Defining circuit mechanisms for the regulation of somatosensory feedback - PROJECT SUMMARY Sensory feedback is critical for reporting the state of the body and how it interacts with the world. Yet the incessant transmission of all sensory stimuli that impinge upon the body would be debilitating. Rather, sensory signals must be regulated dynamically to attenuate the disruptive and facilitate the salient. The dorsal column nuclei complex, located in the brainstem, represents the major conduit of somatosensory information from the periphery to supraspinal targets. The cuneate nucleus receives and processes sensory signals from the upper body, conveying the resulting information to the sensorimotor cortex via projections to the thalamus, including tactile signals from the hand that are especially critical for the effective execution of dexterous behaviors. The recent identification of a ‘shell’ of local inhibitory neurons in the brainstem that can modulate the transmission of tactile signals in the cuneate points to circuit mechanisms that might be used to dynamically regulate somatosensory feedback at its first synapse in the brain. Selective manipulation of these inhibitory circuits can suppress or enhance the transmission of tactile information, affecting dexterous behaviors. Moreover, these circuits are subject to top-down control by descending cortical pathways, suggesting that higher-order sensorimotor regions regulate the sensory signals they receive. Yet several key questions remain unaddressed. Do these same mechanisms for regulating tactile feedback from the hand apply to cutaneous signals more generally, and do they generalize to other somatosensory modalities like proprioception? How do these brainstem circuits and their descending inputs function in behaving animals that require dynamic and bidirectional adjustment of sensory transmission? Based on preliminary evidence, the central hypotheses of this proposal are that: a) similar regulatory mechanisms exist in parallel for somatosensory signals generated across the body; and b) distinct cortical and subcortical pathways can attenuate or amplify the transmission of these signals to match behavioral needs. Aim 1 leverages molecular-genetic, anatomical, and electrophysiological approaches in mice to determine whether local inhibitory motifs are repeated in parallel to regulate feedback across the body and across somatosensory modalities, and whether molecular diversity within these inhibitory populations is indicative of distinct functions. Aim 2 uses recording and optogenetic perturbation approaches to establish how these brainstem inhibitory circuits and their top-down cortical inputs operate during behavior, for example when self-generated feedback needs to be attenuated. Aim 3 sets out to determine whether a newly identified top-down projection from the central amygdala to cuneate circuits can disinhibit somatosensory transmission, potentially as a means to augment sensitivity and enhance sensory vigilance. By defining local and long-distance circuit mechanisms that regulate sensory signals from the body as they first enter the brain, this work will provide insight into how the nervous system adjusts sensory transmission to match behavioral context and clarify how circuit dysfunction can lead to pathological changes in sensory sensitivity.
