Intermittent Failure of Spike Propagation in Primary Afferent Neurons during Tactile Stimulation

Abstract

Primary afferent neurons convey somatosensory information to the CNS. Low-threshold mechanoreceptors are classified as slowadapting (SA) or rapid-adapting (RA) based on whether or not they spike repetitively during sustained tactile stimulation; the former are subclassified as Type 1 or 2 based on the regularity of their spiking. Recording in vivo from DRGs of mice, we observed irregular-and regular-spiking units consistent with SA1 and SA2 low-threshold mechanoreceptors, but some units, which we labeled "semiregular," did not fit cleanly into the existing classification scheme. Analysis of their spiking revealed integer-multiple patterning in which spike trains comprised a fundamental interspike interval and multiples thereof. Integer-multiple-patterned spiking was reproduced by randomly removing spikes from an otherwise regular spike train, suggesting that semiregular units represent SA2 units in which some spikes are "missing." We hypothesized that missing spikes arose from intermittent failure of spikes to initiate or to propagate. Intermittent failure of spike initiation was ruled out by several observations: integer-multiple-patterned spiking was not induced by intradermal lidocaine, was independent of stimulus modality (mechanical vs optogenetic), and could not be reproduced in a conductance-based model neuron given constant input. On the other hand, integer-multiple-patterned spiking was induced by application of lidocaine to the DRG, thus pinpointing intermittent failure of spike propagation as the basis for integer-multiple-patterned spiking. Indeed, half of all SA2 units exhibited some missing spikes, mostly at low rate (Ͻ5%), which suggests that axons are efficient in using the lowest safety factor capable of producing near-perfect propagation reliability.

Dorsal root ganglia control nociceptive input to the central nervous system

“…Single-unit recordings (Fig. 5) revealed that evoked spikes in C and A fibers do fail occasionally under basal conditions (at a rate of ~16% in C and ~6% in A fibers), which was consistent with a recent report (18). Thus, basal filtering does exist but when measuring evoked single-unit spikes it is much lower than ~50% mismatch seen in our multi-unit SN/DR recordings.…”

Interactions among Diameter, Myelination and the Na/K pump Affect Axonal Resilience to High Frequency Spiking

“…Of course, the frequency threshold and the number of spikes required to cause spike failure will depend on the specifics of the expression of neuronal conductances, and will likely show variability as a consequence of variable channel densities (46). Additionally, intrinsic channel noise can cause spike failure (4,27), and the normal function of the Na/K ATPases requires ATP, the supply of which has a limit (35). Both a shortage of ATP after continuous firing and channel noise can further reduce axonal reliability of propagating spikes.…”

“…1B). However, neurons can fire at high frequencies when animals receive stimuli or undergo behavior changes (7,(25)(26)(27). With continuous high frequency spiking, [Na + ] can accumulate if subsequent spikes occur before the complete recovery of a preceding spike elicited [Na + ] rise.…”

“…Both a shortage of ATP after continuous firing and channel noise can further reduce axonal excitability. Interestingly, a recent study observed intermittent spike propagation failure in vivo in dorsal root ganglia of mice during sustained tactile stimuli(27). [Na + ] accumulation may be another important factor causing the failure apart from the channel noise.Axon diameters can be up to 20 μm in the human peripheral nervous system and 1.5 mm in squid giant axons (1).…”

Minimal requirements for a neuron to co-regulate many properties and the implications for ion channel correlations and robustness

“…8). But one must also consider that energy efficiency trades off with functional considerations like propagation safety factor 61 . Target values might emerge from this competition 62 but such mechanisms were beyond the scope of the current study.…”