The sense of touch allows us to perceive and respond to the physical world ?we recognize objects held in our hands, discriminate between different textures and shapes, and sensory-motor feedback circuits coordinate our body movements. The sense of touch also underlies forms of social exchange and is thus an essential component of the human experience. The first step leading to touch perception is activation of a group of cutaneous sensory neurons called low- threshold mechanoreceptors (LTMRs). There are several LTMR types, and each has a unique sensitivity, morphology, physiological property and, presumably, function. Understanding the unique functions of each LTMR type, and how ensembles of LTMR activities are integrated and processed in the CNS to form touch percepts are outstanding questions in the field. Therefore, the overall goals of my laboratory, and thus this R35 proposal, are: 1) to elucidate the sensitivities, mechanisms of excitation, and unique functions of the major classes of mammalian cutaneous LTMRs; 2) to define the logic of LTMR circuit organization in the spinal cord and brainstem, and the nature of ascending pathways to the brain that underlie discriminative and affective touch perception; 3) to establish how the peripheral somatosensory system assembles during development; and 4) to determine whether and how dysfunction of touch circuits and their development underlies tactile deficits in autism spectrum disorders and during neuropathic pain. We are achieving these goals using an array of powerful mouse molecular genetic tools, combined with sophisticated electrophysiological, anatomical, behavioral and developmental assays. Successful completion of this R35's goals will thus reveal mechanisms of somatosensory nervous system development and function, and spinal cord touch information processing underlying perception, under normal and disease conditions.
Research Narrative The organization and essential functions of cutaneous low-threshold mechanosensory neurons, which mediate our sense of touch and includes at least seven neuronal types, are poorly understood. We have generated mouse genetic tools that enable detailed investigation into each LTMR subtype as well as their postsynaptic partners in the spinal cord dorsal horn and brainstem. We propose to use these genetic tools and new technologies to define the development and functional organization of LTMR circuits, the synaptic organization of the dorsal horn and brainstem, and somatosensory dysfunction in models of autism and neuropathic pain.
|Ye, Mengchen; Lehigh, Kathryn M; Ginty, David D (2018) Multivesicular bodies mediate long-range retrograde NGF-TrkA signaling. Elife 7:|
|Wang, Qiang; Chiu, Shu-Ling; Koropouli, Eleftheria et al. (2017) Neuropilin-2/PlexinA3 Receptors Associate with GluA1 and Mediate Sema3F-Dependent Homeostatic Scaling in Cortical Neurons. Neuron 96:1084-1098.e7|
|Severson, Kyle S; Xu, Duo; Van de Loo, Margaret et al. (2017) Active Touch and Self-Motion Encoding by Merkel Cell-Associated Afferents. Neuron 94:666-676.e9|
|Lehigh, Kathryn M; West, Katherine M; Ginty, David D (2017) Retrogradely Transported TrkA Endosomes Signal Locally within Dendrites to Maintain Sympathetic Neuron Synapses. Cell Rep 19:86-100|
|Andreone, Benjamin J; Chow, Brian Wai; Tata, Aleksandra et al. (2017) Blood-Brain Barrier Permeability Is Regulated by Lipid Transport-Dependent Suppression of Caveolae-Mediated Transcytosis. Neuron 94:581-594.e5|
|Abraira, Victoria E; Kuehn, Emily D; Chirila, Anda M et al. (2017) The Cellular and Synaptic Architecture of the Mechanosensory Dorsal Horn. Cell 168:295-310.e19|
|Browne, Liam E; Latremoliere, Alban; Lehnert, Brendan P et al. (2017) Time-Resolved Fast Mammalian Behavior Reveals the Complexity of Protective Pain Responses. Cell Rep 20:89-98|
|Orefice, Lauren L; Zimmerman, Amanda L; Chirila, Anda M et al. (2016) Peripheral Mechanosensory Neuron Dysfunction Underlies Tactile and Behavioral Deficits in Mouse Models of ASDs. Cell 166:299-313|