Spatiotemporally Localized Norepinephrine Modulates the Prefrontal Neural Manifold

Norepinephrine (NE) is a neuromodulator that is released from projections of the locus coeruleus via extra-synaptic vesicle exocytosis (Fuxe, Borroto-Escuela, front. Physiol 2012). Previously, NE in the prefrontal cortex (PFC) was thought to be a homogenous field created by bulk release, but it remains unknown whether phasic (fast, short-term) fluctuations in NE can produce a spatially heterogeneous field, which could then structure cell firing at a fine spatial scale. To understand how spatiotemporal dynamics of NE release in the PFC affect neuronal firing, we performed a novel in-vivo two-photon imaging experiment in layer ⅔ of the prefrontal cortex using a green fluorescent NE sensor and a red fluorescent Ca2+ sensor, which allowed us to simultaneously observe fine-scale neuronal and NE dynamics. We found that the local NE field differs from the global NE field in transient periods of decorrelation, which are influenced by proximal NE release events. Release and reuptake events can occur at the same location but at different times, and differential recruitment of release and reuptake sites over time is a potential mechanism for creating a heterogeneous NE field. Using generalized linear models predicting cell firing dynamics, we showed that cellular Ca2+ fluctuations are overall influenced by both the heterogeneous local NE field and by the global NE field. During periods of local/global NE field decoupling, the heterogeneous local field and not the global field drives cell firing dynamics. To further clarify the relationship between NE and cell firing, we can use the population coding approach to understand how local and global neuromodulation functions to induce off- and on-manifold perturbations. Our results point to the importance of local, small-scale, phasic NE fluctuations for structuring cell firing, which may provide a mechanism for cognitive flexibility.