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Background: IL-1β plays a critical role in the pathophysiology of neuroinflammation. The presence of cleaved IL-1β (cIL-1β) in the neurons of the dorsal root ganglion (DRG) implicates its function in biological signaling arising from the sensory neuron. This study was conducted to analyze the role of IL-1β in nociceptive transduction after tissue injury. Methods: A plantar incision was made in C57BL/6 mice, following which immunohistochemistry and RNA scope in situ hybridization were performed at various time points to analyze cIL-1β, caspase-1, and IL-1 receptor 1 (IL-1R1) expression in the DRG. The effect of intrathecal administration of a caspase-1 inhibitor or regional anesthesia using local anesthetics on cIL-1β expression and pain hypersensitivity was analyzed by immunohistochemistry and behavioral analysis. ERK phosphorylation was also analyzed to investigate the effect of IL-1β on the activity of spinal dorsal horn neurons. Results: cIL-1β expression was significantly increased in caspase-1-positive DRG neurons 5 min after the plantar incision. Intrathecal caspase-1 inhibitor treatment inhibited IL-1β cleavage and pain hypersensitivity after the plantar incision. IL-1R1 was also detected in the DRG neurons, although the majority of IL-1R1-expressing neurons lacked cIL-1β expression. Regional anesthesia using local anesthetics prevented cIL-1β processing. Plantar incision-induced phosphorylation of ERK was inhibited by the caspase-1 inhibitor. Conclusion: IL-1β in the DRG neuron undergoes rapid cleavage in response to tissue injury in an activity-dependent manner. Cleaved IL-1β causes injury-induced functional activation of sensory neurons and pain hypersensitivity. IL-1β in the primary afferent neurons is involved in physiological nociceptive signal transduction. [ABSTRACT FROM AUTHOR]

Carbapenem-resistant Klebsiella pneumoniae (CRKP) causes Gram-negative lung infections and fatal pneumonic sepsis for which limited therapeutic options are available. The lungs are densely innervated by nociceptor sensory neurons that mediate breathing, cough, and bronchoconstriction. The role of nociceptors in defense against Gram-negative lung pathogens is unknown. Here, we found that lung-innervating nociceptors promote CRKP pneumonia and pneumonic sepsis. Ablation of nociceptors in mice increased lung CRKP clearance, suppressed trans-alveolar dissemination of CRKP, and protected mice from hypothermia and death. Furthermore, ablation of nociceptors enhanced the recruitment of neutrophils and Ly6Chi monocytes and cytokine induction. Depletion of Ly6Chi monocytes, but not of neutrophils, abrogated lung and extrapulmonary CRKP clearance in ablated mice, suggesting that Ly6Chi monocytes are a critical cellular population to regulate pneumonic sepsis. Further, neuropeptide calcitonin gene-related peptide suppressed the induction of reactive oxygen species in Ly6Chi monocytes and their CRKP-killing abilities. Targeting nociceptor signaling could be a therapeutic approach for treating multidrug-resistant Gram-negative infection and pneumonic sepsis. [ABSTRACT FROM AUTHOR]

Mutations in the presenilin (PS) genes are a predominant cause of familial Alzheimer's disease (fAD). An ortholog of PS in the genetic model organism Caenorhabditis elegans (C. elegans) is sel-12. Mutations in the presenilin genes are commonly thought to lead to fAD by upregulating the expression of amyloid beta (Aβ), however this hypothesis has been challenged by recent evidence. As C. elegans lack amyloid beta (Aβ), the goal of this work was to examine Aβ-independent effects of mutations in sel-12 and PS1/PS2 on behaviour and sensory neuron morphology across the lifespan in a C. elegans model. Olfactory chemotaxis experiments were conducted on sel-12(ok2078) loss-of-function mutant worms. Adult sel-12 mutant worms showed significantly lower levels of chemotaxis to odorants compared to wild-type worms throughout their lifespan, and this deficit increased with age. The chemotaxis phenotype in sel-12 mutant worms is rescued by transgenic over-expression of human wild-type PS1, but not the classic fAD-associated variant PS1C410Y, when expression was driven by either the endogenous sel-12 promoter (Psel-12), a pan-neuronal promoter (Primb-1), or by a promoter whose primary expression was in the sensory neurons responsible for the chemotaxis behavior (Psra-6, Podr-10). The behavioural phenotype was also rescued by over-expressing an atypical fAD-linked mutation in PS1 (PS1ΔS169) that has been reported to leave the Notch pathway intact. An examination of the morphology of polymodal nociceptive (ASH) neurons responsible for the chemotaxis behavior also showed increased neurodegeneration over time in sel-12 mutant worms that could be rescued by the same transgenes that rescued the behaviour, demonstrating a parallel with the observed behavioral deficits. Thus, we report an Aβ-independent neurodegeneration in C. elegans that was rescued by cell specific over-expression of wild-type human presenilin. [ABSTRACT FROM AUTHOR]

