Biology subjects

Xie, Y.-F.

Publications and source records attributed to Xie, Y.-F..

3 recordsLinked to original sources

bioRxiv2025

Nociceptor clock genes control excitability and pain perception in a sex- and time-dependent manner

Nociception is critical for pain perception and survival and begins with the activation of nociceptors, specialized sensory neurons located in the dorsal root ganglia (DRGs). Both sex and circadian rhythms, governed by clock genes, seem to play a significant role in modulating pain perception. However, the potential interaction between circadian rhythms and sex differences in nociception at the peripheral level has been largely overlooked. Here, we first report that DRGs from mice express clock genes in a time- and sex-dependent manner. Using whole-cell recordings in whole-mounted DRGs and optogenetic stimulation of Nav1.8-expressing neurons, we demonstrate that male nociceptors exhibit reduced excitability during the night, while female nociceptor excitability remains stable across time points. Disruption of the core clock gene Bmal1 in Nav1.8-expressing neurons not only diminished nociceptor activity but also abolished the nighttime reduction in heat sensitivity, highlighting a pivotal role for the molecular clock in regulating nociception. Transcriptomic analyses, voltage-clamp recordings, and pharmacological experiments identified the voltage-gated chloride channel ClC-2, controlled by Bmal1, as a key mediator for the observed fluctuations in male nociceptor excitability. This work opens new avenues for chronobiology-inspired strategies in pain management tailored to sex-specific mechanisms.

neuroscience↗

bioRxiv2024

Quantifying the contribution of somatosensory afferent types and changes therein to pain sensitivity using transcutaneous optogenetic stimulation in behaving mice

Optogenetics provides an unprecedented opportunity to delineate how different somatosensory afferents contribute to sensation, including pain. Afferents expressing channelrhodopsin-2 (ChR2) can be selectively activated by transcutaneous photostimuli applied to behaving mice. Despite care taken to precisely target expression of ChR2 to specific cell types, imprecise photostimulation has hindered quantitative optogenetic-based behavioral testing. Here, we used a robot to reproducibly apply transcutaneous optogenetic stimuli to the hind paw of mice while measuring nocifensive withdrawal. Different photostimulus waveforms (pulses and ramps) and response metrics (threshold and latency) were compared in mice expressing ChR2 in all afferents (Advillin-ChR2) or preferentially in nociceptors (NaV1.8-ChR2). CFA-induced inflammation caused withdrawal from ramped photostimuli to become faster relative to baseline and to vehicle-injected controls whereas pulsed photostimuli revealed a modest increase in threshold. Analgesia caused by NaV1.7 and 1.8 channel blockade was evident in both testing protocols. Overall, ramp-based testing was more effective and more efficient (i.e. required less time and total stimulation) than pulse-based testing. Electrophysiological measurements confirmed that inflammation increases nociceptor excitability without affecting phototransduction, and suggests that withdrawal latency depends on the number of nociceptors activated rather than how strongly each nociceptor is activated. Consistent with changes described in nociceptor somata, the behavioral consequences of peripherally blocking different voltage-gated sodium (NaV) channels showed that nociceptor axons normally rely on NaV1.8 but upregulate NaV1.7 after inflammation, with important clinical implications for drug efficacy. Collectively, these results demonstrate the utility of optogenetic pain testing when reproducibly delivered and strategically designed photostimuli are used.

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↗