Assistant Professor Jack Waters, Department of Physiology, Northwestern University, Chicago, US.
The neocortex contains huge numbers of cholinergic axons and acetylcholine (ACh), released by these axons, shapes neocortical function during many processes, including arousal, attention, learning, memory, sensory perception and motor control. ACh acts at muscarinic and nicotinic ACh receptors on pyramidal neurons, interneurons and presynaptic terminals and together the concerted actions of these receptors increase sensitivity of neocortex to ascending excitatory drive, such as that from thalamus. One long-standing puzzle concerns nicotinic receptors: pyramidal neurons express functional nicotinic and muscarinic receptors in their plasma membranes, but application of ACh to pyramidal neurons typically evokes postsynaptic responses via muscarinic, but not nicotinic receptors.
We have used optogenetic tools to evoke release of ACh from cholinergic axons in primary motor cortex and have found that layer 5 pyramidal neurons respond principally via nicotinic receptors and rarely via muscarinic receptors. Activation of nicotinic receptors increases excitability and can evoke prolonged spiking. Pyramidal neurons in other layers do not respond via nicotinic receptors. Hence ACh acts selectively at layer 5 neurons, which are the main source of axonal projections out of neocortex to subcortical structures. Our results suggest that ACh pushes neocortical circuits towards a 'relay mode' by facilitating the transfer of information from ascending excitatory inputs, e.g. from thalamus, to target structures, e.g. motor circuits in the spinal cord, with reduced 'interference' from intracortical connections.