AbstractEgg-laying is one of the key aspects of female reproductive behavior in insects. Egg-laying has been studied since the dawn of Drosophila melanogaster as a model organism. The female’s internal state, hormones, and external factors, such as nutrition, light, and social environment, affect egg-laying output. However, only recently, neurobiological features of egg-laying behavior have been studied in detail. fruitless and doublesex, two key players in the sex determination pathway, have become focal points in identifying neurons of reproductive significance in both central and peripheral nervous systems. The reproductive tract and external terminalia house sensory neurons that carry the sensory information of egg maturation, mating and egg-laying. These sensory signals include the presence of male accessory gland products and mechanical stimuli. The abdominal neuromere houses neurons that receive information from the reproductive tract, including sex peptide abdominal ganglion neurons (SAGs), and send their information to the brain. In the brain, neuronal groups like aDNs and pC1 clusters modulate egg-laying decision-making, and other neurons like oviINs and oviDNs are necessary for egg-laying itself. Lastly, motor neurons involved in egg-laying, which are mostly octopaminergic, reside in the abdominal neuromere and orchestrate the muscle movements required for laying the egg. Egg-laying neuronal control is important in various evolutionary processes like cryptic female choice, and using different Drosophila species can provide intriguing avenues for the future of the field. [ABSTRACT FROM AUTHOR]

Spontaneous activity in dorsal root ganglion (DRG) neurons is a key driver of neuropathic pain in patients suffering from this largely untreated disease. While many intracellular signalling mechanisms have been examined in preclinical models that drive spontaneous activity, none have been tested directly on spontaneously active human nociceptors. Using cultured DRG neurons recovered during thoracic vertebrectomy surgeries, we showed that inhibition of mitogen-activated protein kinase interacting kinase (MNK) with tomivosertib (eFT508, 25 nM) reversibly suppresses spontaneous activity in human sensory neurons that are likely nociceptors based on size and action potential characteristics associated with painful dermatomes within minutes of treatment. Tomivosertib treatment also decreased action potential amplitude and produced alterations in the magnitude of after hyperpolarizing currents, suggesting modification of Na+ and K+ channel activity as a consequence of drug treatment. Parallel to the effects on electrophysiology, eFT508 treatment led to a profound loss of eIF4E serine 209 phosphorylation in primary sensory neurons, a specific substrate of MNK, within 2 min of drug treatment. Our results create a compelling case for the future testing of MNK inhibitors in clinical trials for neuropathic pain. [ABSTRACT FROM AUTHOR]

Key points Mammalian olfactory sensory neurons (OSNs) generate an odorant‐induced response by sequentially activating two ion channels, which are in their ciliary membranes. First, a cationic, Ca2+‐permeable cyclic nucleotide‐gated channel is opened following odorant stimulation via a G protein‐coupled transduction cascade and an ensuing rise in cAMP. Second, the increase in ciliary Ca2+ opens the excitatory Ca2+‐activated Cl− channel TMEM16B, which carries most of the odorant‐induced receptor current. While the role of TMEM16B in amplifying the response has been well established, it is less understood how this secondary ion channel contributes to response kinetics and action potential generation during single as well as repeated stimulation and, on the other hand, which response properties the cyclic nucleotide‐gated (CNG) channel determines. We first demonstrate that basic membrane properties such as input resistance, resting potential and voltage‐gated currents remained unchanged in OSNs that lack TMEM16B. The CNG channel predominantly determines the response delay and adaptation during odorant exposure, while the absence of the Cl− channels shortens both the time the response requires to reach its maximum and the time to terminate after odorant stimulation. This faster response termination in Tmem16b knockout OSNs allows them, somewhat counterintuitively despite the large reduction in receptor current, to fire action potentials more reliably when stimulated repeatedly in rapid succession, a phenomenon that occurs both in isolated OSNs and in OSNs within epithelial slices. Thus, while the two olfactory ion channels act in concert to generate the overall response, each one controls specific aspects of the odorant‐induced response. Mammalian olfactory sensory neurons (OSNs) generate odorant‐induced responses by activating two ion channels sequentially in their ciliary membranes: a Na+, Ca2⁺‐permeable cyclic nucleotide‐gated (CNG) channel and the Ca2⁺‐activated Cl⁻ channel TMEM16B. The CNG channel controls response delay and adaptation during odorant exposure, while TMEM16B amplifies the response and influences the time required for the response to reach its peak and terminate. OSNs lacking TMEM16B display faster response termination, allowing them to fire action potentials more reliably during rapid repeated stimulation. The CNG and TMEM16B channels have distinct and complementary roles in shaping the kinetics and reliability of odorant‐induced responses in OSNs. [ABSTRACT FROM AUTHOR]

