The biology of somatosensation
Our lab researches the biology of sensory neurons. There are many different types of these specialised neurons (Figure 1); tasked with detecting touch, itch, warming, cooling, and nociception. While we know a lot about the molecular profile of distinct types, we know less about their functional role. We believe that better knowledge of the sensory neuron types that underly normal and pathological pain signaling will help advance our efforts to develop novel pain treatments
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Figure 1. Immunostaining for several population markers in the dorsal root ganglion
Glutamate-gated chloride channel (GluCl)
Figure 2. GluCl is an engineered protein that inhibits neural activity when activated by ivermectin (IVM). GluCl is particularly effective in sensory neurons, with IVM treatment rendering neurons unable to fire action potentials in response to excitatory stimuli for >3 days following a single dose.
Our experimental approach
We use molecular tools to control sensory neuron activity, which allows us to ask fundamental questions on the role that different types play in sensory processing. For example, which population helps us feel warming of the hand? What neurons do mosquito bites activate to cause itch? Or, which population turns light touch painful in chronic pain patients? We have developed a chemogenetic strategy capable of long-term and non-invasive neuronal silencing (Figure 2) to help answer these questions. We use this in combination with electrophysiology, neuroanatomy, and behavioural readouts to investigate the neurobiology underlying somatosensation.
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RESEARCH
Therapeutic targeting
Excess activity of sensory neurons drives pain in patients. Gene therapy approaches to reduce this activity are being developed, however, unbiased silencing of all sensory neurons may have unintended consequences. For example, patients would lose the ability to feel touch, warming or cooling of their skin. We are using molecular profiling and optimised gene delivery design to target only those neurons driving pathological pain, sparing other afferents to continue to perform their important roles. We test our delivery systems in in vivo and in induced pluripotent stem-cell derived sensory neurons (Figure 3).
Population targeting and molecular profiling
Testing
Vector design
Figure 3. We profile discreet populations of sensory neurons in order to design gene delivery approaches capable of targeting specific populations. Candidate systems are testing in classical models, as well as human induced-pluripotent stem cell-derived sensory neurons.
BRN3A/GFP/TUJI
References
1. Using an engineered GluCl channel to silence sensory neurons and treat neuropathic pain at the source (2017). Weir GA, Middleton SJ, Clark AJ, Daniel T, Khovanov N, McMahon SB, Bennett DL. Brain 140: 2570–85.
2. Selective Electrical Silencing of Mammalian Neurons In Vitro by the Use of Invertebrate Ligand-Gated Chloride Channels (2002). Slimko E, McKinney S, Anderson D, Davidson N, Lester H. Journal of Neuroscience 122 (17) 7373-7379