Spatiotemporal Dynamics of Noradrenergic Signaling in the Neocortex

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Project Summary: Noradrenaline is thought to mediate arousal and regulate the behavioral state of animals. In particular, noradrenaline bidirectionally modifies mnemonic and sensory encoding, prioritizing neural resources for imminent behavioral demands. Emerging evidence has suggested a capacity for spatially targeted noradrenergic release, yet the field has lacked tools with sufficient spatiotemporal resolution to resolve this possibility. Cell type specific sensitives to noradrenergic modulation underly the differing action of noradrenaline on mnemonic tuning in the frontal cortex and stimulus encoding in primary visual and somatosensory cortices. However, the study of isolated brain regions has precluded a holistic view of noradrenergic modulation across the cortex. Furthermore, how noradrenergic modulation of cortex-wide networks emerges from the level of single cells is virtually unexplored. Leveraging a recently developed technique from our lab to image the release of neuromodulators with high spatiotemporal resolution across the entirety of the dorsal-cortex, we have begun to characterize the spatiotemporal specificity of noradrenergic release and its relation to neural activity. Our preliminary data shows noradrenergic release is spatially homogenous and associated with distinct behavioral states. We further find the coupling of noradrenergic release to be spatiotemporally heterogenous, implicating noradrenaline in the engagement of distinct cortex-wide networks. To further pursue our preliminary data, we propose simultaneous application of several methodological approaches: 1 photon widefield “mesoscopic” dual channel imaging, local pharmacological infusions, and extracellular electrophysiological recordings with high density silicon probes. Our combinatorial approach will allow us to test the following hypothesis: (1) noradrenergic release is spatially homogenous but temporally heterogenous, with noradrenergic release associated with some behavioral states but not others. (2) Noradrenergic release is heterogeneously coupled with local neural activity through α2a receptors and prone to behavioral state dependent regulation. (3) Noradrenaline modulates the coupling of single cells to large-scale cortical networks in a state dependent manner. Our results will provide an unprecedented characterization of the spatiotemporal dynamics of noradrenergic modulation.