Allergic rhinitis (AR) is a chronic, non-infectious condition affecting the nasal mucosa, primarily mediated mainly by IgE. Recent studies reveal that AR is intricately associated not only with type 2 immunity but also with neuroimmunity. Nociceptive neurons, a subset of primary sensory neurons, are pivotal in detecting external nociceptive stimuli and modulating immune responses. This review examines nociceptive neuron receptors and elucidates how neuropeptides released by these neurons impact the immune system. Additionally, we summarize the role of immune cells and inflammatory mediators on nociceptive neurons. A comprehensive understanding of the dynamic interplay between nociceptive neurons and the immune system augments our understanding of the neuroimmune mechanisms underlying AR, thereby opening novel avenues for AR treatment modalities. [ABSTRACT FROM AUTHOR]

Background: Econazole is a widely used imidazole derivative antifungal for treating skin infections. The molecular targets for its frequent adverse effects of skin irritation symptoms, such as pruritus, burning sensation, and pain, have not been clarified. Transient receptor potential (TRP) channels, non-selective cation channels, are mainly expressed in peripheral sensory neurons and serve as sensors for various irritants. Methods: We investigated the effect of econazole on TRP channel activation by measuring intracellular calcium concentration ([Ca2+]i) through fluorescent ratio imaging in mouse dorsal root ganglion (DRG) neurons isolated from wild-type, TRPA1(−/−) and TRPV1(−/−) mice, as well as in heterologously TRP channel-expressed cells. A cheek injection model was employed to assess econazole-induced itch and pain in vivo. Results: Econazole evoked an increase in [Ca2+]i, which was abolished by the removal of extracellular Ca2+ in mouse DRG neurons. The [Ca2+]i responses to econazole were suppressed by a TRPA1 blocker but not by a TRPV1 blocker. Attenuation of the econazole-induced [Ca2+]i responses was observed in the TRPA1(−/−) mouse DRG neurons but was not significant in the TRPV1(−/−) neurons. Econazole increased the [Ca2+]i in HEK293 cells expressing TRPA1 (TRPA1-HEK) but not in those expressing TRPV1, although at higher concentrations, it induced Ca2+ mobilization from intracellular stores in untransfected naïve HEK293 cells. Miconazole, which is a structural analog of econazole, also increased the [Ca2+]i in mouse DRG neurons and TRPA1-HEK, and its nonspecific action was larger than econazole. Fluconazole, a triazole drug failed to activate TRPA1 and TRPV1 in mouse DRG neurons and TRPA1-HEK. Econazole induced itch and pain in wild-type mice, with reduced responses in TRPA1(−/−) mice. Conclusions: These findings suggested that the imidazole derivatives econazole and miconazole may induce skin irritation by activating nociceptive TRPA1 in the sensory neurons. Suppression of TRPA1 activation may mitigate the adverse effects of econazole. [ABSTRACT FROM AUTHOR]

Human induced pluripotent stem cell-derived sensory neuron (iPSC-dSN) models are a valuable resource for the study of neurotoxicity but are affected by poor replicability and reproducibility, often due to a lack of optimization. Here, we identify experimental factors related to culture conditions that substantially impact cellular drug response in vitro and determine optimal conditions for improved replicability and reproducibility. Treatment duration and cell seeding density were both found to be significant factors, while cell line differences also contributed to variation. A replicable dose–response in viability was demonstrated after 48-h exposure to docetaxel or paclitaxel. Additionally, a replicable dose-dependent reduction in neurite outgrowth was demonstrated, demonstrating the applicability of the model for the examination of additional phenotypes. Overall, we have established an optimized iPSC-dSN model for the study of taxane-induced neurotoxicity. [ABSTRACT FROM AUTHOR]

