Sensory Neurons Research Articles

Ghrelin Modulates Voltage-Gated Ca2+ Channels through Voltage-Dependent and Voltage-Independent Pathways in Rat Gastric Vagal Afferent Neurons.

The orexigenic gut peptide ghrelin is an endogenous ligand for the growth hormone secretagogue receptor type 1a (GHSR1a). Systemic ghrelin administration has previously been shown to increase gastric motility and emptying. While these effects are known to be mediated by the vagus nerve, the cellular mechanism underlying these effects remains unclear. Therefore, the purpose of the present study was to investigate the signaling mechanism by which GHSR1a inhibits voltage-gated Ca2+ channels in isolated rat gastric vagal afferent neurons using whole-cell patch-clamp electrophysiology. The ghrelin pharmacological profile indicated that Ca2+ currents were inhibited with a log (Ic50) = -2.10 ± 0.44 and a maximal inhibition of 42.8 ± 5.0%. Exposure to the GHSR1a receptor antagonist (D-Lys3)-GHRP-6 reduced ghrelin-mediated Ca2+ channel inhibition (29.4 ± 16.7% vs. 1.9 ± 2.5%, n = 6, P = 0.0064). Interestingly, we observed that activation of GHSR1a inhibited Ca2+ currents through both voltage-dependent and voltage-independent pathways. We also treated the gastric neurons with either pertussis toxin (PTX) or YM-254890 to examine whether the Ca2+ current inhibition was mediated by the Gα i/o or Gα q/11 family of subunits. Treatment with both PTX (Ca2+ current inhibition = 15.7 ± 10.6%, n = 8, P = 0.0327) and YM-254890 (15.2 ± 11.9%, n = 8, P = 0.0269) blocked ghrelin's effects on Ca2+ currents, as compared with control neurons (34.3 ± 18.9%, n = 8). These results indicate GHSR1a can couple to both Gα i/o and Gα q/11 in gastric vagal afferent neurons. Overall, our findings suggest GHSR1a-mediated inhibition of Ca2+ currents occurs through two distinct pathways, offering necessary insights into the cellular mechanisms underlying ghrelin's regulation of gastric vagal afferents. SIGNIFICANCE STATEMENT: This study demonstrated that in gastric vagal afferent neurons, activation of GHSR1a by ghrelin inhibits voltage-gated Ca2+ channels through both voltage-dependent and voltage-independent signaling pathways. These results provide necessary insights into the cellular mechanism underlying ghrelin regulation of gastric vagal afferent activity, which may benefit future studies investigating ghrelin mimetics to treat gastric motility disorders.

Sensory neurons regulate stimulus-dependent humoral immunity in mouse models of bacterial infection and asthma

Sensory neurons sense pathogenic infiltration to drive innate immune responses, but their role in humoral immunity is unclear. Here, using mouse models of Streptococcus pneumoniae infection and Alternaria alternata asthma, we show that sensory neurons are required for B cell recruitment and antibody production. In response to S. pneumoniae, sensory neuron depletion increases bacterial burden and reduces B cell numbers, IgG release, and neutrophil stimulation. Meanwhile, during A. alternata-induced airway inflammation, sensory neuron depletion decreases B cell population sizes, IgE levels, and asthmatic characteristics. Mechanistically, during bacterial infection, sensory neurons preferentially release vasoactive intestinal polypeptide (VIP). In response to asthma, sensory neurons release substance P. Administration of VIP into sensory neuron-depleted mice suppresses bacterial burden, while VIPR1 deficiency increases infection. Similarly, exogenous substance P delivery aggravates asthma in sensory neuron-depleted mice, while substance P deficiency ameliorates asthma. Our data, thus demonstrate that sensory neurons release select neuropeptides which target B cells dependent on the immunogen.

Harmonizing neuropathic pain research: outcomes of the London consensus meeting on peripheral tissue studies.

