Blockade of Indoleamine 2, 3-dioxygenase 1 ameliorates hippocampal neurogenesis and BOLD-fMRI signals in chronic stress precipitated depression

• Published in: Aging (Albany, NY.) Vol. 13; no. 4; pp. 5875 - 5891
• Main Authors: Gao, Lei, Gao, Tingting, Zeng, Ting, Huang, Peng, Wong, Nai-Kei, Dong, Zhaoyang, Li, Yunjia, Deng, Guanghui, Wu, Zhiyong, Lv, Zhiping
• Format: Journal Article
• Language: English
• Published: United States Impact Journals 11.02.2021
• Subjects: Animals; Brain-Derived Neurotrophic Factor - metabolism; Depression - diagnostic imaging; Depression - drug therapy; Depression - etiology; Depression - metabolism; Dorsal Raphe Nucleus - metabolism; Drug Evaluation, Preclinical; Hippocampus - diagnostic imaging; Hippocampus - drug effects; Hippocampus - metabolism; Indoleamine-Pyrrole 2,3,-Dioxygenase - antagonists & inhibitors; Indoleamine-Pyrrole 2,3,-Dioxygenase - metabolism; Magnetic Resonance Imaging; Mice; Mice, Inbred C57BL; Neurogenesis - drug effects; Oximes - pharmacology; Oximes - therapeutic use; Research Paper; Stress, Psychological - complications; Stress, Psychological - metabolism; Sulfonamides - pharmacology; Sulfonamides - therapeutic use; Tryptophan - metabolism; Tryptophan Hydroxylase - metabolism; dorsal raphe nucleus; neurogenesis; depression; blood oxygen level-dependent signal; IDO1
• ISSN: 1945-4589; 1945-4589
• DOI: 10.18632/aging.202511

Indoleamine 2, 3-dioxygenase 1 (IDO1) has been implicated in the pathogenesis of depression, though its molecular mechanism is still poorly understood. We investigated the molecular mechanism of IDO1 in depression by using the chronic unpredictable mild stress (CUMS) model in mice and WT mice. The brain blood oxygen level dependent (BOLD) signals in mice were collected by functional magnetic resonance imaging (fMRI) technology. IDO1 inhibitor INCB024360 was intervened in dorsal raphe nucleus (DRN) through stereotactic injection. We found an elevation of serum IDO1 activity and decreased 5-HT in CUMS mice, and the serum IDO1 activity was negatively correlated with 5-HT level. Consistently, IDO1 was increased in hippocampus and DRN regions, accompanied by a reduction of hippocampal BDNF levels in mice with CUMS. Specifically, pharmacological inhibition of IDO1 activity in the DRN alleviated depressive-like behaviour with improving hippocampal BDNF expression and neurogenesis in CUMS mice. Furthermore, ablation of exerted stress resistance and decreased the sensitivity of depression in CUMS mice with the stable BOLD signals, BDNF expression and neurogenesis in hippocampus. Thus, IDO1 hyperactivity played crucial roles in modulating 5-HT metabolism and BDNF function thereby impacting outcomes of hippocampal neurogenesis and BOLD signals in depressive disorder.