Cholinergic disruption of state-dependent retrosplenial layer 1 activity causes temporal associative memory deficit under stress
Memory functions rely on discrete patterns of neuronal activity emerging from individual neurons, their interconnected circuits, and their alignment with global brain states. We show that such patterns are generated by layer 1 inhibitory neurons in the ventral retrosplenial cortex (vRSPL1), whose activity correlated with immobility and specifically contributed to the formation of temporal associative memories. This state-dependent activity was subject to stress-induced cholinergic modulation through muscarinic 1 receptor (M1R) signaling, leading to selective impairments in temporal but not contextual associative memory. Slice studies showed that these effects were likely due to M1R-mediated inhibition of vRSPL1 neurons, transiently disrupting their local connectivity as well as responsiveness to afferent input. Together, we demonstrate a mechanism by which vRSPL1 activity aligned to immobility coordinate the formation of temporal associations. Through its sensitivity to stress-related cholinergic modulation, this mechanism presents vulnerability to traumatic amnesia, especially for temporal details of episodic memories.