Neuropathic pain remains difficult to treat, with drug development hampered by an incomplete understanding of the pathogenesis of the condition, as well as a lack of biomarkers. The problem is compounded by the scarcity of relevant human peripheral tissues, including skin, nerves, and dorsal root ganglia. Efforts to obtain such samples are accelerating, increasing the need for standardisation across laboratories. In this white paper, we report on a consensus meeting attended by neuropathic pain experts, designed to accelerate protocol alignment and harmonization of studies involving relevant peripheral tissues. The meeting was held in London in March 2024 and attended by 28 networking partners, including industry and patient representatives. We achieved consensus on minimal recommended phenotyping, harmonised wet laboratory protocols, statistical design, reporting, and data sharing. Here, we also share a variety of relevant standard operating procedures as supplementary protocols. We envision that our recommendations will help unify human tissue research in the field and accelerate our understanding of how abnormal interactions between sensory neurons and their local peripheral environment contribute towards neuropathic pain.

A microfluidic model of the first sensory synapse for analgesic target discovery.

The synaptic connections between dorsal root ganglia (DRG) and dorsal horn (DH) neurons are a crucial relay point for the transmission of painful stimuli. To delineate how synaptic plasticity may modulate the excitability of DH neurons, we have devised a microfluidic co-culture model that recapitulates the first sensory synapse using postnatal mouse sensory neurons. We show that DRG-DH co-cultures characterize salient features of the in vivo physiology of sensory neurons. Immunocytcochemical experiments of the cultured DH neurons show a co-localization of MAP2 with VGLUT2 and of MAP2 with Synapsin 1, corroborating the glutamatergic identity of the DH neurons and further suggesting the formation of active synapses in this neuronal set. Fluorometric imaging experiments demonstrate the elicitation of calcium responses in DH neurons following the stimulation of DRG cell bodies or axons. Selective NMDA and AMPA receptor blockade appreciably silences DH neuron responses, suggesting that glutamatergic signaling is maintained in vitro. Last, a surrogate model of peripheral nerve injury is introduced in the form of an axotomy, which results in elevated and prolonged calcium responses of DH neurons. Overall, the microfluidic mouse co-cultures provide a method advancement in the study of periphery-to-center pain signaling, where the potential of utilizing the platform for drug target identification is underscored.

Follistatin drives neuropathic pain in mice through IGF1R signaling in nociceptive neurons.

Neuropathic pain is a debilitating chronic condition that lacks effective treatment. The role of cytokine- and chemokine-mediated neuroinflammation in its pathogenesis has been well documented. Follistatin (FST) is a secreted protein known to antagonize the biological activity of cytokines in the transforming growth factor-β (TGF-β) superfamily. The involvement of FST in neuropathic pain and the underlying mechanism remain largely unknown. Here, we report that FST was up-regulated in A-fiber sensory neurons after spinal nerve ligation (SNL) in mice. Inhibition or deletion of FST alleviated neuropathic pain and reduced the nociceptive neuron hyperexcitability induced by SNL. Conversely, intrathecal or intraplantar injection of recombinant FST, or overexpression of FST in the dorsal root ganglion (DRG) neurons, induced pain hypersensitivity. Furthermore, exogenous FST increased neuronal excitability in nociceptive neurons. The biolayer interferometry (BLI) assay and coimmunoprecipitation (co-IP) demonstrated direct binding of FST to the insulin-like growth factor-1 receptor (IGF1R), and IGF1R inhibition reduced FST-induced activation of extracellular signal-regulated kinase (ERK) and protein kinase B (AKT), as well as neuronal hyperexcitability. Further co-IP analysis revealed that the N-terminal domain of FST exhibits the highest affinity for IGF1R, and blocking this interaction with a peptide derived from FST attenuated Nav1.7-mediated neuronal hyperexcitability and neuropathic pain after SNL. In addition, FST enhanced neuronal excitability in human DRG neurons through IGF1R. Collectively, our findings suggest that FST, released from A-fiber neurons, enhances Nav1.7-mediated hyperexcitability of nociceptive neurons by binding to IGF1R, making it a potential target for neuropathic pain treatment.

Mediation of mammalian olfactory response by presence of odor-evoked potassium current.

