Inflammatory dependent mood alterations and immunomodulatory effects of exercise in experimental multiple sclerosis

Multiple sclerosis (MS) causes a variety of motor and sensory deficits and it is also associated with mood disturbances. In recent years, corticostriatal functional connectivity has been implicated in the pathophysiology of MS. The striatum is a sub-cortical gray matter structure whose activity is finely regulated by both glutamate and GABA inputs. It is highly sensitive to the neurodegenerative process associated with MS, besides demyelination it undergoes complex alterations of glutamate transmission and spine loss during experimental autoimmune encephalomyelitis (EAE), a well recognized mouse model of MS. The present PhD thesis addressed two main issues that have in common inflammatory dependent defects of the striatal circuitry, underlying behavioral comorbidities and motor disability, as potential targets of anti-inflammatory treatments and rehabilitative therapy. Mood disturbances, including anxiety and depression, are frequent in patients with MS, even in non-disabled patients and in the remitting stages of the disease. It is still largely unknown how the pathophysiological process underlying MS causes anxiety and depression, but a growing body of evidence highlights the involvement of inflammatory pathways in specific neuronal circuits with an impact on neurotransmission. Proinflammatory cytokines, such interferon-gamma (IFN-γ), are implicated in the pathogenesis of multiple sclerosis (MS) and in its animal models. The first aim of this study was to verify whether IFN-γ could exert a role in the anxiety- and depressive-like behavior observed in mice with EAE, and in the modulation of type-1 cannabinoid receptors (CB1Rs). CB1Rs are heavily involved in MS pathophysiology, and a growing body of evidence suggests that mood disturbances reflect specific effects of proinflammatory cytokines on neuronal activity. We performed biochemical, behavioral and electrophysiological experiments to assess the role of IFN-γ on mood control and on synaptic transmission in mice. Intracerebroventricular delivery of IFN-γ caused a depressive and anxiety-like behavior in mice, associated with the selective dysfunction of CB1Rs controlling GABA transmission in the striatum. In the second study we provided first evidence for the beneficial effects of voluntary exercise during toxic central demyelination. Growing data from human and animal studies indicate the beneficial effects of exercise on several clinical outcomes in MS patients, suggesting that it may slow down the disease progression, by reducing brain damage. However, the mechanisms involved are still elusive. Aim of this study was to address the effects of voluntary running wheel in a toxic-demyelinating model of MS, in which demyelination and brain inflammation occur in response to cuprizone (CPZ) treatment. Mice were housed in standard or wheel-equipped cages starting from the day of CPZ or normal chow feeding for three or six weeks and evaluated for weight changes, locomotor skills and neuromuscular functions over the course of the experimental design. Biochemical, molecular biology and immunohistochemical analyses were performed. Exercise prevented early weight loss caused by CPZ, indicating improved wellness in these mice. Both neuromuscular function and motor coordination were significantly enhanced by exercise in CPZ-treated mice. Moreover, exercise induced an early protection against axonal damage and the loss of the myelin associated proteins, myelin basic protein (MBP) and 2′,3′-Cyclicnucleotide 3′-phosphodiesterase (CNPase), in the striatum and the corpus callosum, in coincidence of a strongly attenuated microglia activation in both brain areas. Further, during the late phase of the treatment, exercise in CPZ mice reduced the recruitment of new OLs compared to sedentary CPZ mice, likely due to the precocious protection against myelin damage. Overall, these results suggest that life-style interventions can be effective against the demyelinating-inflammatory processes occurring in the brains of MS patients. Collectively, our data contribute to clarify the synaptic and, at least in part, molecular basis of mood disturbances in EAE and, possibly, MS. In addition, our data suggest that promoting MS patient engagement in physical activity tightly tailored to their degree of disability represents a good non-pharmacological tool to control disease progression.