Biology subjects

Ratte, S.

Publications and source records attributed to Ratte, S..

6 recordsLinked to original sources

bioRxiv2025

Adaptation in somatosensory afferents improves rate and temporal coding of vibrotactile stimulus features

Adaptation is a common neural phenomenon wherein sustained stimulation evokes fewer action potentials (spikes) over time. Rather than simply reduce firing rate, adaptation may help neurons form better (i.e. more discriminable) representations of sensory input. To study effects of adaptation in low-threshold mechanoreceptors (LTMRs), we recorded single unit LTMR responses to 30-second-long vibrotactile stimuli with different intensities and frequencies applied to the hind paw of rats. To assess the impact of adaptation on somatosensory encoding, decoders were applied to the initial and late (adapted) phases of population-level responses to assess the decodability (discrimination) of stimulus intensity and frequency. Adaptation-mediated changes in the rate and timing (phase-locking) of spikes were quantified. Rate coding of stimulus intensity was improved by the nonuniform reduction in firing rate across responses to different stimuli, and across neurons. This improvement was absent in simulations with uniform reductions in firing rate, thus revealing the necessity of stimulus-dependent variability in adaptation effects. Spike timing (quantified as interspike intervals) remained highly informative about stimulus frequency throughout stimulation despite the progressive reduction in spike count over time. When the drop in spike count was accounted for, adaptation was found to improve temporal coding of stimulus frequency by increasing the precision of phase-locking. In other words, adaptation improved the precision of spike timing, and this increased the information about stimulus frequency conveyed by each spike. These results show that adaptation, by modulating spiking in different ways, can improve encoding of different stimulus features using different coding schemes. SIGNIFICANCE STATEMENTFiring rate adaptation refers to the progressive reduction in spiking during sustained stimulation. Adaptation is often ascribed to fatigue and could conceivably introduce ambiguity into neural representations by causing (the probability or timing of) spike generation to depend not only on the current stimulus, but also on past stimulation. By recording from rat primary somatosensory afferents during vibrotactile stimulation of the paw, we show that nonuniform adaptation across sets of afferents improves rate-based coding of stimulus intensity. We also show that adaptation improves spike timing (phase-locking to a periodic stimulus) which, in turn, improves temporal coding of stimulus frequency. These results demonstrate that early-stage adaptation improves somatosensory signals relayed centrally.

neuroscience↗

bioRxiv2024

Encoding of vibrotactile stimuli by mechanoreceptors in rodent glabrous skin

Somatosensory coding in rodents has been mostly studied in the whisker system and hairy skin, whereas the function of low-threshold mechanoreceptors (LTMRs) in rodent glabrous skin has received scant attention, unlike in primates where glabrous skin has been the focus. The relative activation of different LTMR subtypes carries information about vibrotactile stimuli, as does the rate and temporal patterning of LTMR spikes. Rate coding depends on the probability of a spike occurring on each stimulus cycle (reliability) whereas temporal coding depends on the timing of spikes relative to the stimulus cycle (precision). Using in vivo extracellular recordings in rats and mice, we measured the reliability and precision of LTMR responses to different tactile stimuli including sustained pressure and vibration. Similar to other species, rodent LTMRs were separated into rapid-adapting (RA) or slow-adapting (SA) based on their response to sustained pressure. However, unlike the dichotomous frequency preference characteristic of RAI and RAII afferents in other species, rodent RAs fell along a continuum. Fitting generalized linear models (GLMs) to experimental data reproduced the reliability and precision of rodent RAs. The resulting model parameters highlight key mechanistic differences across the RA spectrum; specifically, the integration window of different RAs transitions from wide to narrow as tuning preferences across the population move from low to high frequencies. Our results show that rodent RAs can support both rate and temporal coding, but their heterogeneity suggests that co-activation patterns play a greater role in population coding than for dichotomously tuned primates RAs. Significance StatementOur sense of touch starts with activation of nerve fibres in the skin. Although response properties of various fibre types are well-established in other species (e.g. primates), quantitative characterization in rats and mice is limited. To fill this gap, we performed a comprehensive electrophysiological investigation into the coding properties of tactile fibres in rodent non-hairy skin and then simulated these fibres to explain differences in their responses. We show that rodent tactile fibres resemble those from other species, but that their heterogeneity at the population level may differ, with potentially important implications for encoding of touch. Simulations reveal intrinsic mechanisms that support this heterogeneity and provide a useful tool to explore somatosensation in rodents.

neuroscience↗

bioRxiv2023

Paresthesia during spinal cord stimulation depends on synchrony of dorsal column axon activation

