Retrosplenial Cortex Activity During REM Sleep Is Increased in a Mouse Model of Depression

Abstract Paradoxical sleep, also known as rapid eye movement (REM) sleep, is altered in depression and chronic stress, yet the underlying neuronal substrates remain unidentified. Here, we combined whole-brain TRAP-based neuronal tagging, c-Fos mapping and two-photon calcium imaging to determine whether and how unpredictable chronic mild stress (UCMS) reshapes REM-associated brain activity in mice. Three weeks of UCMS induced a sustained increase in REM sleep amounts together with stress and depression-related behavioral traits. A whole-brain mapping across 114 brain structures further revealed that UCMS did not globally modify REM-associated neuronal activation, but instead selectively enhanced activity within restricted cortical regions. The dorsal retrosplenial cortex (RSPd) emerged as the region showing the strongest increase in REM-associated c-Fos expression following UCMS compared to control condition. This effect was restricted to neurons in the superficial layer 2/3, which also exhibited increased reactivation of neurons that had been recruited during REM sleep prior to UCMS exposure. Supporting these data, longitudinal two-photon calcium imaging showed that UCMS selectively amplified high-amplitude neuronal activity in RSPd layer 2/3 during REM sleep, whereas it remained largely unaffected during NREM sleep. Moreover, stronger REM-associated RSPd activity was associated with fewer stress-related behavioral alterations. Together, these findings identify for the first time layers 2/3 of the RSPd as a prominent substrate of chronic stress-induced neuronal alterations that emerge selectively during REM sleep. Based on these results, we propose that REM-related remodeling of the retrosplenial cortex could play a role in the adaptive responses to chronic stress and depression.