Insects rely on olfaction for mating, finding oviposition sites, and locating hosts. Hyphantria cunea is a serious pest that severely damages forests. Differential expression analysis of olfactory-related genes between males and females is the basis for elucidating the functions of olfactory-related proteins in H. cunea. In this study, Illumina HiSeqTM 4000 high-throughput sequencing technology was used to perform transcriptome sequencing of the antennal tissues of adult male and female H. cunea. Functional annotation was conducted using the NR, Swiss-Prot, KOG, KEGG, and GO databases, and the results showed that the antennal transcriptome of adult H. cunea contained 50,158 unigenes. Differential expression analysis identified 3923 genes that were significantly differentially expressed between male and female antennae. A total of 221 olfactory-related genes were annotated, and 96 sex-biased genes were identified, including 13 odorant receptors (ORs), 48 odorant binding proteins (OBPs), 7 chemosensory proteins (CSPs), 10 ionotropic receptors (IRs), 10 sensory neuron membrane proteins (SNMPs), 2 gustatory receptors (GRs), and 6 odorant-degrading enzymes (ODEs), indicating that there were differences in olfaction between male and female H. cunea. Quantitative real-time PCR was used to verify the expression levels of 21 putative general odorant receptor genes in male and female antennae. HcunOR4 and HcunOR5 showed female-biased expression; HcunOR48, HcunOR49 and HcunOR50 showed male-biased expression. The results were consistent with the transcriptome differential analysis. The screening of male-biased odorant receptor genes might provide a theoretical basis for the functional characterization of odorant receptors for recognizing sex pheromones in H. cunea. [ABSTRACT FROM AUTHOR]

The TRESK (K2P18.1, KCNK18) background potassium channel is expressed in primary sensory neurons and has been reported to contribute to the regulation of pain sensations. In the present study, we examined the interaction of TRESK with NDFIP1 (Nedd4 family-interacting protein 1) in the Xenopus oocyte expression system by two-electrode voltage clamp and biochemical methods. We showed that the coexpression of NDFIP1 abolished the TRESK current under the condition where the other K+ channels were not affected. Mutations in the three PPxY motifs of NDFIP1, which are responsible for the interaction with the Nedd4 ubiquitin ligase, prevented a reduction in the TRESK current. Furthermore, the overexpression of a dominant-negative Nedd4 construct in the oocytes coexpressing TRESK with NDFIP1 partially reversed the down-modulating effect of the adaptor protein on the K+ current. The biochemical data were also consistent with the functional results. An interaction between epitope-tagged versions of TRESK and NDFIP1 was verified by co-immunoprecipitation experiments. The coexpression of NDFIP1 with TRESK induced the ubiquitination of the channel protein. Altogether, the results suggest that TRESK is directly controlled by and highly sensitive to the activation of the NDFIP1-Nedd4 system. The NDFIP1-mediated reduction in the TRESK component may induce depolarization, increase excitability, and attenuate the calcium dependence of the membrane potential by reducing the calcineurin-activated fraction in the ensemble background K+ current. [ABSTRACT FROM AUTHOR]

We report that diazepam binding inhibitor (DBI) is a glial messenger mediating crosstalk between satellite glial cells (SGCs) and sensory neurons in the dorsal root ganglion (DRG). DBI is highly expressed in SGCs of mice, rats, and humans, but not in sensory neurons or most other DRG-resident cells. Knockdown of DBI results in a robust mechanical hypersensitivity without major effects on other sensory modalities. In vivo overexpression of DBI in SGCs reduces sensitivity to mechanical stimulation and alleviates mechanical allodynia in neuropathic and inflammatory pain models. We further show that DBI acts as an unconventional agonist and positive allosteric modulator at the neuronal GABAA receptors, particularly strongly affecting those with a high-affinity benzodiazepine binding site. Such receptors are selectively expressed by a subpopulation of mechanosensitive DRG neurons, and these are also more enwrapped with DBI-expressing glia, as compared with other DRG neurons, suggesting a mechanism for a specific effect of DBI on mechanosensation. These findings identified a communication mechanism between peripheral neurons and SGCs. This communication modulates pain signaling and can be targeted therapeutically. [ABSTRACT FROM AUTHOR]

