Endometriosis leads to central nervous system-wide glial activation in a mouse model of endometriosis

Abstract

Background Chronic pelvic pain (CPP) is a common symptom of endometriosis. Women with endometriosis are also at a high risk of suffering from anxiety, depression, and other psychological disorders. Recent studies indicate that endometriosis can affect the central nervous system (CNS). Changes in the functional activity of neurons, functional magnetic resonance imaging signals, and gene expression have been reported in the brains of rat and mouse models of endometriosis. The majority of the studies thus far have focused on neuronal changes, whereas changes in the glial cells in different brain regions have not been studied. Methods Endometriosis was induced in female mice (45-day-old; n = 6–11/timepoint) by syngeneic transfer of donor uterine tissue into the peritoneal cavity of recipient animals. Brains, spines, and endometriotic lesions were collected for analysis at 4, 8, 16, and 32 days post-induction. Sham surgery mice were used as controls (n = 6/timepoint). The pain was assessed using behavioral tests. Using immunohistochemistry for microglia marker ionized calcium-binding adapter molecule-1 (IBA1) and machine learning “Weka trainable segmentation” plugin in Fiji, we evaluated the morphological changes in microglia in different brain regions. Changes in glial fibrillary acidic protein (GFAP) for astrocytes, tumor necrosis factor (TNF), and interleukin-6 (IL6) were also evaluated. Results We observed an increase in microglial soma size in the cortex, hippocampus, thalamus, and hypothalamus of mice with endometriosis compared to sham controls on days 8, 16, and 32. The percentage of IBA1 and GFAP-positive area was increased in the cortex, hippocampus, thalamus, and hypothalamus in mice with endometriosis compared to sham controls on day 16. The number of microglia and astrocytes did not differ between endometriosis and sham control groups. We observed increased TNF and IL6 expression when expression levels from all brain regions were combined. Mice with endometriosis displayed reduced burrowing behavior and hyperalgesia in the abdomen and hind-paw. Conclusion We believe this is the first report of central nervous system-wide glial activation in a mouse model of endometriosis. These results have significant implications for understanding chronic pain associated with endometriosis and other issues such as anxiety and depression in women with endometriosis. Graphical Abstract

Vitamin D and reproductive disorders: a comprehensive review with a focus on endometriosis

“…Researchers found that microglial cells in various regions of the brain were enlarged in a mouse model of endometriosis, indicating overall activation of these cells. This finding may have implications for understanding chronic pain and other neurological symptoms associated with endometriosis [ 218 ]. As the potential favorable effects of vitamin D in the context of neurological disorders [ 219 , 220 ], investigating the role of vitamin D in relieving neurologic complications related to endometriosis would be an active research area.…”

Digging deeper into pain – an ethological behavior assay correlating well-being in mice with human pain experience

“…It will be interesting to see how digging behaviors are affected by other models of visceral conditions associated with pain. Bashir and colleagues [4] have recently shown that mice undergoing a model of endometriosis are slower to burrow, from a tube filled with food pellets, than sham animals, however, both groups successfully clear the burrow within 24-hours. Such findings align with our argument that the burrowing assay is more task driven than digging.…”

Autocrine positive feedback of tumor necrosis factor from activated microglia proposed to be of widespread relevance in chronic neurological disease

“…The hallmark chronicity of this condition is consistent with the finding, discussed throughout this review, 2 of the TNF generated by activated microglia keeping these cells activated. Moreover, much evidence exists for microglial activation in this condition – particularly in experimental models, where it is very widespread 117 . It is also discussed in patient research 118,119 .…”

“…Moreover, much evidence exists for microglial activation in this condition – particularly in experimental models, where it is very widespread. 117 It is also discussed in patient research. 118 , 119 Should microglial activation become accepted as a key phenomenon in human endometriosis pain, an interest in perispinal administration of anti‐TNF therapy, as for post‐stroke pain, 17 , 53 is likely to be compelling.…”