Nonlinear relationship between multimodal adrenergic responses and local dendritic activity in primary sensory cortices

The axonal projections of the adrenergic system to the neocortex, originating from the locus coeruleus (LC), form a dense network. These axons release the neuromodulator norepinephrine (NE) which is involved in many cognitive functions such as attention, arousal, and working memory. Using two-photon Ca2+ imaging of NE axons in the cortex of awake mice, we investigated what drives their phasic activity. We discovered that NE axons in the primary somatosensory cortex responded robustly and reliably to somatosensory stimulation. Surprisingly, the same axons also responded to stimuli of other modalities (auditory and visual). Similar responses to all three modalities were observed in the primary visual cortex as well. These results indicate that phasic responses of NE axons to sensory stimuli provide a robust multimodal signal. However, despite the robustness, we also noticed consistent variations in the data. For example, responses to whisker stimulations were larger than to auditory and visual stimulations in both the barrel and the visual cortices. To test whether the variations in NE axonal responses can carry behaviorally meaningful information, we trained mice in an associative auditory fear conditioning paradigm. We found that following conditioning the response of NE axons increased only for CS+, namely the signal undergoes experience-dependent plasticity and is specific to meaningful sounds. To test if variations in NE axonal responses can differentially affect the cortical microcircuit, we used dual-color two-photon Ca2+ imaging and studied the relationship between the activity of NE axons and local dendrites. We found dendritic Ca2+ signals in barrel cortex in response to auditory stimuli, but these responses were variable and unreliable. Strikingly, the probability of such dendritic signals increased nonlinearly with the Ca2+ signals of NE axons. Our results demonstrate that the phasic activity of the noradrenergic neurons may serve as a robust multimodal and plastic signal in sensory cortices. Furthermore, the variations in the NE axonal activity carry behaviorally meaningful signals and can predict the probability of local dendritic Ca2+ events.