Primary open-angle glaucoma (POAG) is a leading cause of irreversible blindness. Magnetic resonance imaging (MRI) studies report an association between POAG and nonvisual pathway alterations. Locus coeruleus (LC) is a major source of norepinephrine released in the brain, and norepinephrine can reduce intraocular pressure via increasing aqueous outflow. This study aimed to investigate the relationship between glaucoma and the LC in patients with POAG and animal models. Resting-state functional MRI was performed using a 3-Tesla MR scanner with an eight-channel phased-array head coil, and MRI data were analyzed. A rat model of chronic glaucoma was generated by episcleral vein ligation and cauterization. DBA/2J mice that develop glaucoma with age were also acquired. Immunohistochemistry and immunofluorescence staining were used to investigate LC tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (D beta H) expression, as well as cell apoptosis by terminal deoxynucleotidyl transferase dUTP Nick-End Labeling staining. Patients with POAG showed significantly increased amplitude of low-frequency fluctuation (ALFF) in the LC compared with controls. LC ALFF values showed significant correlations with cup-to-disk ratio, retinal nerve fiber layer thickness, and visual function (P < 0.05). Functional connectivity (FC) between the LC and frontal and insular lobes was reduced, but elevated between the LC and parahippocampal gyrus, compared with controls. Glaucoma animal models revealed reduced expression of TH and D beta H in the LC, and increased cell apoptosis. In this study, we provide novel evidence for the relationship between the LC and glaucoma. The LC may act as a network in POAG pathogenesis and intraocular pressure regulation. (C) 2018 IBRO. Published by Elsevier Ltd. All rights reserved.