Neuromodulatory inputs to the neocortex play a central role in regulating the behavioral state of an animal. The neuromodulator acetylcholine (ACh), in particular, is essential for arousal and attention. Cholinergic axons (that release ACh) in neocortex originate from nucleus basalis and loss or elimination of these neurons results in deficits in many behavioral tasks that require cortical function, including many learning and memory tasks. Neocortical pyramidal neurons express both ionotropic ‘nicotinic’ ACh receptors (nAChRs) and metabotropic ‘muscarinic’ ACh receptors (mAChRs) on their plasma membranes. mAChR-mediated responses of neocortical pyramidal neurons to exogenous ACh have been described by many authors (McCormick, 1992), but direct nAChR-mediated effects of ACh on pyramidal neurons have not previously been described. The roles of the nAChRs expressed by neocortical pyramidal neurons are therefore completely unknown. We have developed a novel method of selectively stimulating cholinergic axons in neocortex, using optogenetic tools (see Research Plan). In preliminary experiments we have found that release of ACh from cholinergic synapses evokes both nAChR- and mAChR-mediated responses from layer 5 pyramidal neurons. Hence we have discovered a novel nAChR-mediated direct effect of ACh on neocortical pyramidal neurons. Here we propose to determine the mechanism and functional consequences of activating nAChRs on neocortical layer 5 pyramidal neurons.
Jack Waters, Ph.D.