CRC 1436 External Speaker Lecture

Abstract: Bridging Basic Orexin Circuitry and MS Models: L6 OX2R as a Therapeutic Entry Point Background. Multiple sclerosis (MS) is a chronic demyelinating disease affecting the brain and spinal cord. Experimental autoimmune encephalomyelitis (EAE) is a well-established mouse model that mimics key features of MS. The orexin (hypocretin) neuropeptide system—mainly known for regulating arousal—has emerging roles in neuroimmune modulation. Orexins communicate through two G protein–coupled receptors: orexin receptor-1 (OX1R) and orexin receptor-2 (OX2R). Recent research identifies a subset of cortical layer-6 (L6) neurons that express OX2R and can “gate” cortical network states.

Our findings. In EAE, we observe an early increase in neuronal network activity. Rather than being uniformly harmful, we hypothesize that modest, orexin-tuned activity reorganizes rhythms to promote remyelination. Following EAE induction, clinical outcomes diverge by age despite identical genotypes and immunization protocols: older mice show significantly higher clinical scores than younger cohorts. Orexin levels inversely correlate with clinical severity—higher orexin is linked to lower scores. At the receptor level, we detect an age-dependent downregulation of OX1R, with no change in OX2R.

Conclusion. The combination of early hyperexcitability and improved outcomes in animals with higher orexin supports a neuroimmune-modulatory role for the orexinergic system. These findings connect fundamental orexin circuit biology to MS models and highlight L6 OX2R as a promising therapeutic target. Abbreviations: MS, multiple sclerosis; EAE, experimental autoimmune encephalomyelitis; L6, cortical layer 6; OX1R/OX2R, orexin receptor-1/-2.