Biology subjects

Espinosa, F.

Publications and source records attributed to Espinosa, F..

5 recordsLinked to original sources

bioRxiv2025

Mycobacterium tuberculosis sulfolipid-1 (Sl-1) increases the excitability of mouse and human TRPV1-positive sensory neurons in a YM254890-reversible fashion

Cough is a hallmark sign of tuberculosis and key driver of transmission. While traditionally attributed to host-driven inflammation, we previously demonstrated that Mycobacterium tuberculosis lipid extract (Mtb extract) and its component sulfolipid-1 (SL-1) directly activate nociceptive neurons to induce cough in guinea pigs. However, the cellular mechanisms by which Mtb extract and SL-1 modulate nociceptive sensory neurons remain incompletely understood. Here, we show that Mtb extract enhances action potential (AP) generation in mouse nodose nociceptors via an SL-1-dependent mechanism. Using calcium imaging, we found that Mtb extract and SL-1 increased intracellular Ca{superscript 2} signals in TRPV1 neurons from both mouse nodose and human dorsal root ganglia (hDRG). These Ca{superscript 2} signals were attenuated by the Gq/11 pathway inhibitor YM254890, even in the absence of extracellular Ca{superscript 2}, suggesting involvement of intracellular Ca{superscript 2} stores. Together, these findings indicate that SL-1 engages Gq/11-coupled pathways to sensitize nociceptors via intracellular Ca2+ release, providing mechanistic insight into tuberculosis-associated cough and potential targets for therapeutic intervention.

neuroscience↗

bioRxiv2025

Type I interferons enhance human dorsal root ganglion nociceptor excitability and induce TRPV1 sensitization

Type I interferons (IFNs) are critical cytokines for antiviral defense and are linked to painful inflammatory diseases like rheumatoid arthritis and neuropathic pain in humans. Studies in rodent models demonstrate a direct action on sensory neurons in the dorsal root ganglion (DRG) to promote hyperexcitability but rodent behavioral results are conflicting with some reports of pro-nociceptive actions and others of anti-nociception. Given the role of type I IFNs in human disease, we sought to clarify the action of action of IFN- and IFN-{beta} on human DRG (hDRG) nociceptors. We found that IFN receptor subunits IFNAR1 and IFNAR2 are functionally expressed by these neurons and their engagement induces canonical STAT1 signaling and non-canonical MAPK activation as measured by increased phosphorylation of the cap-binding protein eIF4E by MNK1/2 kinases. Using patch clamp electrophysiology, Ca2+-imaging, and multi-electrode arrays we demonstrate that IFN- and -{beta} increase the excitability of hDRG neurons with short (30 min) and long-term (24-48 h) exposure and prolong the duration of capsaicin responses, an effect that is blocked by inhibition of MNK1/2 with eFT508, a specific inhibitor of these kinases. Our studies support the conclusion that type I IFNs are pronociceptive when they interact with hDRG nociceptors in the periphery.

neuroscience↗

bioRxiv2025

Suzetrigine (VX-548) exhibits activity-dependent effects on human dorsal root ganglion neurons

Non-selective antagonists of voltage-gated sodium channels (VGSCs) provide effective local analgesia, but systemic administration is fraught with unwanted cardiovascular and central nervous system toxicity. The development of antagonists targeting VGSCs preferentially expressed in peripheral neurons, such as NaV1.7, 1.8, and 1.9, could mitigate these risks. One such new small molecule that selectively inhibits NaV1.8, is orally bioavailable, and has recent FDA approval for the treatment of acute pain is suzetrigine (VX-548). Here we tested the effects of this agent on human dorsal root ganglion (hDRG) neurons obtained from either patients undergoing surgical thoracic vertebrectomy or from organ donors in parallel electrophysiology studies across 2 laboratories. Bath application of 10 nM suzetrigine abolished spontaneous discharges previously shown to be associated with on-going neuropathic pain within minutes. In contrast, suppression of discharges evoked by intracellular current injection required more prolonged application times. These results suggest that suzetrigine will likely show efficacy versus spontaneous pain but may have less robust effects on evoked or breakthrough pain.

neuroscience↗

bioRxiv2022

Electrophysiological properties of neurons in the intermediate thoracolumbar spinal cord mediating proprioception.

