisms through which this occurs and the pathological significance of the disruption are incompletely understood. Here, we show that chronic corticosterone (CORT) treatment increases lactate in the hippocampus and reduces monocarboxylate transporter 1 (MCT1) expression in hippocampal cerebrovascular endothelial cells. Cerebrovascular-specific overexpression of MCT1 reduced hippocampal lactate accumulation and ameliorated impaired hippocampal neurogenesis, depression-like behavior, and cognitive impairment in chronically CORT-treated mice. Conversely, knockdown of cerebrovascular MCT1 expression increased lactate accumulation in the hippocampus and caused impaired hippocampal neurogenesis and cognitive impairment. These findings suggest that chronic glucocorticoid elevation induces lactate accumulation via dysregulation of cerebrovascular lactate transport, thereby impairing neurogenesis and inducing behavioral abnormalities. This mechanism may contribute to stress-related brain dysfunction and the pathogenesis of psychiatric disorders.