Profound alteration in cutaneous primary afferent activity produced by inflammatory mediators

Smith‐Edwards, Kristen; DeBerry, Jennifer J.; Saloman, Jami L.; Davis, Brian M.; Woodbury, C. Jeffery

doi:10.7554/elife.20527

Cited by 30 publications

(24 citation statements)

References 51 publications

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“…The results of our experiments indicate that GCaMP6 fluorescence in DRG neurons is a sensitive reflection of neuronal activity, with good temporal resolution. Interestingly our approach resulted in much greater numbers of neurons detected at much faster rates, compared to previously published works (Emery et al, 2016; Kim et al, 2016; Smith-Edwards et al, 2016). As expected, the majority of L4 DRG neurons responded to stimulation in a frequency dependent manner: low threshold electrical stimuli recruited fewer cells in the DRG, and these tended to have larger DRG somata.…”

Section: Discussionmentioning

confidence: 52%

“…These techniques have been applied to a variety of central nervous system (CNS) structures, including sensory, motor and visual cortex and spinal cord (Stosiek et al, 2003; Dombeck et al, 2007; Flusberg et al, 2008; Tian et al, 2009; Johannssen and Helmchen, 2010; Ghosh et al, 2011; Chen et al, 2012, 2013; Zariwala et al, 2012; Sun et al, 2013; Dana et al, 2014; Sekiguchi et al, 2016) and, very recently, some peripheral networks (Barretto et al, 2014; Williams et al, 2016; Wu et al, 2015). In recent months a number of papers have describe the application of in vivo imaging also to the dorsal root ganglia (Emery et al, 2016; Kim et al, 2016; Smith-Edwards et al, 2016) but due to the novelty of the technique the peripheral nervous system still remains relatively unexplored.…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, it is evident from this small string of papers, that the application of this technique to the peripheral nervous system is still an evolving field. For example initially slower version of the calcium indicator GCaMP as well as very slow image acquisition speeds may have hampered a more detailed analysis of the pathophysiology of the peripheral nervous system (Kim et al, 2016; Smith-Edwards et al, 2016) while small numbers of sampled cells could reduce the benefits inherent to this approach (Emery et al, 2016; Smith-Edwards et al, 2016). One such evolving claim suggested that the vast majority of primary afferent exhibit modality specificity (Emery et al, 2016) in contrast to frequently observed nociceptive polymodality seen using microneurography, electrophysiology and multiple lines of in vitro evidence.…”

Section: Introductionmentioning

confidence: 99%

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Large scalein vivorecording of sensory neuron activity with GCaMP6

Chisholm

Khovanov

Lopes

et al. 2017

Preprint

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Greater emphasis on the study of intact cellular networks in their physiological environment has led to rapid advances in intravital imaging in the central nervous system, while the peripheral system remains largely unexplored. To assess large networks of sensory neurons we selectively label primary afferents with GCaMP6s and visualise their functional responses in vivo to peripheral stimulation. We show that we are able to monitor simultaneously the activity of hundreds of sensory neurons with sensitivity sufficient to detect, in most cases, single action potentials with a typical rise time of around 200 milliseconds, and an exponential decay with a time constant of approximately 700 milliseconds. Using this sensitive technique we are able to show that large scale recordings demonstrate the recently disputed polymodality of nociceptive primary afferents with between 40-80% of thermally sensitive DRG neurons responding also to noxious mechanical stimulation. We also specifically assess the small population of peripheral cold fibres and demonstrate significant sensitisation to cooling after a model of sterile and persistent inflammation, with significantly increased sensitivity already at decreases of 5°C when compared to uninflamed responses. This not only reveals interesting new insights into the (patho)physiology of the peripheral nervous system but also demonstrates the sensitivity of this imaging technique to physiological changes in primary afferents.Significance StatementMost of our functional understanding of the peripheral nervous system has come from single unit recordings. However, the acquisition of such data is labour-intensive and usually ‘low yield’. Moreover, some questions are best addressed by studying populations of neurons. To this end we report on a system that monitors activity in hundreds of single sensory neurons simultaneously, with sufficient sensitivity to detect in most cases single action potentials. We use this technique to characterise nociceptor properties and demonstrate polymodality in the majority of neurons and their sensitization under inflammatory conditions. We therefore believe this approach will be very useful for the studies of the somatosensory system in general and pain in particular.