The evolutionary expansion of sensory neuron populations detecting important environmental cues is widespread, but functionally enigmatic. We investigated this phenomenon through comparison of homologous olfactory pathways of Drosophila melanogaster and its close relative Drosophila sechellia, an extreme specialist for Morinda citrifolia noni fruit. D. sechellia has evolved species-specific expansions in select, noni-detecting olfactory sensory neuron (OSN) populations, through multigenic changes. Activation and inhibition of defined proportions of neurons demonstrate that OSN number increases contribute to stronger, more persistent, noni-odour tracking behaviour. These expansions result in increased synaptic connections of sensory neurons with their projection neuron (PN) partners, which are conserved in number between species. Surprisingly, having more OSNs does not lead to greater odour-evoked PN sensitivity or reliability. Rather, pathways with increased sensory pooling exhibit reduced PN adaptation, likely through weakened lateral inhibition. Our work reveals an unexpected functional impact of sensory neuron population expansions to explain ecologically-relevant, species-specific behaviour. Sensory neuron population expansions are common in evolution but of unclear function. Here, the authors show that, in drosophilid olfactory systems, increased sensory neuron number impacts interneuron dynamics, but not sensitivity, to promote olfactory-guided behaviour. [ABSTRACT FROM AUTHOR]

Traumatic spinal cord injury (SCI) results in immediate tissue necrosis and delayed secondary expansion of neurological damage, often resulting in lifelong paralysis, neurosensory dysfunction, and chronic pain. Progressive hemorrhagic necrosis (PHN) and excessive excitation are the main sources of secondary neural injury. Recent approaches to attenuate PHN by glibenclamide can improve locomotor function after SCI. However, use of glibenclamide can exacerbate development of SCI-induced chronic pain by inhibiting KATP channels to increase neuronal excitation and glial activation. In this study, we explored a treatment strategy involving administration of glibenclamide, which suppresses PHN, and diazoxide, which protects against neuronal excitation and inflammation, at different time intervals following spinal cord contusion. Our goal was to determine whether this combined approach enhances both sensory and motor function. Contusive SCI was induced at spinal segment T10 in adult rats. We found that KATP channels opener, diazoxide, decreased the hyperexcitability of primary sensory neurons after SCI by electrophysiology. Timed application of glibenclamide and diazoxide following contusion significantly improved locomotor function and mitigated development of SCI-induced chronic pain, as shown by behavioral evidence. Finally, we found that timed application of glibenclamide and diazoxide attenuates the inflammatory activity in the spinal cord and increases the survival of spinal matters following SCI. These preclinical studies introduce a promising potential treatment strategy to address SCI-induced dysfunction. [ABSTRACT FROM AUTHOR]

The development of noninvasive approaches to precisely control neural activity in mammals is highly desirable. Here, we used the ion channel transient receptor potential ankyrin-repeat 1 (TRPA1) as a proof of principle, demonstrating remote near-infrared (NIR) activation of endogenous neuronal channels in mice through an engineered nanoagonist. This achievement enables specific neurostimulation in nongenetically modified mice. Initially, target-based screening identified flavins as photopharmacological agonists, allowing for the photoactivation of TRPA1 in sensory neurons upon ultraviolet A/blue light illumination. Subsequently, upconversion nanoparticles (UCNPs) were customized with an emission spectrum aligned to flavin absorption and conjugated with flavin adenine dinucleotide, creating a nanoagonist capable of NIR activation of TRPA1. Following the intrathecal injection of the nanoagonist, noninvasive NIR stimulation allows precise bidirectional control of nociception in mice through remote activation of spinal TRPA1. This study demonstrates a noninvasive NIR neurostimulation method with the potential for adaptation to various endogenous ion channels and neural processes by combining photochemical toolboxes with customized UCNPs. [ABSTRACT FROM AUTHOR]

