Noradrenergic locus coeruleus ensembles evoke different states in rat prefrontal cortex

Identifying the neurons that control global brain state has been a fundamental topic of research that has largely focused on diffusely-projecting neuromodulatory centers, such as the locus coeruleus (LC). This noradrenergic brain stem nucleus, which projects throughout the forebrain, is thought to act as an "undifferentiated state controller" across all forebrain targets because LC neurons spike synchronously. However, recent work demonstrated ensembles in the LC and therefore made targeted neuromodulation a possibility. In order to demonstrate that LC ensembles cause targeted neuromodulation, it is necessary to resolve LC ensemble dynamics over time in relation to ongoing cortical states. Here, we used non-negative matrix factorization on LC single unit recordings to investigate the spatial and temporal properties of ensemble activation patterns. We assessed the potential for targeted neuromodulation of the prefrontal cortex (PFC) using LC ensemble activity-triggered local field potential (LFP) power spectrograms. We analyzed 285 single units recorded from 15 urethane-anesthetized rats (range of 5 to 34 simultaneously recorded units). LC ensembles became active at different times. Analysis of auto-correlograms and ensemble-pair cross-correlograms demonstrated that self- and lateral-inhibition of activity is a property of LC ensembles, which may contribute to their sparse activity. Neuromodulatory effects on cortical state were diverse across ensembles. We observed four types of ensemble-triggered LFP spectrograms in the PFC. These results demonstrate that the LC is capable of differentiated neuromodulation of its forebrain targets by dynamic firing patterns across subsets of LC neurons.