The Spatial and Temporal Scale of Neuromodulation in Mouse Sensory Cortex

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The neuromodulators acetylcholine (ACh) and norepinephrine (NE) are associated with an activated cortical brain state characterized by an increase in the reliability of cortical responses to external stimuli and enhanced performance on behavioral tasks. A key unresolved question is the spatial and temporal scale at which these neuromodulators exert their effects. New methods to directly record the local availability of ACh and NE simultaneously with the activity of neural populations in mice opens up the possibility to answer this question. In a first set of experiments we will test the hypothesis that neural signatures of the activated state may vary across cortex due to spatial inhomogeneities in moment-to-moment neuromodulator availability. In a second set of experiments we will test the hypothesis that mice can recruit neuromodulators independently to auditory and visual cortex to enhance performance on a multimodal attention task. Given that disruption of these systems is a key feature of a variety of human diseases including Alzheimer’s disease, ADHD, and Autism Spectrum Disorders, understanding the baseline variability in neuromodulator activity in healthy animals will be critical for identifying subtle changes in the effects of neuromodulators that may occur in different disease states and for evaluating the efficacy of treatments. From the perspective of neuroscientists attempting to understand the encoding of stimuli in population activity, the effects of neuromodulators appear as stimulus-independent noise that adds variability to sensory responses. Understanding the spatiotemporal resolution of the effects of ACh and NE will enable modeling of these effects as state variables shaping the response of cortical populations. The cortical effects of both ACh and NE release in mice are strikingly similar to neural correlates of attention recorded in humans and primates. While it is unlikely that mice have fine-grained spatial or feature attention like humans, understanding the spatiotemporal dynamics of these two neuromodulators in mice will be a significant step towards dissociating their influence on attentional mechanisms more generally. Having a clear understanding of the relative time course of the influence of these two neuromodulators on cortical processing will provide important constraints for future studies of the cellular and circuit mechanisms underlying their effects.