We seek to understand the neurobiological basis of touch perception and the mechanisms by which touch circuitry is assembled during development. Our specific research goals are to elucidate the morphological and physiological properties and functions of somatosensory neuron subtypes and to decipher the organizational logic of sensory neuron–spinal cord–brainstem circuits that allow us to perceive and react to the physical world. We also strive to uncover general principles of nervous system development by identifying key molecular events that orchestrate neuronal growth and survival and the establishment of somatosensory neuron connectivity.
The Organization and Function of Neurons That Underlie the Sense of Touch
How do we perceive and react to the physical world? The somatosensory system endows us with a remarkable capacity for object recognition, texture discrimination, sensory-motor feedback, and social exchange. Innocuous or gentle touch of the skin is detected by a large group of physiologically distinct low-threshold mechanoreceptors (LTMRs), whose cell bodies are located in dorsal root ganglia and cranial ganglia. These neurons have one axonal branch that extends to the periphery and another that projects into the spinal cord, thereby providing the means by which touch information is conveyed from the skin to the central nervous system (CNS). LTMR subtypes are uniquely tuned to different types of mechanical stimuli, including hair deflection and pulling, skin indentation, stroking, and stretching. LTMR subtypes are classified as Aβ-, Aδ-, and C-LTMRs based on their action potential conduction velocities, and they can be further distinguished by their slow or rapid adaptation in response to a sustained tactile stimulus. We have established a comprehensive mouse LTMR molecular-genetic toolbox that allows for detailed investigations into the physiology, morphology, function, and development of each LTMR subtype.
We have used our genetic tools and an array of anatomical and physiological approaches to define morphological and functional properties of LTMRs as well as ultrastructural features of their endings that enable remarkably sensitive detection of mechanical stimuli acting on the skin. For example, we discovered that C-LTMRs, implicated in the perception of pleasurable touch, form longitudinal lanceolate endings associated with hair follicles. These C-LTMR axonal endings terminate remarkably close to, and along the longitudinal axis of, hair follicles, rendering this LTMR subtype highly sensitive to hair follicle deflection and gentle stroking of hairy skin. Our analyses have also revealed novel tuning properties of LTMR subtypes, combinations and arrangements of LTMR subtype endings in the skin of hands and feet, and unique morphologies of LTMR endings that underlie subtype sensitivities. Our findings support an integrated model of mechanosensation in which individual qualities of complex tactile stimuli are captured by distinct combinations of LTMR endings in the skin. Thus, a wide range of LTMR subtype activity ensembles underlies our ability to perceive a rainbow of tactile experiences as we interact with the physical world.
Spinal Cord Circuits That Process and Convey Touch Information to the Brain
What is the organizational logic of touch circuits in the CNS? Interestingly, morphologically and physiologically distinct LTMR subtypes whose peripheral projections innervate the same small region of skin exhibit central projections that terminate within narrow, three-dimensional columns of the spinal cord dorsal horn. We believe that these spinal cord LTMR columns represent fundamental units of functional organization that receive and process the range of LTMR subtype activity ensembles emanating from the skin. We further posit that spinal cord interneurons directly receive and process LTMR activities, whereas spinal cord projection neurons carry processed touch information from spinal cord LTMR columns to the brain. To test this model and to gain insight into touch information processing in the spinal cord, we have generated an array of spinal cord dorsal horn neuron subtype–specific molecular-genetic tools that enable analysis and functional characterization of spinal cord dorsal horn neuronal populations. We have so far developed tools that enable analysis of 11 distinct spinal cord interneuron subtypes with the LTMR-recipient zone of the spinal cord. These tools are being used to elucidate the physiological properties, morphologies, synaptic connectivity patterns, and functions of spinal cord interneuron subtypes in processing LTMR inputs to the dorsal horn. In addition, we are striving to gain genetic access to distinct dorsal horn projection neuron subtypes: the postsynaptic dorsal column neurons, spinocervical tract neurons, and anterolateral system neurons. We are also addressing how touch information processing in the spinal cord is affected in disease states, with a particular focus on mouse models of autism spectrum disorders (ASD). We recently found an LTMR-spinal cord synaptic locus of dysfunction that underlies the hypersensitivity to gentle touch in ASD models. Our long-term goal is thus to define the circuitry logic, cellular organization, and functional contributions of specific LTMR–spinal cord–brain pathways that underlie the perception of touch during normal and disease states.
The Development of Somatosensory and Autonomic Nervous System Circuitry
What are the signals that promote development of the peripheral nervous system (PNS) neurons and sculpt the neural circuits in which these neurons participate? In our research, we use mouse molecular-genetic approaches to define the cues that control sensory and sympathetic neuron growth, axonal guidance, and synapse formation and the mechanisms by which target-derived growth factors retrogradely control neuronal maturation and survival during development. We have found that developmental competition among sympathetic neurons for survival is initiated by target field innervation and retrograde nerve growth factor (NGF) signaling. This competition is critically dependent on feedback loops involving sensitization to NGF signaling, paracrine apoptotic signaling, and protection from paracrine apoptotic signals. We also discovered that retrograde NGF signaling and a balance between the activities of these same prosurvival and pro-apoptotic signals similarly determine the amount of synaptic connectivity between sympathetic neurons and their presynaptic partners. Thus, target field innervation triggers rapid and robust competition for both neuron survival and synapse formation through long-range retrograde signaling, the initiation of feedback loops, and a balance of the activities of prosurvival/growth and prodeath/disassembly signals.
Mechanistically, we found that Trk receptor signaling endosomes are key mediators of long-range retrograde signaling in PNS neurons. We have also defined novel axonal growth and guidance mechanisms underlying the establishment of sensory and sympathetic neuron target innervation. Current laboratory efforts seek to establish the mechanisms of somatosensory neuron maturation; the development of unique morphological properties of LTMR subtypes; the nature, molecular composition, and functions of NGF signaling endosomes in sympathetic and sensory neurons; and the functions and mechanisms of growth and guidance cues during the establishment of sensory neuron circuits.
Some of this research is also supported by grants from the National Institutes of Health.
As of February 26, 2016