Project Summary Primary motor cortex (M1) and the locus ceruleus (LC) both contribute in essential ways to the generation of purposive movements – with M1 and its pyramidal tract (PT) neurons involved in action planning and execution, the and LC and its noradrenergic axonal projections involved in aspects relating to arousal and attention. The cellular- and circuit-level mechanisms by which these two major brain systems communicate and interact are not well understood. Prior anatomical studies have described axonal projections and virally traced putative synaptic connections between the LC and neocortex that include M1, but functional aspects of LC inputs to M1 have not been characterized, and still unexplored is the possibility of direct bidirectional interactions between M1 and LC. Yet, there is growing evidence, though mostly indirect, to suggest such a circuit mediating direct LC-M1 communication. Here we will develop and test the hypothesis that LC→M1 and M1→LC projections are tightly linked to form a reciprocal, looping circuit. We posit that pyramidal tract (PT) neurons in M1 are the key cortical cell type mediating these interactions, receiving neuromodulatory inputs from the norepinephrine-releasing LC axons – and quite possibly also excitatory inputs from co-released glutamate – and sending excitatory afferents back to the brainstem, including branches to the LC neurons to close a recurrent loop. To investigate these possibilities, we will apply multiple methods for cell-type-specific circuit analysis in the mouse. In the ascending LC→M1 pathway, we will optogenetically label and excite presynaptic LC axons while recording from identified classes of M1 neurons, to characterize noradrenergic and synaptic actions on PT neurons and other potential cellular targets. In the descending M1→LC pathway, we will adapt the methods to assess glutamatergic synaptic connectivity to LC neurons, including those with recurrent projections to M1. In both pathways we will test and quantitatively characterize the monosynaptic excitatory and disynaptic inhibitory circuits. The overall outcome will be detailed new framework delineating the cellular mechanisms mediating direct LC-M1 interactions. Results from this discovery-oriented research program will lay the groundwork for future hypothesis-oriented studies to investigate – at the mechanistically important level of specific cell types and their synaptic connections and neuromodulatory properties – how signaling in ceruleo-cortical circuits contributes to mammalian motor function in vivo.

NARRATIVE The proposed research on circuits linking motor cortex and locus ceruleus is directly relevant to public health because pathology in these circuits impairs the control of movements. By elucidating basic aspects of the cellular/synaptic-level functional organization of these circuits, this research can lead to new approaches to treat disease, and is thus relevant to those aspects of the NIH mission aimed at improving health through understanding pathophysiological mechanisms in disorders causing disability.