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Section: Discussionmentioning

confidence: 52%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Large scalein vivorecording of sensory neuron activity with GCaMP6

Chisholm

Khovanov

Lopes

et al. 2017

Preprint

View full text Add to dashboard Cite

show abstract

“…The recent advances in intracellular calcium indicators allow optical methods of recording rapid calcium transients as surrogate of neural action potentials. However, image recordings have not been conducted at peripheral nerve axons but only at neural somata in the DRG, and not all DRG neurons have detectable calcium transients[43]. …”

Section: Discussionmentioning

confidence: 99%

In vitro multichannel single-unit recordings of action potentials from the mouse sciatic nerve

Chen

Ilham

Guo

et al. 2017

Biomed. Phys. Eng. Express

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Electrode arrays interfacing with peripheral nerves are essential for neuromodulation devices targeting peripheral organs to relieve symptoms. To modulate (i.e., single-unit recording and stimulating) individual peripheral nerve axons remains a technical challenge. Here, we report an in vitro setup to allow simultaneous single-unit recordings from multiple mouse sciatic nerve axons. The sciatic nerve (~30 mm) was harvested and transferred to a tissue chamber, the ~5mm distal end pulled into an adjacent recording chamber filled with paraffin oil. A custom-built multi-wire electrode array was used to interface with split fine nerve filaments. Single-unit action potentials were evoked by electrical stimulation and recorded from 186 axons, of which 49.5% were classed A-type with conduction velocities (CV) greater than 1 m/s and 50.5% were C-type (CV < 1 m/s). The single-unit recordings had no apparent bias towards A- or C-type axons, were robust and repeatable for over 60 minutes, and thus an ideal opportunity to assess different neuromodulation strategies targeting peripheral nerves. For instance, ultrasonic modulation of action potential transmission was assessed using the setup, indicating increased nerve conduction velocity following ultrasound stimulus. This setup can also be used to objectively assess the design of next-generation electrode arrays interfacing with peripheral nerves.

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“…GCaMP6f) (Chen et al, 2013) would enable us to directly examine the tuning properties of large populations of molecularly defined neurons (Emery et al, 2016; Smith-Edwards et al, 2016; Yarmolinsky et al, 2016) to uncover the existence of subclasses with specialized functions. Here, we use functional in vivo imaging to demonstrate that cutaneous Cacla neurons that project to hairy skin form two distinct groups: polymodal nociceptors and high threshold mechanoreceptors (that we call Circ-HTMRs).…”

Section: Introductionmentioning

confidence: 99%

Specialized Mechanosensory Nociceptors Mediating Rapid Responses to Hair Pull

Ghitani

Barik

Szczot

et al. 2017

Neuron

107

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SUMMARY The somatosensory system provides animals with the ability to detect, distinguish and respond to diverse thermal, mechanical and irritating stimuli. While there has been progress in defining classes of neurons underlying temperature sensation and gentle touch, less is known about the neurons specific for mechanical pain. Here, we use in vivo functional imaging to identify a class of cutaneous sensory neurons that are selectively activated by high threshold mechanical stimulation (HTMRs). We show that their optogenetic excitation evokes rapid protective and avoidance behaviors. Unlike other nociceptors, these HTMRs are fast conducting Ad-fibers with highly specialized circumferential endings wrapping the base of individual hair follicles. Notably, we find that Ad-HTMRs innervate unique but overlapping fields and can be activated by stimuli as precise as the pulling of a single hair. Together the distinctive features of this class of Ad-HTMRs appear optimized for accurate and rapid localization of mechanical pain.

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Profound alteration in cutaneous primary afferent activity produced by inflammatory mediators

Cited by 30 publications

References 51 publications

Large scalein vivorecording of sensory neuron activity with GCaMP6

Large scalein vivorecording of sensory neuron activity with GCaMP6

In vitro multichannel single-unit recordings of action potentials from the mouse sciatic nerve

Specialized Mechanosensory Nociceptors Mediating Rapid Responses to Hair Pull

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