Targeting the lateral mammillary nucleus rescues sleep disturbances in Parkinson’s disease

Abstract Sleep disturbances are highly prevalent, early‑onset non‑motor symptoms in Parkinson’s disease (PD) that severely compromise quality of life. However, these neural substrates for sleep disturbance of PD remain poorly understood. Here, we reveal that the lateral part of the medial mammillary nucleus (ML) within the mammillary body (MB) is a critical hub for sleep-wake control and a key substrate of PD-related sleep dysfunction. Radiomic analysis of multi-modal MRI data from PD patients reveal that structural heterogeneity within the MB robustly predicts the presence of significant sleep disturbances, establishing it as a novel imaging biomarker. In mice, we demonstrate that ML neurons exhibit heterogeneous, state-specific activity patterns across sleep-wake cycles. Chemogenetic manipulation establishes that ML neuronal activity is both sufficient to promote NREM and REM sleep, and necessary for normal sleep architecture. Electrode recordings demonstrate that broad suppression of ML neuronal firing alongside a paradoxical hyperactivity of REM-active subpopulations. Strikingly, chemogenetic activation of ML neurons rescues these sleep disturbances, increasing total, NREM, and REM sleep without altering motor function. Therefore, our findings reveal a pathological neural mechanism underlying sleep dysfunction in PD and highlight the ML as a promising therapeutic target for PD-related sleep disorders.