Graphosoma rubrolineatum (Hemiptera: Pentatomidae) is an important pest of vegetables and herbs (e.g., Umbelliferae and Cruciferae) in China, Siberia, Korea, and Japan. Insects are highly dependent on their olfactory system to detect odorants. However, no molecular-mediated olfactory genes in G. rubrolineatum have yet been identified. In this study, we first established the antennal transcriptome of G. rubrolineatum and identified 189 candidate olfactory genes, including 31 odorant-binding proteins (OBPs), 15 chemosensory proteins (CSPs), four sensory neuron membrane proteins (SNMPs),94 odorant receptors (ORs), 23 ionotropic receptors (IRs), and 22 gustatory receptors (GRs). Additionally, phylogenetic trees were constructed for olfactory genes between G. rubrolineatum and other hemipteran insects. We also detected the expression profiles of ten OBPs, five CSPs, two SNMPs, five ORs, four IRs, and four GRs by real-time quantitative PCR. The results revealed that most genes (GrubOBP1/11/31, GrubCSP3/8, GrubSNMP1a/1b, GrubOrco/OR9/11/13, GrubGR1/4/22, GrubIR25/75h/76b/GluR1) were highly expressed in the antennae, GrubOBP13/31 and GrubCSP4/11/12 were highly expressed in the legs, while GrubOBP20 and GrubGR19 were highly expressed in the wings. Our results will enrich the gene inventory of G. rubrolineatum and provide further insight into the molecular chemosensory mechanisms of G. rubrolineatum. [ABSTRACT FROM AUTHOR]

Insulin has been shown to modulate neuronal processes through insulin receptors. The ion channels located on neurons may be important targets for insulin/insulin receptor signaling. Both insulin receptors and acid-sensing ion channels (ASICs) are expressed in dorsal root ganglia (DRG) neurons. However, it is still unclear whether there is an interaction between them. Therefore, the purpose of this investigation was to determine the effects of insulin on the functional activity of ASICs. A 5 min application of insulin rapidly enhanced acid-evoked ASIC currents in rat DRG neurons in a concentration-dependent manner. Insulin shifted the concentration–response plot for ASIC currents upward, with an increase of 46.2 ± 7.6% in the maximal current response. The insulin-induced increase in ASIC currents was eliminated by the insulin receptor antagonist GSK1838705, the tyrosine kinase inhibitor lavendustin A, and the phosphatidylinositol-3 kinase antagonist wortmannin. Moreover, insulin increased the number of acid-triggered action potentials by activating insulin receptors. Finally, local administration of insulin exacerbated the spontaneous nociceptive behaviors induced by intraplantar acid injection and the mechanical hyperalgesia induced by intramuscular acid injections through peripheral insulin receptors. These results suggested that insulin/insulin receptor signaling enhanced the functional activity of ASICs via tyrosine kinase and phosphatidylinositol-3 kinase pathways. Our findings revealed that ASICs were targets in primary sensory neurons for insulin receptor signaling, which may underlie insulin modulation of pain. [ABSTRACT FROM AUTHOR]

Cadaverine is an endogenous metabolite produced by the gut microbiome with various activity in physiological and pathological conditions. However, whether cadaverine regulates pain or itch remains unclear. In this study, we first found that cadaverine may bind to histamine 4 receptor (H4R) with higher docking energy score using molecular docking simulations, suggesting cadaverine may act as an endogenous ligand for H4R. We subsequently found intradermal injection of cadaverine into the nape or cheek of mice induces a dose-dependent scratching response in mice, which was suppressed by a selective H4R antagonist JNJ-7777120, transient receptor potential vanilloid 1 (TRPV1) antagonist capsazepine and PLC inhibitor U73122, but not H1R antagonist or TRPA1 antagonist or TRPV4 antagonist. Consistently, cadaverine-induced itch was abolished in Trpv1 −/− but not Trpa1 −/− mice. Pharmacological analysis indicated that mast cells and opioid receptors were also involved in cadaverine-induced itch in mice. scRNA-Seq data analysis showed that H4R and TRPV1 are mainly co-expressed on NP2, NP3 and PEP1 DRG neurons. Calcium imaging analysis showed that cadaverine perfusion enhanced calcium influx in the dissociated dorsal root ganglion (DRG) neurons, which was suppressed by JNJ-7777120 and capsazepine, as well as in the DRG neurons from Trpv1 −/− mice. Patch-clamp recordings found that cadaverine perfusion significantly increased the excitability of small diameter DRG neurons, and JNJ-7777120 abolished this effect, indicating involvement of H4R. Together, these results provide evidences that cadaverine is a novel endogenous pruritogens, which activates H4R/TRPV1 signaling pathways in the primary sensory neurons. [ABSTRACT FROM AUTHOR]