It is well understood that odorants interact with specialized G-protein coupled receptors embedded in the ciliary membrane of olfactory sensory neurons (OSN) which initiates a voltage-generating intracellular cascade of signal transduction events that can be recorded at the epithelial level as an electroolfactogram (EOG). While the depolarizing excitatory pathway in vertebrates involving cyclic adenosine monophosphate (cAMP)-induced Na+/Ca2+ influx and calcium-induced Cl- efflux is well established, there is evidence of potassium-associated inhibitory currents that correspond with cellular activation. While several Ca2+-dependent feedback mechanisms contribute to cellular deactivation which have been commonly attributed to these inhibitory currents, the frequently observed positive ionic conductance prior to excitatory depolarization have led many to suggest an additional earlier inhibitory mechanism at the receptor level that may be independent of downstream calcium influx. Due to conflicting conclusions, the role and mechanism behind Ca2+-independent inhibitory currents in olfactory cells is not fully understood. We investigated the functional and temporal involvement of potassium channels in odor transduction by comparing electroolfactogram (EOG) recordings in rat olfactory epithelia following ion channel inhibition and targeted activation of downstream components with or without potassium-blocking. Several K+-channel blocking agents (4-Aminopyridine, charybdotoxin, & iberiotoxin) demonstrated a diminished pre-action potential positive current that corresponded with reduced excitatory response to odor stimulation that was recovered when blockers were removed. We further assessed EOG responses in the absence of odor or with odor response enhancing zinc nanoparticles. Chemically eliciting membrane excitation in the absence of odor stimulation with a phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IBMX), in combination with K+-channel inhibition, further indicated potassium channel activation precedes excitatory events and is independent of cAMP-induced calcium influx. These results support previous findings of odor-activated inhibitory potassium currents that may play a functional role in subsequent G-protein activity.

Small-molecule natural product sophoricoside reduces peripheral neuropathic pain via directly blocking of NaV1.6 in dorsal root ganglion nociceptive neurons.

Peripheral neuropathic pain poses a significant global health challenge. Current drugs for peripheral neuropathic pain often fall short in efficacy or come with severe side effects, emphasizing the critical need for the development of highly effective and well-tolerated alternatives. Sophoricoside (SOP) is a nature product-derived isoflavone that possesses various pharmacological effects on inflammatory and neuropathy diseases. Here, in this study, analgesic effect was investigated by intrathecally administration of SOP/vehicle to spared nerve injury (SNI) or paclitaxel-induced peripheral neuropathic pain (PINP) rodent models, and mechanical allodynia was measured in Von Frey tests. Ipsilateral L4-L6 dorsal root ganglia (DRG) were used for protein expression. In silico molecular docking analysis was applied for assessing compound-target binding affinity. Primary cultured DRG neurons were utilized to investigate SOP's effect on veratridine-triggered nociceptor activities and its selective inhibition of voltage-gated sodium channels subtype 1.6 (NaV1.6). The results showed SOP treatment alleviated mechanical allodynia in SNI and PINP rodent models (paw withdrawal threshold after 1 h of injection: SNI-vehicle: 1.385 ± 0.338 g; SNI-SOP: 9.963 ± 2.029 g, P < 0.001; PINP-vehicle: 5.040 ± 0.985 g; PINP-SOP: 8.287 ± 3.812 g, P = 0.004). SOP presented effects on both inhibiting veratridine-triggered nociceptor activities (oscillatory population: vehicle: 39.9 ± 7.3%; SOP: 30.7 ± 9.8%, P = 0.021) and selectively blocking NaV1.6 in DRG sensory neurons. Molecular docking analysis indicated direct binding between SOP and NaV1.6, leading to its endocytosis in DRG Sensory Neurons. In conclusion, SOP alleviated nociceptive allodynia induced by peripheral nerve injury via selectively blocking of NaV1.6 in DRG nociceptive neurons. we highlight its potential as an analgesic and elucidate its mechanism involving NaV1.6 endocytosis. This research opens avenues for exploring the analgesic effects of SOP and its potential impact on neuropathic pain therapy.

