Amygdala Oligodendrocyte MDH1 Dysregulation and Mitochondrial Dysfunction in High Urea‐Induced Anxiety‐Like Behavior

ABSTRACT The high incidence and mortality rates of anxiety disorders in patients with chronic kidney disease (CKD) have drawn attention. Prior studies identified urea as an independent risk factor for mental disorders in CKD. While urea accumulation is known to impair synaptic plasticity, its effects on glial cells remain unclear. How urea influences oligodendrocyte lineage differentiation may represent a critical node in neuron–glia interactions. Previous studies have shown that OL‐lineage cells may be underrepresented in scRNA‐seq datasets. We selected amygdala tissue from wild‐type and high‐urea (UT‐B − / − ) mice and performed single‐nucleus RNA sequencing (snRNA‐seq), behavioral tests, and cellular experiments to delineate the impact of urea on oligodendrocyte lineage dynamics. In UT‐B − / − mice, the relative abundance of oligodendrocyte subpopulations enriched for mitochondrial transcripts decreased, suggesting vulnerability to urea toxicity. Dlat and MDH1, genes associated with TCA cycle‐related metabolism, were downregulated alongside alterations in mitochondrial and oxidative phosphorylation‐related transcriptional programs. Urea dose‐dependently decreased MDH1 expression, mitochondrial membrane potential, and intracellular ATP content in MO3.13 cells. Regulatory analyses linked MDH1 to energy metabolism and neurodegenerative pathways. Trajectory reconstruction suggested altered differentiation‐ and myelination‐related transcriptional programs in mitochondria‐related oligodendrocytes (MitOLs). The cytoplasmic concentration and fate of oxaloacetic acid (OAA) are regulated by the reversible catalysis of MDH1. OAA supplementation partially restored amygdalar MDH1 expression and alleviated anxiety‐like behaviors in UT‐B − / − mice, while improving mitochondrial bioenergetics in urea‐exposed MO3.13 cells. These findings support a candidate metabolic–glial model linking elevated urea, MDH1 dysregulation, oligodendrocyte bioenergetic dysfunction, and anxiety‐like behavior, with potential relevance to CKD‐associated anxiety.