Acute and chronic itch are prevalent and incapacitating, yet the neural mechanisms underlying both acute and chronic itch are just starting to be unraveled. Activated transcription factor 4 (ATF4) belongs to the ATF/CREB transcription factor family and primarily participates in the regulation of gene transcription. Our previous study has demonstrated that ATF4 is expressed in sensory neurons. Nevertheless, the role of ATF4 in itch sensation remains poorly understood. Here, we demonstrate that ATF4 plays a significant role in regulating itch sensation. The absence of ATF4 in dorsal root ganglion (DRG) neurons enhances the itch sensitivity of mice. Overexpression of ATF4 in sensory neurons significantly alleviates the acute and chronic pruritus in mice. Furthermore, ATF4 interacts with the transient receptor potential cation channel subfamily V member 4 (TRPV4) and inhibits its function without altering the expression or membrane trafficking of TRPV4 in sensory neurons. In addition, interference with ATF4 increases the itch sensitivity in nonhuman primates and enhances TRPV4 currents in nonhuman primates DRG neurons; ATF4 and TRPV4 also co-expresses in human sensory neurons. Our data demonstrate that ATF4 controls pruritus by regulating TRPV4 signaling through a nontranscriptional mechanism and identifies a potential new strategy for the treatment of pathological pruritus. [ABSTRACT FROM AUTHOR]

Chemotherapy-induced peripheral neuropathy (CIPN) is a major long-lasting side effect of some chemotherapy drugs, which threatens cancer survival rate. CIPN mostly affects sensory neurons and occasionally motor neurons, causing numbness, tingling, discomfort, and burning pain in the upper and lower extremities. The pathophysiology of CIPN is not completely understood; however, it is believed that chemotherapies induce peripheral neuropathy via directly damaging mitochondria, impairing the function of ion channels, triggering immunological mechanisms, and disrupting microtubules. The treatment of CIPN is a medical challenge, and there are no approved pharmacological options. Currently, duloxetine and other antidepressants, antioxidant, anti-inflammatory, and ion-channel targeted therapies are commonly used in clinics to relieve the symptoms of CIPN. Several other types of drugs, such as cannabinoids, sigma−1 receptor antagonists, and nicotinamides ribose, are being evaluated in preclinical and clinical studies. This paper summarizes the information related to the physiology of CIPN and medicines that could be used for treating this condition. [ABSTRACT FROM AUTHOR]

[Display omitted] • Cross-fostering induced social deficit involved in the vagal gut-to-brain axis in the adulthood of mice. • Gut-innervating sensory neurons connect with PVN oxytocin neurons across multiple synapses. • Sex-specific alteration in gut microbiota and its metabolites may be involved in social impairments and immune imbalances brought by cross-fostering via the gut-brain axis. • Cross-fostering social cognitive impairment may result from a combination of PVN oxytocinergic neurons, gut microbiota, and metabolites. The gut microbiota and neurological development of neonatal mice are susceptible to environmental factors that may lead to altered behavior into adulthood. However, the role that changed gut microbiota and neurodevelopment early in life play in this needs to be clarified. In this study, by modeling early-life environmental changes by cross-fostering BALB/c mice, we revealed the effects of the environment during the critical period of postnatal development on adult social behavior and their relationship with the gut microbiota and the nervous system. The neural projections exist between the ascending colon and oxytocin neurons in the paraventricular nuclei (PVN), peripheral oxytocin levels and PVN neuron numbers decreased after cross-fostering, and sex-specific alteration in gut microbiota and its metabolites may be involved in social impairments and immune imbalances brought by cross-fostering via the gut-brain axis. Our findings also suggest that social cognitive impairment may result from a combination of PVN oxytocinergic neurons, gut microbiota, and metabolites. [ABSTRACT FROM AUTHOR]