Electrophysiological Changes in Median Nerve among Young Male Cigarette Smokers

Background: Cigarette smoking has been associated with numerous cardiovascular and respiratory disorders. Chronic smoking may also disrupt neuronal function and damage neurons in the peripheral nervous system. Median nerve conduction study is an important electrodiagnostic test for the detection of peripheral nerve dysfunction. Objectives: To observe the impact of cigarette smoking on the electrophysiological status of median motor and sensory nerves in apparently healthy male cigarette smokers. Materials and Methods: This case-control study was carried out in the Department of Physiology, Sir Salimullah Medical College, Dhaka, from July 2017 to June 2018 on thirty male cigarette smokers aged 25 to 40 years. For comparison, thirty age and BMI matched non-smoker healthy male subjects were selected as controls. Motor and sensory nerve conduction parameters (latency, amplitude and nerve conduction velocity) of right median nerve were evaluated by standard methods, using standard nerve conduction study and electromyography machines in the Department of Neurology, Dhaka Medical College Hospital. For statistical analysis, unpaired t test was performed. Results: In this study, median sensory nerve latency was significantly prolonged (p ˂ 0.001) and sensory nerve conduction velocity was significantly slower (p ˂ 0.001) in cigarette smokers. The mean amplitude was also slightly reduced in smokers, but statistically, it was insignificant. However, the distal latency of median motor nerve was slightly prolonged whereas, the amplitude and motor nerve conduction velocity were slightly reduced in cigarette smokers in comparison to those of non-smokers. But the differences were not statistically significant. In addition, 10% of cigarette smokers had subclinical impairment in median sensory nerve function. Conclusion: Chronic cigarette smoking induces significant electrophysiological changes in median sensory nerve fibers and causes sensory nerve dysfunction, while it does not markedly affect median motor nerve fibers in young individuals. KYAMC Journal Volume: 15, No: 01, April 2024: 03-07.

MrgprC11+ Jugular Neurons Control Airway Hyperresponsiveness in Allergic Airway Inflammation.

The lung is densely innervated by sensory nerves, the majority of which are derived from the vagal sensory neurons. Vagal ganglia consist of two different ganglia, termed nodose and jugular ganglia, with distinct embryonic origins, innervation patterns, and physiological functions in the periphery. Since nodose neurons constitute the majority of the vagal ganglia, our understanding of the function of jugular nerves in the lung is very limited. This study aims to investigate the role of MrgprC11+ jugular sensory neurons in a mouse allergic asthma model. Our previous study has shown that MrgprC11+ jugular neurons mediate cholinergic bronchoconstriction. In this study, we found that in addition to MrgprC11, several other Mrgpr family members including MrgprA3, MrgprB4, and MrgprD are also specifically expressed in the jugular sensory neurons. MrgprC11+ jugular neurons exhibit dense innervation in the respiratory tract including the larynx, trachea, proximal, and distal bronchus. We also found that receptors for IL-4 and oncostatin M, two critical cytokines promoting allergic airway inflammation, are mainly expressed in jugular sensory neurons. Both IL-4 and oncostatin M can sensitize the neuronal responses of MrgprC11+ jugular neurons. Moreover, ablation of MrgprC11+ neurons significantly inhibited airway hyperresponsiveness in the asthmatic lung, demonstrating the critical role of MrgprC11+ neurons in controlling airway constriction. Our results emphasize the critical role of jugular sensory neurons in respiratory diseases.

Constitutive sodium permeability in a C. elegans two-pore domain potassium channel

Two-pore domain potassium (K2P) channels play a central role in modulating cellular excitability and neuronal function. The unique structure of the selectivity filter in K2P and other potassium channels determines their ability to allow the selective passage of potassium ions across cell membranes. The nematode C. elegans has one of the largest K2P families, with 47 subunit-coding genes. This remarkable expansion has been accompanied by the evolution of atypical selectivity filter sequences that diverge from the canonical TxGYG motif. Whether and how this sequence variation may impact the function of K2P channels has not been investigated so far. Here, we show that the UNC-58 K2P channel is constitutively permeable to sodium ions and that a cysteine residue in its selectivity filter is responsible for this atypical behavior. Indeed, by performing in vivo electrophysiological recordings and Ca2+ imaging experiments, we demonstrate that UNC-58 has a depolarizing effect in muscles and sensory neurons. Consistently, unc-58 gain-of-function mutants are hypercontracted, unlike the relaxed phenotype observed in hyperactive mutants of many neuromuscular K2P channels. Finally, by combining molecular dynamics simulations with functional studies in Xenopus laevis oocytes, we show that the atypical cysteine residue plays a key role in the unconventional sodium permeability of UNC-58. As predicting the consequences of selectivity filter sequence variations in silico remains a major challenge, our study illustrates how functional experiments are essential to determine the contribution of such unusual potassium channels to the electrical profile of excitable cells.

