Microglia mediate sex-dependent memory deficits in pelvic pain

Chronic pain is associated with memory deficits clinically and in animal models. Similarly, interstitial cystitis/bladder pain syndrome (IC/BPS) afflicts patients with severe chronic pelvic pain and urinary dysfunction as well as cognitive effects, including anxiety/depression and patient-reported memory deficits. In a genetic model of IC/BPS, mice deficient for the lipase acyloxyacyl hydrolase (AOAH) mimic key symptoms, including rodent correlates of chronic pelvic pain and anxiety/depression. Recently, we observed that pelvic pain of female AOAH-deficient mice is associated with microglial activation in the prefrontal cortex and paraventricular nucleus, and pain is dependent upon microglia. Because chronic pain is associated with memory deficits and microglia support learning and memory, we hypothesized that chronic pelvic pain is associated with memory deficits in IC/BPS models. In the hippocampus, we observed microglia in the dentate gyrus of AOAH-deficient females that exhibited a hyper-ramified morphology with increased branching, number of endpoints, and process length. In contrast, dentate gyrus microglia of AOAH-deficient males had an amoeboid morphology. Using specific memory tests, female AOAH-deficient mice exhibited deficits in both spatial and recognition memory relative to wild-type controls, whereas males had a modest phenotype. Depleting microglia pharmacologically with an antagonist of colony-stimulating factor-1 receptor resolved the deficit in recognition memory but did not improve spatial memory in females and had no significant effect in males. Overall, these data suggest a role for microglial modulation of cognitive function in pelvic pain that is sex-specific and thus identify a potential target for treating cognitive symptoms in female patients.NEW & NOTEWORTHY Interstitial cystitis/bladder pain syndrome (IC/BPS) afflicts patients with debilitating pelvic pain, voiding dysfunction, and cognitive deficits, but effective therapies are lacking. Using acyloxyacyl hydrolase-deficient mice as a genetic model of IC/BPS, we previously showed that microglia mediate pelvic pain and now show that microglia mediate sex-specific memory deficits. These findings identify microglia as potential therapeutic targets for pain and cognitive dysfunction in IC/BPS.