Differential locus coeruleus-hippocampus interactions during offline states.

Patterns of locus coeruleus (LC) activity and norepinephrine (NE) release during non-rapid-eye-movement sleep suggest a critical role for the LC-NE system in offline modulation of forebrain circuits. NE transmission promotes synaptic plasticity and is required for memory consolidation, but the field has only begun to uncover how LC activity contributes to coordinated forebrain network dynamics. Hippocampal ripples, a hallmark of memory replay, are temporally coupled with thalamocortical oscillations; however, the circuit mechanisms underlying system-level consolidation across larger brain networks remain incompletely understood. Here, using multi-site electrophysiology, we examined LC firing in relation to hippocampal ripples in freely behaving rats. LC activity and ripple occurrence were state-dependent and inversely related: heightened arousal was associated with increased LC firing and reduced ripple rates. At finer timescales, LC spiking decreased ∼1-2 s before ripple onset, with the strongest modulation during awake ripples but minimal change during ripple-spindle coupling. These findings reveal state-dependent dynamics of LC-hippocampal interactions, positioning the LC as a key component of a cortical-subcortical network supporting system-level memory consolidation.