Numerous reports, including the Epidemiology of LUTS (EpiLUTS) study, support an association between urinary dysfunction and mood disorders such as depression and anxiety.  Regarding benign prostatic hyperplasia, patients with a concurrent diagnosis of clinical depression have a higher rate of reported LUTS while patients with significant BPH symptoms are more likely to develop depression.  This suggests a bidirectional relationship between urinary dysfunction and mood disorders, but a causative mechanism has never been postulated. 
Critically, inflammation in areas of the brain are well-established to cause mood disorders such as depression. Recent breakthroughs demonstrate that a local inflammatory response in a peripheral organ can trigger an inflammatory response in the brain, particularly the hippocampus, and this is mediated through the NLRP3 inflammasome. The NLRP3 inflammasome is a multimeric complex that senses Damaged Associated Molecular Patterns (DAMPS) and send out an inflammatory response by activating caspase-1 to cleave pro-IL-1β into its active form and promote its release, where it acts as a strong pro-inflammatory cytokine. 
 A previous study from our laboratory demonstrated that chemical cystitis (cyclophosphamide-induce hemorrhagic cystitis) elicits NLRP3-dependent inflammation in the hippocampus in rats and was associated with depressive behavior.  Since BOO, a much clearer and pathologically relevant bladder-centric insult, also evokes a local inflammatory response in the bladder, we hypothesize that it will also induce inflammation in the hippocampus and mood disorders and will do so in an NLRP3-dependent manner.  Here, we investigate this hypothesis and define an immunologically driven bladder-brain axis.

Female rats were divided into 4 groups: control, sham, BOO or BOO + gly (glyburide; an NLRP3 inhibitor). BOO was created by urethral ligation over a 1 mm transurethral catheter. Glyburide was provided by subcutaneous pellet (50 mg, 21 day release, replaced as needed). Rats were analyzed 12 weeks post-op. Hippocampal inflammation was quantitated by Evan’s blue extravasation. Microglia and neurogenesis by IbA-1 and Ki-67 staining, respectively.  Depression was assessed by open field and sucrose preference tests. As an additional control for the mood disorder assays a separate group of BOO rats were provided with fluoxetine (an antidepressant) in the drinking water (0.50 mg/ml) for the last 4 weeks of the experiment. Fluoxetine concentration was adjusted twice weekly to insure ≈20 mg/kg/day.

As shown in Figure 1, there was an increase in inflammation (Evans blue) in the hippocampus in BOO rats which was blocked by glyburide. To confirm this result we quantitated the density of microglia (activated immune cells) in the fascia dentate, which is the critical brain location first identified in our cyclophosphamide mood disorder studies. BOO was accompanied by an increase in activated microglia and this change was reduced back to control levels by glyburide. 
In the hippocampus BOO also caused a significant decrease in neurogenesis (Ki-67+ cells). Decreases in neurogenesis, and more generally plasticity, in the hippocampus have been directly linked with neuroinflammation and depression and it is thought that these changes may lead to permanent, or at least long lasting, changes in cognitive function or mood.  This decrease was also blocked by glyburide.
To assess mood disorders we performed the open field (a measure of anxiety) and sucrose preference (a measure of anhedonia) assays. As shown in Figure 2, there was a decrease in exploratory behavior in the open field behavioral assay and a decrease in sucrose preference in the BOO rats, both of which are signs of mood disorders such as depression. Like inflammation, these symptoms were diminished to control values by glyburide. These behaviors were also blocked by the anti-depressant fluoxetine.

BOO, a bladder-localized event, stimulates NLRP3-dependent inflammation in the hippocampus of rats after 12 weeks and depressive behavior indicative of mood disorders in behavioral studies.

This study provides the first-ever causative explanation of the previously anecdotal link between BOO and mood disorders.

Coyne, K. S., Wein, A. J., Tubaro, A. et al.: The burden of lower urinary tract symptoms: evaluating the effect of LUTS on health-related quality of life, anxiety and depression: EpiLUTS. BJU Int, 103 Suppl 3: 4, 2009