Neuromodulatory regulation of cortical functional connectivity

PROJECT SUMMARY: Neuromodulatory signaling is thought to play key roles in regulating the activity of local and long-range circuits in the brain and in mediating behavioral state-dependent changes in circuit function and cognition. Despite extensive anatomical evidence, there is little functional data on neuromodulatory signaling across the cortex during behavior. Recent work has highlighted the complex, state-dependent spatiotemporal pattern of acetylcholine (ACh) release in the neocortex. In contrast, little is known about the spatiotemporal dynamics of norepinephrine (NE) signaling. Previous work has suggested that fluctuations in cholinergic and noradrenergic signals may occur in tight coordination, particularly at moments of transition between behavioral states such as quiescence and arousal. However, technical limitations have precluded simultaneous observation of multiple neuromodulatory systems. To address these gaps, we propose to combine novel imaging approaches, including multicolor wide-field `mesoscopic' imaging of neuronal, NE, and ACh signaling across the entire cortex in awake behaving animals, with high-density electrophysiology and pharmacological manipulations. Using this combination of imaging and electrophysiology, we will test the following hypotheses: (1) Noradrenergic signaling regulates cortical activity at key transitions between behavioral states. (2) Noradrenergic and cholinergic signaling patterns exhibit selective spatiotemporal coordination. Our results will provide an unprecedented level of insight into the relationship between noradrenergic signaling and neocortical activity and provide novel data on coordination between neuromodulatory systems.