A distinct Down-to-Up transition assembly in retrosplenial cortex during slow-wave sleep

Understanding the intricate mechanisms underlying slow-wave sleep (SWS) is crucial for deciphering the brain's role in memory consolidation and cognitive functions. It is well-established that cortical delta oscillations (0.5–4 Hz) coordinate communications among cortical, hippocampal, and thalamic regions during SWS. These delta oscillations feature periods of Up and Down states, with the latter previously thought to represent complete cortical silence; however, new evidence suggests that Down states serve important functions for information exchange during memory consolidation. The retrosplenial cortex (RSC) is pivotal for memory consolidation due to its extensive connectivity with memory-associated regions, although it remains unclear how RSC neurons engage in delta-associated consolidation processes. Here, we employed multi-channel in vivo electrophysiology to study RSC neuronal activity in freely behaving male mice during natural SWS. We discovered a discrete assembly of putative excitatory RSC neurons (∼20%) that initiated firing at SWS Down states and reached maximal firing at the Down-to-Up transitions. Therefore, we termed these RSC neurons the Down-to-Up transition Assembly (DUA), and the remaining RSC excitatory neurons as non-DUA. Compared to non-DUA, DUA neurons appear to exhibit higher firing rates, larger cell body size, and lack monosynaptic connectivity with nearby RSC neurons. Furthermore, optogenetics combined with electrophysiology revealed differential innervation of RSC excitatory neurons by memory-associated inputs. Collectively, these findings provide insight into the distinct activity patterns of RSC neuronal subpopulations during sleep and their potential role in memory processes. Significance statement Newly formed memories must undergo memory consolidation, integrating hippocampal-dependent information into pre-existing cortical networks. Recent research highlights a cortical-hippocampal-cortical loop during SWS in this process, indicating the cortex's role in initiating memory consolidation. To investigate how the RSC contributes to SWS and associated consolidation processes, we characterized a novel assembly of RSC neurons that are highly active during SWS Down states, preceding the activity of other RSC neurons during Down-to-Up transitions. We further explored how RSC neurons receive innervation from memory-associated inputs. Our findings shed light on the RSC's role in orchestrating SWS oscillations, revealing a unique assembly of cortical excitatory neurons in potentially promoting SWS Up states.