A pH-sensitive opioid does not exhibit analgesic tolerance in a mouse model of colonic inflammation.

Tolerance to the analgesic effects of opioids and resultant dose escalation is associated with worsening of side effects and greater addiction risk. Here, we compare the development of tolerance to the conventional opioid fentanyl with a novel pH-sensitive μ-opioid receptor (MOR) agonist, (±)-N-(3-fluoro-1-phenethylpiperidine-4-yl)-N-phenyl propionamide (NFEPP) that is active only in acidic inflammatory microenvironments. An opioid tolerance model was developed in male C57BL/6 mice, with and without dextran sulphate sodium colitis, using increasing doses of either fentanyl or NFEPP over 5 days. Visceral nociception was assessed in vivo by measuring visceromotor responses (VMRs) to noxious colorectal distensions and in vitro measuring colonic afferent nerve activity of mesenteric nerves and performing patch-clamp recordings from isolated dorsal root ganglia neurons. Somatic thermal nociception was tested using a tail immersion assay. Cardiorespiratory effects were analysed by pulse oximeter experiments. VMRs and tail immersion tests demonstrated tolerance to fentanyl, but not to NFEPP in colitis mice. Cross-tolerance also occurred to fentanyl, but not to NFEPP. The MOR agonist DAMGO inhibited colonic afferent nerve activity in colitis mice exposed to chronic NFEPP, but not those from fentanyl-treated mice. Similarly, in patch-clamp recordings from isolated dorsal root ganglia neurons, DAMGO inhibited neurons from NFEPP-, but not fentanyl-treated mice. NFEPP did not exhibit tolerance in an inflammatory pain model, unlike fentanyl. Consequently, dose escalation to maintain analgesia during an evolving inflammation could be avoided, mitigating the potential risk of side effects.

Balance performance in aged mice is dependent on unipolar brush cells.

The vestibular processing regions of the cerebellum integrate vestibular information with other sensory modalities and motor signals to regulate balance, gaze stability, and spatial orientation. A class of excitatory glutamatergic interneurons known as unipolar brush cells (UBCs) are highly concentrated within the granule cell layer of these regions. UBCs receive vestibular signals directly from primary vestibular afferents and indirectly from mossy fibers. Each UBC excites numerous granule cells and could contribute to computations necessary for balance-related motor function. Prior research has implicated UBCs in motor function, but their influence on balance performance remains unclear, especially in aged mice that have age-related impairment. Here we tested whether UBCs contribute to motor coordination and balance by disrupting their activity with chemogenetics in aged and young mice. Age-related balance deficits were apparent in mice > 6 months old. Disrupting the activity of a subpopulation of UBCs caused aged mice to fall off a balance beam more frequently and altered swimming behaviors that are sensitive to vestibular dysfunction. These effects were not seen in young (7-week-old) mice. Thus, disrupting the activity of UBCs impairs mice with age-related balance issues and suggest that UBCs are essential for balance and vestibular function in aged mice.

Amplification of olfactory transduction currents implements sparse stimulus encoding.

Sensory systems must perform the dual and opposing tasks of being sensitive to weak stimuli while also maintaining information content in dense and variable sensory landscapes. This occurs in the olfactory system, where OSNs are highly sensitive to low concentrations of odors and maintain discriminability in complex odor environments. How olfactory sensory neurons (OSNs) maintain both sensitivity and sparsity is not well understood. Here, we investigated whether the calcium-activated chloride channel, TMEM16B, may support these dual roles in OSNs. We used multiphoton microscopy to image the stimulus-response density of OSNs in the olfactory epithelium. In TMEM16B knockout mice, we found that sensory representations were denser, and the magnitude of OSN responses was increased. Behaviorally, these changes in sensory representations were associated with an increased aversion to the odorant trimethylamine, which switches perceptual valence as its concentration increases, and a decreased efficiency of olfactory-guided navigation. Together, our results indicate that the calcium-activated chloride channel TMEM16B sparsens sensory representations in the peripheral olfactory system and contributes to efficient integrative olfactory-guided behaviors.

