NOREPINEPHRINE COORDINATES BRAIN STATE TRANSITIONS UNDERLYING FLEXIBLE BEHAVIOR

Adaptive behavior and learning require internal state changes that enable flexible reorganization of brain circuit activity in response to experience and context. Norepinephrine (NE), released by the locus coeruleus (LC), has long been proposed to regulate brain state and adaptive gain, enabling flexible responses to changing environmental demands. More recently, LC activity has been shown to transiently decrease prior to hippocampal sharp-wave ripples (SPW-Rs) during wakefulness, network events critical for ongoing learning that coordinate activity across cortical and subcortical circuits. These findings suggest that noradrenergic tone is linked to the expression of distinct network modes. Threat offers a tractable way to elicit internal state transitions, producing shifts from exploration to defensive strategies. Yet, how NE dynamics contribute to internal state transitions and behavioral flexibility remains unclear.
Here, we simultaneously monitored norepinephrine dynamics using fiber photometry of a genetically encoded sensor and neural population activity with high-density silicon probes in the hippocampus in freely behaving mice performing a task in which brief looming threat stimuli drive natural transitions between behavioral states. This design allowed us to relate NE fluctuations to changes in behavioral strategy, gamma dominated online processing during active states, and modulation of SPW-Rs expression during quiescent periods. Specifically, we examined how noradrenergic dynamics during threat exposure predict the transition from threat-driven flight to learned threat suppression.
Together, these findings provide insight into how noradrenergic signalling coordinates brain state transitions to support flexible behavior, highlighting NE as a central mechanism linking threat, network dynamics, and internal state updating.