MONOAMINERGIC AND TRYPTOPHAN PATHWAY DYSREGULATION UNDERLIES EARLY ANHEDONIC-LIKE BEHAVIOR IN EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS

Neuropsychiatric symptoms such as anhedonia, anxiety and pain frequently precede motor disability in multiple sclerosis (MS), suggesting early dysfunction of neuroimmune-regulated brain circuits. Monoaminergic transmission and the kynurenine pathway (KP) are key modulators of reward processing, emotional behavior and neuroinflammation.
In this study, we investigated functional and molecular alterations of these pathways in experimental autoimmune encephalomyelitis (EAE), a validated preclinical model of progressive MS induced by active immunization with myelin oligodendrocyte glycoprotein 35–55 (MOG_35–55) at disease onset. At 10 ± 1 days post immunization, EAE mice exhibited depressive-like behavior in the splash test, anxiety-like behavior in the open field test and increased tactile allodynia in the Von Frey test, in the absence of motor deficits. In vivo single-unit electrophysiological recordings revealed a reduction in firing frequency and bursting activity of ventral tegmental area dopaminergic neurons, with no changes in GABAergic or glutamatergic neuronal activity, indicating an early dopaminergic circuit impairment. Ex vivo neurochemical analyses showed region-specific alterations of monoamines and KP metabolites in brain areas involved in emotional and reward processing, including prefrontal cortex, hippocampus, amygdala and nucleus accumbens. Notably, noradrenaline and serotonin levels were increased in the amygdala, together with increased kynurenine/tryptophan ratio and 3-hydroxykynurenine levels, supporting their pro-anxiety and neuroinflammatory role.
Overall, these findings demonstrate that early EAE is characterized by monoaminergic and KP dysfunction associated with anhedonic-like behaviors, highlighting these pathways as potential early targets for interventions addressing both MS neuropsychiatric and immune components.
The project is funded by Next-GenerationEU, Mission4 Component1 (PRIN2022PNRR P202224ZTX CUPD53D2302144000).