Animals must know where their body is in relationship to their environment to move appropriately. Proprioception, the sense of limb and body position, is required to produce feedforward predictions of future movement as well as provide feedback information during movement to update the system. How proprioception is processed at the level of the spinal cord is not well understood. Most work has focused on Clarkes column (CC) neurons, a component of the dorsal spinocerebellar tract (DSCT). CC neurons receive hindlimb proprioceptive information and send it directly to the cerebellum with no axon collaterals to other neurons in the spinal cord. In contrast to CC neurons, we previously found that a subset of thoracolumbar Atoh1-lineage neurons also receives proprioceptive afferent inputs, but project locally within the spinal cord including synapsing on motor neurons. We set out to understand how CC and Atoh1-lineage neurons in the thoracolumbar spinal cord respond to electrical activity. Using in vitro acute spinal cord slices and whole-cell patch clamp, we characterized the passive and active electrical properties of CC and thoracolumbar Atoh1-lineage neurons. We find that most CC neurons increase their action potential firing frequency linearly upon increased current injection up to high frequencies likely due to a hyperpolarization-activated current (Ih). In contrast, most Atoh1-lineage neurons do not have an Ih current and therefore, their firing frequency fades with increasing current injection. Interestingly, although Atoh1-lineage neurons are classically subdivided into a contralaterally-projecting Medial and ipsilaterally-projecting Lateral population, we find no obvious electrophysiological signatures that could distinguish these spatially distinct populations. Finally, we set out to determine the organization of the inputs to CC and Atoh1-lineage neurons. In a hemisected spinal cord preparation, while recording from neurons in the lower thoracic to upper lumbar segments, we find that CC neurons receive low threshold inputs (proprioceptive or low threshold mechanoreceptor) from lumbar 2 to 4 dorsal roots, while Atoh1-lineage Medial neurons do not. This raises the possibility that Atoh1-lineage Medial neurons receive proprioceptive inputs from more local dorsal roots. Altogether, we find that CC and Atoh1-lineage neurons have distinct membrane properties and sensory input organization even though they are both reported to receive proprioceptive information and are in close proximity in lamina V-VII of the thoracolumbar spinal cord.

neuroscience↗

bioRxiv2020

Motor neurons involved in fine motor control are labeled by tracing Atoh1-lineage neurons in the spinal cord

Motor neurons (MNs) innervating the digit muscles of the intrinsic hand and foot (IH and IF) control fine motor movements. Previous studies suggest that the IH and IF MN pools have a unique developmental history in comparison to limb MN pools. Consistent with having this unique development, we find that the IH and IF MN pools are labeled postnatally using a CRE knock-in mouse line of Atoh1, a developmentally expressed basic helix-loop-helix (bHLH) transcription factor, while limb-innervating MN pools are not. Approximately 60% of the IH and IF MN pools are labeled and are a mixture of alpha and gamma-MNs. In addition, because Atoh1 is known developmentally to specify many cerebellar-projecting neurons, we tested the hypothesis that IH and IF MNs can send axon collaterals to the cerebellum as a mechanism of corollary discharge. Using intersectional genetic, viral labeling, and retrograde labeling strategies, we were unable to provide evidence in support of this idea. As a secondary finding of our viral labeling experiments, we report here that injection of both AAV and Lentiviruses in the periphery can cross the blood-brain barrier to infect Purkinje cells within the central nervous system. Altogether, though, we find that labeling of the IH and IF motor neurons using the Atoh1 CRE knock-in mouse suggests that IH and IF MNs have a unique developmental history and that this mouse strain might be a useful tool to target these specific sets of neurons allowing for functional studies of fine motor control. Significance StatementMotor neurons (MNs) of the intrinsic hand and foot (IH and IF) are labeled postnatally using a CRE knock-in mouse line of the basic helix-loop-helix (bHLH) transcription factor Atoh1 indicating a unique developmental history. We tested whether IH and IF MNs send axon collaterals rostrally to the cerebellum as a mechanism of direct corollary discharge from MNs, but the question remains unresolved. As a resource for the community, we report that injection of both AAV and Lentiviruses in the periphery can cross the blood-brain barrier and infect Purkinje cells within the central nervous system.

developmental biology↗