Publications

A stimulus–state geometry in somatosensory cortex reorganizes during inflammatory pain

Ara Schorscher-Petcu, Isobel Parkes, Liam E. Browne

bioRxiv

Mechanical input was carried in the organisation of activity across the S1 population, embedded with movement and arousal, rather than by a distinct class of stimulus-selective neurons. Inflammatory injury reorganised this stimulus–state geometry, coupling mechanical responses more tightly to movement and arousal.

Identified a cortical injury mode, in which inflammation reconfigured S1 population geometry to bind mechanical input to widespread protective control.

Precision cutaneous stimulation in freely moving mice

Isobel Parkes, Ara Schorscher-Petcu, Qinyi Gan, Liam E. Browne

eLife

Closed-loop control combined real-time body-part tracking with remote optical stimulation, allowing defined areas of skin to be targeted automatically as mice explored arenas and mazes, and allowing stimulation to depend on what the animal was doing and where it was.

Brought precise, remote cutaneous stimulation into freely moving, behaviourally structured experiments.

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Naturalistic climbing reveals adaptive strategies for interlimb coordination in freely moving mice

Christopher J. Black, Marco Beato, Liam E. Browne, Robert M. Brownstone, Stephanie C. Koch

iScience

Climbing preserved some features of ordinary gait but required a different organisation of the limbs: forelimbs alternated, hindlimbs tended to move together, and both patterns changed to overcome a gap.

Established an approach to quantify naturalistic climbing in freely moving mice.

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Epineural optogenetic activation of nociceptors initiates and amplifies inflammation

Frédéric Michoud, Corey Seehus, Philipp Schönle, Noé Brun, Daniel Taub, Zihe Zhang, Aakanksha Jain, Ivan Furfaro, Outman Akouissi, Rachel Moon, Pascale Meier, Katia Galan, Benjamin Doyle, Michael Tetreault, Sébastien Talbot, Liam E. Browne, Qiuting Huang, Clifford J. Woolf, Stéphanie P. Lacour

Nature Biotechnology

A soft, wireless implant allowed nociceptor axons in the sciatic nerve to be activated selectively and repeatedly in freely moving mice. Signals travelling towards the spinal cord produced pain-related behaviour; signals travelling towards the skin mobilised immune cells and amplified inflammation when it was already present.

Neural interface for selective control of nociceptors, allowing their behavioural and immune effects to be studied together.

DOI

Scanned optogenetic control of mammalian somatosensory input to map input-specific behavioral outputs

Ara Schorscher-Petcu, Flóra Takács, Liam E. Browne

eLife

Scanned transdermal optogenetics activated genetically defined sensory afferents with free-space spatiotemporal precision without touching the animal. High-speed behavioural mapping showed that nociceptors and low-threshold mechanoreceptors recruit distinct whole-body actions, and that rapid protective responses depend on the animal’s starting pose.

Introduced “remote touch”: non-contact free-space control of defined cutaneous inputs with millisecond-scale mapping of local and whole-body behaviour.

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Vagal sensory neurons drive mucous cell metaplasia

Sébastien Talbot, Benjamin Doyle, Junwei Huang, Jo-Chiao Wang, Maryam Ahmadi, David P. Roberson, Ajay Yekkirala, Simmie L. Foster, Liam E. Browne, Bruce P. Bean, Bruce D. Levy, Clifford J. Woolf

Journal of Allergy and Clinical Immunology

Airway sensory neurons were not passive to allergic inflammation: their activation shifted mucin production towards Muc5AC, while silencing them prevented goblet-cell hyperplasia and mucus metaplasia. The effect depended on sensory-neuron release of Substance P.

Defined a vagal sensory pathway linking allergic inflammation to pathological mucus production through Substance P.

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Controlling engineered P2X receptors with light

Benjamin N. Atkinson, Vijay Chudasama, Liam E. Browne

Methods in Molecular Biology

This chapter sets out the complete protocol for expressing, chemically modifying, and recording engineered P2X receptors that can be opened and closed rapidly with different wavelengths of light.

DOI

Optical cuff for optogenetic control of the peripheral nervous system

Frédéric Michoud, Loïc Sottas, Liam E. Browne, Léonie Asboth, Alban Latremoliere, Miyuki Sakuma, Grégoire Courtine, Clifford J. Woolf, Stéphanie P. Lacour

Journal of Neural Engineering

A soft optical cuff delivered light directly to genetically targeted axons in the sciatic nerve of mice. Motor recruitment could be graded by the stimulus, while prolonged implantation left nerve structure, sensation and movement intact.

