electron microscopy; primary somatosensory cortex; serotonergic; pyramidal neurons; two photon microscopy; synaptic circuits; barrel cortex; whisker mediated behavior; neocortex; neuromodulation; whole-cell recordings; cholinergic; cortical state
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Neuromodulatory inputs to the cerebral cortex play a significant role in many fundamental brain processes such as: sensory perception, motor function, learning, sensory map plasticity and states of wakefulness. Here, we will focus on the extensive serotonergic and cholinergic innervation of the neocortex. Although a great deal of evidence supports the involvement of these systems, particularly in behaviors such as feeding, reward seeking, alertness and anxiety, little is understood about how they function. This represents a significant and important challenge for neuroscience research today. Dysfunction of these modulatory systems have been identified in various neurological and psychiatric diseases, therefore understanding how these inputs to the cortex are able to influence its function is paramount for opening new perspectives in therapeutic development.This application aims to understand how serotonergic and cholinergic inputs modulate the function of the mouse barrel cortex. Studying the mouse offers significant advantages in the specificity of manipulations offered through the precision of mouse genetics combined with localised viral injections. The barrel cortex offers a well-defined sensory system amenable to quantitative analyses and is thus well-suited to the investigation of neuromodulation. We will express genetically-encoded calcium indicators specifically in serotonergic and cholinergic axons in order to measure their activity during sensory processing and during whisker behaviour. We will also express optogenetic actuators to precisely control the activity of serotonergic and cholinergic neurons, allowing the investigation of their causal contributions to cortical states, psychophysical thresholds for sensory perception and neuronal plasticity. Expression of fluorescent proteins specifically in serotonergic and cholinergic neurons will also be used to reveal the morphology of their axonal projections in the mouse barrel cortex. The fluorescently labelled axons will be studied using 3D volume electron microscopy, allowing quantitative analyses of structure-function relationships, which are critical for being able to provide a mechanistic basis of neuromodulation.This collaborative Swiss National Science Foundation (SNSF) Sinergia grant application brings together three neuroscience laboratories with unique skills ideally suited for this task. Each has a significant standing in the fields of cortical plasticity, processing and structure. Combining their expertise will bring together the very latest technological advances for understanding the mechanistic basis of neuromodulation in a well-defined and functionally important region of the neocortex.