Circuit Organization of the Forelimb-Related M2-to-M1 Corticocortical Pathway in the Mouse

Communication from secondary (M2, premotor) to primary (M1) motor cortex is implicated in forelimb motor control. We investigated the underlying synaptic circuits in this corticocortical pathway in male and female mice using cell-type-specific optogenetic-electrophysiology methods, focusing on identifying the cell-type-specific synaptic connections in the excitatory and feedforward inhibitory circuits impinging on cervically projecting M1 corticospinal neurons. In forelimb M1 brain slices, recordings from layer (L)5B corticospinal neurons during brief photostimulation of M2 axons showed strong monosynaptic excitatory currents that, although accompanied by potent feedforward inhibitory currents, were capable of evoking action potentials (APs) in most neurons. In contrast, responses in L2/3 pyramidal neurons were generally much weaker. Parvalbumin (PV)-expressing neurons, particularly in deeper layers, showed direct excitation from M2 axons without feedforward inhibition and could fire APs robustly. Somatostatin (SST) neurons received generally weak inputs, whereas vasoactive intestinal protein (VIP) and neuron-derived neurotrophic factor (Ndnf) neurons received stronger excitation and inhibition from M2 axons. Corticospinal neurons received little or no local inhibition from Ndnf and VIP interneurons but relatively strong soma-targeting PV and dendrite-targeting SST inhibitory inputs, as functionally imaged by laser-scanning synaptic input mapping ("sCRACM"). The domains of PV and SST inputs were partly overlapping around the corticospinal somata but broader for PV and more vertical for SST inputs. Collectively, the results provide a working model for the cell-type-specific synaptic circuits of this "top-down" corticocortical pathway, organized around direct M2 excitation and PV-mediated inhibition of M1 corticospinal neurons.