1-methyltryptophan treatment ameliorates high-fat diet induced depression in mice through reversing perineuronal nets changes

Abstract Depression and obesity are prevalent disorders that have significant public health implications. To investigate the mechanism underlying high-fat diet (HFD)-induced depression-like behaviors, we used a mouse model of HFD-induced obesity. The HFD-induced obese mouse exhibited a depression-like phenotype in behavioral assays, as well as a reduction in hippocampus volume. These phenotypes were reversed by treating HFD mice with the indoleamine 2,3-dioxygenase (IDO) inhibitor 1-methyltryptophan (1-MT). Interestingly, no changes in IDO levels were observed post 1-MT treatment, suggesting that the anti-depressive effect of 1-MT has an IDO-independent mechanism. To clarify the mechanism of 1-MT in reversing HFD-induced depression-like behaviors, we conducted RNA sequencing analysis which showed a significant enrichment of shared differential genes in the extracellular matrix (ECM) organization pathway between the 1-MT-treated and untreated HFD-induced depression mice. Therefore, we hypothesized that changes in ECM play a crucial role in the anti-depressive effect of 1-MT. To this end, we investigated perineuronal nets (PNNs), which are ECM assemblies that preferentially ensheath parvalbumin (PV)-positive interneurons and are involved in many abnormalities. We found that HFD is associated with excessive accumulation of PV-positive neurons and the upregulation of PNNs, which, in turn, affect synaptic transmission in PV-positive neurons and lead to glutamate-gamma-aminobutyric acid imbalances in the hippocampus. 1-MT effectively reversed these changes, highlighting an IDO-independent mechanism by which 1-MT exerts its anti-depressive effect.