Artificial afferent neurons based on the metal-insulator transition of VO2

Artificial afferent neurons based on the metal-insulator transition of VO2

Infectious Neuropathies.

This review explores diverse infectious etiologies of peripheral nervous system (PNS) dysfunction, spanning sensory and motor neurons, nerves, and associated structures. Progress in viral and bacterial infections reveals multifaceted mechanisms underlying neuropathies, including viral neurotoxicity and immune-mediated responses. Latest diagnostic advances facilitate early PNS complication detection, with ongoing research offering promising treatment avenues. Emerging pathogens like severe acute respiratory syndrome coronavirus 2, Zika virus, and EV-D68 highlight the evolving infectious neuropathy paradigm. Recognizing characteristic patterns and integrating clinical factors are pivotal for precise diagnosis and tailored intervention. Challenges persist in assessment and management due to varied pathogenic mechanisms. Advancements in understanding pathogenesis have improved targeted therapies, yet gaps remain in effective treatments. Ongoing research is crucial for optimizing approaches and improving patient outcomes.

Odorant receptors tuned to isothiocyanates in Drosophila melanogaster and their evolutionary expansion in herbivorous relatives.

Plants release complex volatile compounds to attract mutualists, deter herbivores, and deceive pollinators. Here, we used herbivorous specialist flies that feed on mustard plants ( Scaptomyza spp.) and microbe-feeding species ( Drosophila melanogaster and Scaptomyza spp.) to investigate how plant-derived electrophilic toxins such as isothiocyanates (ITCs) affect insects, and how flies detect these compounds through olfaction. In survival assays, D. melanogaster exposed to volatile allyl isothiocyanate (AITC), a toxin derived from many Brassicales plants, were acutely intoxicated, demonstrating the high toxicity of this volatile compound to non-specialized insects. Through single sensillum recordings (SSR) from olfactory organs and behavioral assays, we found that the Odorant receptor 42a (Or42a) is necessary for AITC detection and behavioral aversion. Comparative transcriptome and RNA FISH studies across the drosophilid genus Scaptomyza revealed lineage-specific triplication of Or42a in the Brassicales specialists and a doubling of Or42a -positive-olfactory sensory neurons. Heterologous expression experiments showed that Or42a paralogs in Brassicales-specialists exhibited broadened sensitivity to ITCs in a paralog-specific manner. Finally, AlphaFold2 modeling followed by site-directed mutagenesis and SSR identified two critical amino acid substitutions that conferred Or42a heighten sensitivity to Brassicales-derived ITCs. Our findings suggest that ITCs, which are toxic to most insects, can be detected and avoided by non-specialists like D. melanogaster through olfaction. In Brassicales specialists, these same Ors experienced gene duplication events that resulted in an expanded sensitivity to ITC compounds. Thus, the insect's olfactory system can rapidly adapt to toxic ecological niches provided by chemically-defended host plants through co-option of chemosensory capabilities already present in their ancestors.

Effects of unconscious tactile stimuli on autonomic nervous activity and afferent signal processing

Autonomic nervous system (ANS) is a mechanism that regulates our internal environment. In recent years, the interest in how tactile stimuli presented directly to the body affect ANS function and cortical processing in humans has been renewed. However, it is not yet clear how subtle tactile stimuli below the level of consciousness affect human heart rate and cortical processing. To examine this, subthreshold electrical stimuli were presented to the left forearm of 43 participants during an image-viewing task, and electrocardiogram (ECG) and electroencephalogram (EEG) data were collected. The changes in the R-wave interval of the ECG immediately after the subthreshold electrical presentation and heartbeat-evoked potential (HEP), the afferent signal processing of cardiac activity, were measured. The results showed that heart rate decelerated immediately after the presentation of subthreshold electrical stimuli. The HEP during stimulus presentation was amplified for participants with greater heart rate acceleration immediately after this deceleration. The magnitude of these effects depended on the type of the subthreshold tactile stimuli. The results suggest that even with subthreshold stimulation, the changes in autonomic activity associated with orienting response and related afferent signal processing differ depending on the clarity of the tactile stimuli.

