A Neuroimmune Feedforward Circuit Linking REM Sleep with Stress-Related Behavioral Susceptibility

Abstract

Rapid eye movement (REM) sleep is strongly associated with stress susceptibility, yet the underlying neuroimmune mechanisms remain unclear, limiting therapeutic targeting. Here, we identify a pathway by which chronic stress increases splenic nerve activity, promoting recruitment of circulating monocytes to the brain through the choroid plexus. In the external globus pallidus (GPe), recruited monocytes drive regionally restricted microglial remodeling toward a pro-inflammatory state. These microglia, in turn, potentiate the sustained excitability of parvalbumin-positive (PV) neurons via IL6-gp130 signaling. Functionally, activity of GPe PV neurons during REM sleep, but not wakefulness, bidirectionally regulates anxiety-like and defensive behaviors, establishing REM sleep as a critical state through which this neuroimmune circuit governs behavioral susceptibility. Together, these findings establish a neuroimmune feedforward mechanism linking peripheral immune activation to neuronal dysregulation underlying behavioral abnormalities, and position REM sleep as a predictive and actionable physiological entry point for mitigating stress-related emotional dysregulation.