Neural interface for optogenetic control of peripheral nerves.

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Time-resolved fast mammalian behavior reveals the complexity of protective pain responses

Liam E. Browne, Alban Latremoliere, Brendan P. Lehnert, Alyssa Grantham, Catherine Ward, Chloe Alexandre, Michael Costigan, Frédéric Michoud, David P. Roberson, David D. Ginty, Clifford J. Woolf

Cell Reports

Minimal nociceptor input acted less like a command to withdraw one limb than a tripwire: it recruited rapid, coordinated movements across the body, and even rapid awakening, while posture and context determined the sequence of protective behaviour.

Mapped the whole-animal consequences of a single nociceptor volley at millisecond resolution.

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Casting light on pain

Liam E. Browne, Clifford J. Woolf

Nature Biotechnology

Discussed the emerging use of optogenetics to activate and silence nociceptors selectively in vivo, and how precise control of peripheral pain pathways could reveal their contribution to pain and provide new ways to test interventions.

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Optical control of trimeric P2X receptors and acid-sensing ion channels

Liam E. Browne, João P. M. Nunes, Joan A. Sim, Vijay Chudasama, Laricia Bragg, Stephen Caddick, R. Alan North

Proceedings of the National Academy of Sciences

Engineered P2X receptors could be opened and closed within milliseconds using different wavelengths of light, without their normal extracellular ligand. The same strategy controlled P2X2/3 receptors and acid-sensing ion channels, linking optical control to the molecular movements that open these trimeric channels.

Converted P2X receptors and ASICs into reversible, millisecond optical switches.

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P2X7 receptor channels allow direct permeation of nanometer-sized dyes

Liam E. Browne, Vincent Compan, Laricia Bragg, R. Alan North

Journal of Neuroscience

Combined electrophysiology, fluorescent dye measurements and pore mutagenesis to test how large molecules enter cells when P2X7 receptors open. Changes to the ion permeation pathway altered ion and dye selectivity together, providing direct evidence that nanometre-sized molecules can pass through the receptor channel itself.

Helped resolve the long-standing P2X7 “large-pore” problem by linking ion permeation, dye entry and pore accessibility to show that nanometre-sized molecules can pass through the receptor channel directly.

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P2X receptor intermediate activation states have altered nucleotide selectivity

Liam E. Browne, R. Alan North

Journal of Neuroscience

Binding of ATP to only part of the trimeric P2X receptor changed the properties of the remaining binding sites before the channel opened. These intermediate closed states became sensitive to nucleotides that were ineffective at the resting receptor.

Identified functionally distinct intermediate states during the stepwise activation of P2X receptors.

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P2X receptor channels show threefold symmetry in ionic charge selectivity and unitary conductance

Liam E. Browne, Lishuang Cao, Helen E. Broomhead, Laricia Bragg, William J. Wilkinson, R. Alan North

Nature Neuroscience

Altering the same pore-forming position in one, two, or all three subunits of a P2X receptor produced progressive changes in ion selectivity and single-channel conductance, revealing how each subunit contributes to the channel's permeation pathway.

Showed that each of the three P2X receptor subunits contributes symmetrically to the pore, determining ionic selectivity and single-channel conductance.

DOI

Structural determinants of drugs acting on the NaV1.8 channel

Liam E. Browne, Frank E. Blaney, Shahnaz P. Yusaf, Jeff J. Clare, Dennis Wray

Journal of Biological Chemistry

Systematic changes to the pore-forming regions of NaV1.8 revealed how channel structure determines the actions of sodium-channel inhibitors, defining the regions of the channel that contribute to drug binding.

Provided the first experimental map of drug-binding sites in NaV1.8. The binding region for a selective NaV1.8 inhibitor was later confirmed by structural studies, and NaV1.8 is now targeted by an FDA-approved non-opioid analgesic.

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Functional and pharmacological properties of human and rat NaV1.8 channels

Liam E. Browne, Jeff J. Clare, Dennis Wray

Neuropharmacology

Human and rat NaV1.8 differed substantially in their gating and in how inhibition developed and recovered during activity. The work showed that both species and channel state strongly influence NaV1.8 pharmacology, including an unexpected activity-dependent relief of inhibition.

Defined fundamental properties of human NaV1.8 pharmacology, including species dependence, state dependence and activity-dependent disinhibition, for a channel that has since become used for the treatment of pain.

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