Bilateral differences in structural connectivity of the afferent visual pathways of children with perinatal stroke

Bilateral differences in structural connectivity of the afferent visual pathways of children with perinatal stroke

Human dorsal root ganglia are either preserved or completely lost after deafferentation by brachial plexus injury

BackgroundPlexus injury results in lifelong suffering from flaccid paralysis, sensory loss, and intractable pain. For this clinical problem, regenerative medicine concepts set high expectations. However, it is largely unknown how dorsal root ganglia (DRG) are affected by accidental deafferentation. MethodsHere, we phenotyped DRG of a clinically and MRI-characterised cohort of 13 patients with plexus injury. Avulsed DRG were collected during reconstructive nerve surgery. For control, we used DRG from forensic autopsy. The cellular composition of the DRG was analysed in histopathological slices with multicolour high-resolution immunohistochemistry, tile microscopy, and deep-learning-based bioimage analysis. We then sequenced the bulk RNA of corresponding DRG slices. ResultsIn about half of the patients we found loss of the typical DRG units consisting of neurones and satellite glial cells. The DRG cells were replaced by mesodermal/connective tissue. In the remaining patients, the cellular units were well preserved. Preoperative plexus MRI neurography was not able to distinguish the two types. Patients with ‘neuronal preservation’ had less maximum pain than patients with ‘neuronal loss’. Arm function improved after nerve reconstruction, but severe pain persisted. Transcriptome analysis of preserved DRGs revealed expression of subtype-specific sensory neurone marker genes, but downregulation of neuronal attributes. Furthermore, they showed signs of ongoing inflammation and connective tissue remodelling. ConclusionsPatients with plexus injury separate into two groups with either neuronal preservation or neuronal loss. The former could benefit from anti-inflammatory therapy. For the latter, studies should explore mechanisms of neuronal loss especially for regenerative approaches. Clinical trial registrationDRKS00017266.

A Retrospective Study of Lateral Antebrachial Cutaneous Nerve Neuropathy: Electrodiagnostic Findings and Etiologies in 49 Cases.

The lateral antebrachial cutaneous nerve (LACN) is the terminal sensory branch of the musculocutaneous nerve and is rarely entrapped or injured. This study describes the electrodiagnostic (EDX) findings and etiologies of LACN neuropathy. This is a review of 49 patients with pain and/or paresthesia of the forearm who underwent EDX studies. The diagnosis of LACN neuropathy was based on clinical and sensory conduction abnormalities. The most common etiology of LACN neuropathy was iatrogenic injury in 30 (61.2%) patients, primarily due to biceps tendon repair at the elbow (11 [36.7%]) and phlebotomy (5 [16.7%]). Fifteen (30.6%) patients sustained a non-iatrogenic injury at the proximal forearm/elbow, consisting of six (60%) laceration injuries and five (33.3%) stretch injuries. Four (8.2%) patients comprised the "other" etiology category, including two mass lesions causing LACN compression. Pain, paresthesia, and/or numbness in the LACN distribution were reported in 33 (67.3%), 27 (55.1%), and 23 (46.9%) patients, respectively. Hypoesthesia was detected in 45 (91.8%) patients, and dysesthesia in 7 (14.3%). The sensory nerve action potentials (SNAPs) of the LACN on the symptomatic side were absent in 44 (89.8%) patients. Of the five patients whose SNAPs of the LACN were detected, all had a decreased amplitude, and two had increased sensory latency. The most common etiology for LACN neuropathy in this series was iatrogenic injury; repair of biceps tendon at the elbow was the most frequent provoking cause. Protection of the LACN during surgical procedures at the elbow and forearm is vital to prevent iatrogenic injury.