Sex differences in central nervous system plasticity and pain in experimental autoimmune encephalomyelitis

Abstract

Multiple sclerosis (MS) is a neurodegenerative autoimmune disease with many known structural and functional changes in the central nervous system. A well-recognized, but poorly understood, complication of MS is chronic pain. Little is known regarding the influence of sex on the development and maintenance of MS-related pain. This is important to consider, as MS is a predominantly female disease. Using the experimental autoimmune encephalomyelitis (EAE) mouse model of MS, we demonstrate sex differences in measures of spinal cord inflammation and plasticity that accompany tactile hypersensitivity. Although we observed substantial inflammatory activity in both sexes, only male EAE mice exhibit robust staining of axonal injury markers and increased dendritic arborisation in morphology of deep dorsal horn neurons. We propose that tactile hypersensitivity in female EAE mice may be more immune-driven, whereas pain in male mice with EAE may rely more heavily on neurodegenerative and plasticity-related mechanisms. Morphological and inflammatory differences in the spinal cord associated with pain early in EAE progression supports the idea of differentially regulated pain pathways between the sexes. Results from this study may indicate future sex-specific targets that are worth investigating for their functional role in pain circuitry.

Exogenous activation of tumor necrosis factor receptor 2 promotes recovery from sensory and motor disease in a model of multiple sclerosis

“…Whereas microglia were required for pain development in male mice, adaptive immune cells, like T cells mediated hypersensitivity in females (Sorge et al, 2015). Similar, a recent study proposed that tactile hypersensitivity in female EAE mice may be more immune-driven, whereas pain in male mice with EAE may rely more heavily on neurodegenerative and plasticity-related mechanisms (Catuneanu et al, 2019). This is in line with our data indicating that blocking T cell mediated neuroinflammation is therapeutic on female pain.…”

Profiling the microRNA signature of the peripheral sensory ganglia in experimental autoimmune encephalomyelitis (EAE)

“…To detect a transcriptional signature within the DRG of EAE mice, we performed next-generation sequencing (NGS) of DRGs taken from mice at the onset of the disease when pain hypersensitivity is evident [2, 3, 20]. Roughly 20,000 genes were detected by sequencing.…”

“…Experimental autoimmune encephalomyelitis (EAE) is a mouse model used to study the pathophysiology of MS, where an autoimmune response is artificially induced against the myelin of the central nervous system (CNS). The model produces immune-related demyelination of the CNS [2–4]. People with MS experience altered motor function but recent estimates report that 63% of people living with MS are additionally negatively impacted by disturbances to sensation such as chronic, neuropathic pain [5].…”

“…Recently, our laboratory has described differences in the development of pain states between female and male mice in the EAE model. These differences include differences in immune and neurodegenerative histochemical and oxidative stress profiles [2, 4]. These sex differences extend beyond the CNS, affecting the DRG [3].…”

High Speed Ventral Plane Videography as a Convenient Tool to Quantify Motor Deficits during Pre-Clinical Experimental Autoimmune Encephalomyelitis

“…In our study, Swing Time , which is essentially the same as Swing Duration , was found to be increased in both experimental cohorts and the difference was verified by two independent observers. Of note, it has been shown that Swing Duration increases with pain [57,58,59], and pain, which is a frequent and disabling symptom in MS patients, as well characterizes EAE animals to some extent [60]. Of note, a recent study showed that pain can as well be observed during the pre-clinical EAE phase [61].…”