AIMS: Reports link urinary dysfunction and mood disorders, such as depression, but a causative mechanism has never been postulated. Contemporary discoveries demonstrate a local inflammatory response in peripheral organs can trigger inflammation in the brain, particularly the hippocampus, mediated through the NLRP3 inflammasome. Critically, central inflammation causes depressive behavior. Since bladder outlet obstruction (BOO) evokes a local inflammatory response in the bladder, we hypothesize it will induce NLRP3-dependent inflammation in the hippocampus and depressive behavior. METHODS: There were four groups of rats: control, sham, BOO, or BOO + glyburide (an NLRP3 inhibitor). BOO was created by urethral ligation over a 1 mm catheter. Sham was tied loosely. Glyburide was provided by slow-release pellet (subcutaneous 50 mg, 21 day, replaced as needed). Rats were analyzed 12 weeks post-op for: hippocampal inflammation, microglial density, neurogenesis, and depression symptoms (open field and sucrose preference). RESULTS: BOO elicited hippocampal inflammation, accompanied by an increase in activated microglia (22%) and a decrease in neurogenesis (35%), which was blocked by glyburide. In addition, BOO rats displayed anxiety (57% decrease in exploratory behavior in the open field assay) and anhedonia (21% decrease in sucrose preference), two symptoms of depression. Like inflammation, these symptoms were diminished by glyburide to levels not statistically significantly different from controls. CONCLUSIONS: BOO, a bladder-localized event, stimulates NLRP3-dependent inflammation in the rat hippocampus after 12 weeks and this inflammation causes depressive behavior. This is the first mechanistic explanation of the link between BOO and depression and provides evidence for a distinct bladder-brain axis.
AIMS: Reports link urinary dysfunction and mood disorders, such as depression, but a causative mechanism has never been postulated. Contemporary discoveries demonstrate a local inflammatory response in peripheral organs can trigger inflammation in the brain, particularly the hippocampus, mediated through the NLRP3 inflammasome. Critically, central inflammation causes depressive behavior. Since bladder outlet obstruction (BOO) evokes a local inflammatory response in the bladder, we hypothesize it will induce NLRP3-dependent inflammation in the hippocampus and depressive behavior. METHODS: There were four groups of rats: control, sham, BOO, or BOO + glyburide (an NLRP3 inhibitor). BOO was created by urethral ligation over a 1 mm catheter. Sham was tied loosely. Glyburide was provided by slow-release pellet (subcutaneous 50 mg, 21 day, replaced as needed). Rats were analyzed 12 weeks post-op for: hippocampal inflammation, microglial density, neurogenesis, and depression symptoms (open field and sucrose preference). RESULTS: BOO elicited hippocampal inflammation, accompanied by an increase in activated microglia (22%) and a decrease in neurogenesis (35%), which was blocked by glyburide. In addition, BOO rats displayed anxiety (57% decrease in exploratory behavior in the open field assay) and anhedonia (21% decrease in sucrose preference), two symptoms of depression. Like inflammation, these symptoms were diminished by glyburide to levels not statistically significantly different from controls. CONCLUSIONS: BOO, a bladder-localized event, stimulates NLRP3-dependent inflammation in the rat hippocampus after 12 weeks and this inflammation causes depressive behavior. This is the first mechanistic explanation of the link between BOO and depression and provides evidence for a distinct bladder-brain axis.
Authors: Fernanda N Kaufmann; Ana Paula Costa; Gabriele Ghisleni; Alexandre P Diaz; Ana Lúcia S Rodrigues; Hugo Peluffo; Manuella P Kaster Journal: Brain Behav Immun Date: 2017-03-02 Impact factor: 7.217
Authors: Jesse A Stokum; Kaspar Keledjian; Erik Hayman; Jason K Karimy; Adam Pampori; Ziyan Imran; Seung Kyoon Woo; Volodymyr Gerzanich; J Marc Simard Journal: Behav Brain Res Date: 2017-06-27 Impact factor: 3.332
Authors: Robin Lütolf; Francis M Hughes; Brian M Inouye; Huixia Jin; Jennifer C McMains; Elena S Pak; Johanna L Hannan; J Todd Purves Journal: Neurourol Urodyn Date: 2017-10-06 Impact factor: 2.696
Authors: Mohamed Lamkanfi; James L Mueller; Alberto C Vitari; Shahram Misaghi; Anna Fedorova; Kurt Deshayes; Wyne P Lee; Hal M Hoffman; Vishva M Dixit Journal: J Cell Biol Date: 2009-10-05 Impact factor: 10.539
Authors: Nathan A Hirshman; Francis M Hughes; Huixia Jin; William T Harrison; Simon W White; Isabelle Doan; Shelby N Harper; Patrick D Leidig; J Todd Purves Journal: Am J Physiol Renal Physiol Date: 2019-12-23
Authors: Francis M Hughes; Shelby N Harper; Brent D Nosé; Armand Allkanjari; Michael T Zheng; Huixia Jin; J Todd Purves Journal: Am J Physiol Renal Physiol Date: 2021-08-16