Wednesday, May 8, 2024
5/8/2024
SUMMARY/ABSTRACT Goal-directed movements of the arms and hands are essential for many activities of daily living. Dysfunction of the cortical areas controlling these behaviors is a common cause of disability. Basic neuroscience research on the underlying circuits can help to identify pathophysiological mechanisms and ultimately inform treatments of these disorders. Our prior progress has advanced basic knowledge about the synaptic circuit organization of the forelimb-related primary motor cortex (M1) in the mouse, including local circuits, cortico-thalamo-cortical loops, and input pathways from forelimb-related primary somatosensory cortex (S1) and other parietal areas. We now propose to address a major remaining gap in knowledge: the cellular/synaptic basis for inter-areal communication in premotor¿motor pathways. These appear important for coordinating the functions associated with premotor areas (e.g. motor planning) with those of primary motor areas (e.g. movement execution), in the context of predicted and actual sensory feedback. Premotor¿M1 axonal projections are anatomically prominent, but the underlying corticocortical circuits are only partly characterized. Both M2 and S1 feed into M1, but the behavioral functions of these afferent streams are profoundly different, with S1 conveying bottom-up somatosensory information reporting ongoing changes in the sensory environment, and M2 providing top-down signals related to action planning and sensorimotor prediction. We therefore hypothesize that the M2¿M1 circuits and S1¿M1 circuits are also asymmetrically implemented, reflecting the asymmetric behavior-related computations they support. We speculate that M2¿M1 circuits are configured through cell-type-specific connections and synaptic dynamics to provide M2 with relatively more direct influence on M1 output neurons. Using the mouse as model organism for genetically accessing specific cell types together with viral labeling methods, we will apply electrophysiological and optogenetic methods to characterize circuits linking the forelimb- related secondary motor cortex (M2; rostral forelimb area) to forelimb M1 (caudal forelimb area). Additionally, we will investigate how top-down projections from M2 integrate in M1 with bottom-up inputs from S1. Our strategy is two-pronged: in a series of slice-based experiments (Aim 1) we will use in vivo labeling methods combined with ex vivo brain slice optogenetics and whole-cell recordings to characterize mono- and polysynaptic M2¿M1 circuits. In a series of in vivo experiments (Aim 2), we will use linear-array electrophysiological recordings of cortical spiking activity in the awake mouse, at rest and during natural forelimb movements, combined with optogenetic manipulations of M2 input to assess in dynamics in M2¿M1 circuits. Overall, we expect our findings to be broadly significant for their relevance to current concepts about hierarchical cortical networks and corticocortical signaling in general, as well as for advancing basic knowledge about motor cortex circuit organization and the mechanistic basis for premotor¿motor communication.
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