Spinal cord stimulation (SCS) reduces chronic pain. Conventional (40-60 Hz) SCS engages spinal inhibitory mechanisms by activating low-threshold mechanoreceptive afferents with axons in the dorsal columns (DCs). But activating DC axons typically causes a buzzing sensation (paresthesia) that can be uncomfortable. Kilohertz-frequency (1-10 kHz) SCS produces analgesia without paresthesia and is thought, therefore, not to activate DC axons, leaving its mechanism unclear. Here we show in rats that kilohertz-frequency SCS activates DC axons but causes them to spike less synchronously than conventional SCS. Spikes desynchronize because axons entrain irregularly when stimulated at intervals shorter than their refractory period, a phenomenon we call overdrive desynchronization. Effects of overdrive desynchronization on evoked compound action potentials were verified in simulations, rats, pigs, and a chronic pain patient. Whereas synchronous spiking in DC axons is necessary for paresthesia, asynchronous spiking is sufficient to produce analgesia. Asynchronous activation of DC axons thus produces paresthesia-free analgesia.

neuroscience↗

bioRxiv2022

Equivalent excitability through different sodium channel subtypes and implications for analgesia by subtype-selective drugs

Nociceptive sensory neurons convey pain-related signals to the CNS using action potentials. Loss-of-function mutations in the voltage-gated sodium channel NaV1.7 cause insensitivity to pain (presumably by reducing nociceptor excitability) but efforts to treat pain by inhibiting NaV1.7 pharmacologically have largely failed. This may reflect the variable contribution of NaV1.7 to nociceptor excitability. Contrary to claims that NaV1.7 is necessary for nociceptors to initiate action potentials, we show that nociceptors can achieve equivalent excitability using different combinations of NaV1.3, NaV1.7, and NaV1.8. Selectively blocking one of those NaV subtypes reduces nociceptor excitability only if the other two subtypes are weakly expressed. For example, excitability relies on NaV1.8 in acutely dissociated nociceptors but responsibility shifts to NaV1.7 and NaV1.3 by the fourth day in culture. A similar shift in NaV dependence occurs in vivo after inflammation, impacting ability of the NaV1.7-selective inhibitor PF-05089771 to reduce pain in behavioral tests. Flexible use of different NaV subtypes exemplifies degeneracy - equivalent function using different components - and compromises the reliable modulation of nociceptor excitability by subtype-selective inhibitors. Identifying the dominant NaV subtype to predict drug efficacy is not trivial. Degeneracy at the cellular level must be considered when choosing drug targets at the molecular level. SIGNIFICANCE STATEMENTNociceptors can achieve equivalent excitability using different sodium channel subtypes. The analgesic efficacy of subtype-selective drugs hinges on which subtype controls excitability. This contingency likely contributes to poor clinical outcomes.

neuroscience↗

bioRxiv2021

Spike initiation properties in the axon support high-fidelity signal transmission

The axon initial segment (AIS) converts graded depolarization into all-or-none spikes that are transmitted by the axon to downstream neurons. Analog-to-digital transduction and digital signal transmission call for distinct spike initiation properties (filters) and those filters should, therefore, differ between the AIS and distal axon. Here we show that unlike the AIS, which spikes repetitively during sustained depolarization, the axon spikes transiently and only if depolarization reaches threshold before KV1 channels activate. Rate of depolarization is critical. This was shown by optogenetically evoking spikes in the distal axon of CA1 pyramidal neurons using different photostimulus waveforms and pharmacological conditions while recording antidromically propagated spikes at the soma, thus circumventing the prohibitive difficulty of patching intact axons. Computational modeling shows that KV1 channels in the axon implement a high-pass filter that is matched to the axial current waveform associated with spike propagation, thus maximizing the signal-to-noise ratio to ensure high-fidelity transmission of spike-based signals.

neuroscience↗

bioRxiv2019

Excitatory neurons are more disinhibited than inhibitory neurons by chloride dysregulation in the spinal dorsal horn

Neuropathic pain is a debilitating condition caused by the abnormal processing of somatosensory input. Synaptic inhibition in the spinal dorsal horn plays a key role in that processing. Mechanical allodynia - the misperception of light touch as painful - occurs when inhibition is compromised. Disinhibition is due primarily to chloride dysregulation caused by hypofunction of the potassium-chloride co-transporter KCC2. Here we show, in rats, that excitatory neurons are disproportionately affected. This is not because chloride is differentially dysregulated in excitatory and inhibitory neurons, but, rather, because excitatory neurons rely more heavily on inhibition to counterbalance strong excitation. Receptive fields in both cell types have a center-surround organization but disinhibition unmasks more excitatory input to excitatory neurons. Differences in intrinsic excitability also affect how chloride dysregulation affects spiking. These results deepen understanding of how excitation and inhibition are normally balanced in the spinal dorsal horn, and how their imbalance disrupts somatosensory processing.

neuroscience↗