Cholinergic and noradrenergic axonal activity contains a behavioral-state signal that is coordinated across the dorsal cortex

Abstract

Fluctuations in brain and behavioral state are supported by broadly projecting neuromodulatory systems. In this study, we use mesoscale two-photon calcium imaging to examine spontaneous activity of cholinergic and noradrenergic axons in awake mice in order to determine the interaction between arousal/movement state transitions and neuromodulatory activity across the dorsal cortex at distances separated by up to 4 mm. We confirm that GCaMP6s activity within axonal projections of both basal forebrain cholinergic and locus coeruleus noradrenergic neurons track arousal, indexed as pupil diameter, and changes in behavioral engagement, as reflected by bouts of whisker movement and/or locomotion. The broad coordination in activity between even distant axonal segments indicates that both of these systems can communicate, in part, through a global signal, especially in relation to changes in behavioral state. In addition to this broadly coordinated activity, we also find evidence that a subpopulation of both cholinergic and noradrenergic axons may exhibit heterogeneity in activity that appears to be independent of our measures of behavioral state. By monitoring the activity of cholinergic interneurons in the cortex we found that a subpopulation of these cells also exhibit state-dependent (arousal/movement) activity. These results demonstrate that cholinergic and noradrenergic systems provide a prominent and broadly synchronized signal related to behavioral state, and therefore may contribute to state-dependent cortical activity and excitability.

Brain-wide arousal signals are segregated from movement planning in the superior colliculus

“…These findings are consistent with neuroimaging studies showing that changes in brain state lead to coordinated fluctuations of activity across the brain (Liu et al, 2018;Turchi et al, 2018;Setzer et al, 2022), and research that recorded simultaneously from neurons in cortical areas and subcortical areas such as the LC (Joshi and Gold, 2022;Collins et al, 2023). Furthermore, our results suggest that arousal-related fluctuations are more characteristic of neurons residing in the intermediate layers of the SC.…”

Cortical acetylcholine dynamics are predicted by cholinergic axon activity and behavior state

“…1d). As expected based on previous studies [15][16][17][20][21][22] , we observed strong increases in ACh levels which tracked spontaneous locomoYon periods and the accompanying large pupil dilaYons (Fig. 1e).…”

“…Over the past decade, the mouse has served as an important model for understanding the mechanisms underlying these changes in state, which include neuromodulators 10 such as acetylcholine (ACh) [11][12][13][14] . Indeed, acYvity in cholinergic axons from the basal forebrain (BF) projecYng to the cortex is increased during whisking [15][16][17][18][19] , locomoYon [15][16][17][20][21][22] , and pupil dilaYon outside of exploratory periods 20,22 , and geneYcally-encoded ACh sensors have confirmed some of these effects 21,[23][24][25][26] . Axonal GCaMP acYvity might not have a straighiorward relaYonship to ACh levels, which depend on local release probabiliYes and clearance kineYcs, as well as the kineYcs of the fluorescent sensors themselves.…”

State dependent constraints on claustrocortical communication and function

“…Brain state was measured as the ratio between gamma power to delta power (cortical desynchrony). Facial movement of the vibrissae occurs throughout wake-sleep states and therefore, we used this face motion as a proxy for behavioral state similar to previous reports 52,54 . We found a strong relationship between cortical desynchrony and claustrum activity (R 2 =0.56, p<0.001, Figure 2K ) which was also present within individual sessions ( Figure S3M-N ).…”