A SEROTONERGIC SENSORY-GATING PATHWAY FOR ADAPTIVE LOCOMOTION

Serotonin (5-HT) is a key neuromodulator of spinal locomotor circuits, but the identity and functional contribution to behavior of the serotonergic neurons underlying this modulation remain poorly defined. A longstanding hypothesis posits that serotonin influences locomotion by shaping sensorimotor processing, an essential determinant of adaptive movement. Here, we selectively target midline serotonergic neurons of the caudal raphe (CR⁵ᴴᵀ) in mice to dissect their connectivity and function across spinal circuits and locomotor behaviors. Optogenetic activation of CR⁵ᴴᵀ neurons in an ex vivo newborn brainstem-spinal cord preparation fails to recruit lumbar motoneurons but robustly suppresses motoneuron responses to sensory stimulation, suggesting a role in sensorimotor gating. Consistent with this, CR⁵ᴴᵀ projections in the adult lumbar spinal cord are enriched in the dorsal horn, a core hub for somatosensory integration. To determine whether this modulation impacts motor output, we manipulated CR⁵ᴴᵀ activity in vivo during both spontaneous and skilled locomotion. While CR⁵ᴴᵀ activation or silencing does not initiate (nor arrests) locomotion nor alters overall mobility in open-field conditions, they both significantly impair paw placement accuracy during horizontal ladder walking. Finally, retrograde trans-synaptic tracing uncovers a restricted set of direct presynaptic inputs to CR⁵ᴴᵀ neurons from discrete brainstem and midbrain regions. Together, these findings identify CR⁵ᴴᵀ neurons as a dedicated serotonergic pathway for sensory information processing that is required for precise, adaptive locomotion.