Tactile stimulation is an integral component of the human sensory experience, and also one of the most complex. Skin is the largest sensory organ, yet little is known about how sensations, such as touch, pain, and itch, are represented and decoded by the somatosensory circuit. A promising approach is to gain genetic access to the neuronal subtypes that comprise the circuit, so that their morphological and physiological properties, synaptic connections, and distinct roles in touch perception can be elucidated. To this end, novel mouse genetic strategies have been developed to molecularly label the subtypes of sensory neurons, known as low-threshold mechanoreceptors (LTMRs), that convey innocuous mechanosensory information from mouse hairy skin to the spinal cord dorsal horn and brainstem. The objective of this research proposal is to utilize this molecular genetic toolbox, in combination with electrophysiological and immunohistochemical approaches, to gain mechanistic insight into the developmental events that underlie the formation and organization of functional touch circuits. The development of morphological properties, including central and peripheral innervation patterns, axonal branching and pruning, and receptive field refinement, will be assessed in vivo throughout development for each LTMR subpopulation. The maturation of LTMR physiological responses to a variety of touch stimuli will be evaluated using in vivo loose-patch recordings of genetically labeled neurons. As preliminary evidence suggests that LTMR subtypes display functional organization through tiling of peripheral receptive fields and somatotopic arrangements of spinal cord columns, the formation of this exquisite organizational logic will also be examined. Finally, the role of neural activity in these processes will be define through silencing of LTMR intrinsic excitability and synaptic activity. Collectively, these experiments will elucidate the developmental mechanisms that generate unique representations within the touch circuit. Because patients with autism spectrum disorder (ASD) display substantial deficits in somatosensation, future studies will investigate LTMR wiring in mouse models of ASD and related neurodevelopmental disorders.
Individuals with autism spectrum disorder (ASD) and other neurodevelopmental disabilities exhibit significant impairments in touch sensation, yet the molecular basis for these deficits is not well understood. The goal of this proposal is to shed light on the fundamental processes that sculpt development of the touch circuit, and to ultimately identify the sources of improper wiring in ASD and related disorders.