Although methods for generating human induced pluripotent stem cell (hiPSC)-derived motor nerve organoids are well established, those for sensory nerve organoids are not. Therefore, this study investigated the feasibility of generating sensory nerve organoids composed of hiPSC-derived sensory neurons using a microfluidic approach. Notably, sensory neuronal axons from neurospheres containing 100,000 cells were unidirectionally elongated to form sensory nerve organoids over 6 mm long axon bundles within 14 days using I-shaped microchannels in microfluidic devices composed of polydimethylsiloxane (PDMS) chips and glass substrates. Additionally, the organoids were successfully cultured for more than 60 days by exchanging the culture medium. The percentage of nuclei located in the distal part of the axon bundles (the region 3−6 mm from the entrance of the microchannel) compared to the total number of cells in the neurosphere was 0.005% for live cells and 0.008% for dead cells. Molecular characterization confirmed the presence of the sensory neuron marker ISL LIM homeobox 1 (ISL1) and the capsaicin receptor transient receptor potential vanilloid 1 (TRPV1). Moreover, capsaicin stimulation activated TRPV1 in organoids, as evidenced by significant calcium ion influx. Conclusively, this study demonstrated the feasibility of long-term organoid culture and the potential applications of sensory nerve organoids in bioengineered nociceptive sensors. [ABSTRACT FROM AUTHOR]

The process of hematopoiesis, at steady state as well as during stress, is controlled by rhythmic/circadian sympathetic innervation. Nociception titrates the extent of myeloid cell influx to sites of inflammation and the ability of such cells to clear pathogens. Sympathetic innervation contributes to chronic inflammation, as in the case of atherosclerosis; it governs circadian and stress-induced arterial leukocyte recruitment and controls hematopoiesis that is accelerated by cardiovascular risk factors. Recent work provides increasing evidence of the importance of nociception in modulating tissue repair, including in epithelial surfaces. Steady state and stress-accelerated hematopoiesis are partly controlled by the mammalian autonomous nervous system; in turn, sensory innervation is crucially involved in titrating leukocyte infiltration during inflammation to achieve tissue repair. An in-depth understanding of the intricate neuro-immune crosstalk during such processes may enable the development of interference strategies to curb pathologies such as acute infections and chronic inflammatory disorders. Innate immune cells are primary effectors during host defense and in sterile inflammation. Their production in the bone marrow is tightly regulated by growth and niche factors, and their activity at sites of inflammation is orchestrated by a network of alarmins and cytokines. Yet, recent work highlights a significant role of the peripheral nervous system in these processes. Sympathetic neural pathways play a key role in regulating blood cell homeostasis, and sensory neural pathways mediate pro- or anti-inflammatory signaling in a tissue-specific manner. Here, we review emerging evidence of the fine titration of hematopoiesis, leukocyte trafficking, and tissue repair via neuro-immune crosstalk, and how its derailment can accelerate chronic inflammation, as in atherosclerosis. [ABSTRACT FROM AUTHOR]

Objective: This study was undertaken to explore manipulation of the Myc protein interactome, members of an oncogene group, in enhancing the intrinsic growth of injured peripheral adult postmitotic neurons and the nerves they supply. New approaches to enhance adult neuron growth properties are a key strategy in improving nerve regeneration. Methods: Expression and impact of Myc interactome members c‐Myc, N‐Myc, Mad1, and Max were evaluated within naive and "preconditioned" adult sensory neurons and Schwann cells (SCs), using siRNA and transfection of CRISPR/Cas9 or luciferase reporter in vitro. Morphological, behavioral, and electrophysiological indices of nerve regeneration were analyzed in vivo. Results: c‐Myc, N‐Myc, Max, and Mad were expressed in adult sensory neurons and in partnering SCs. In vitro knockdown (KD) of either Mad1 or Max, competitive inhibitors of Myc, unleashed heightened neurite outgrowth in both naive uninjured or preconditioned adult neurons. In contrast, KD or inhibition of both isoforms of Myc was required to suppress growth. In SCs, Mad1 KD not only enhanced migratory behavior but also conditioned increased outgrowth in separately cultured adult sensory neurons. In vivo, local Mad1 KD improved electrophysiological, behavioral, and structural indices of nerve regeneration out to 60 days of follow‐up. Interpretation: Members of the Myc interactome, specifically Mad1, are novel targets for improving nerve regeneration. Unleashing of Myc growth signaling through Mad1 KD enhances the regrowth of both peripheral neurons and SCs to facilitate better regrowth of nerves. ANN NEUROL 2024;96:216–230 [ABSTRACT FROM AUTHOR]

Summary Food allergy is classically characterized by an inappropriate type‐2 immune response to allergenic food antigens. However, how allergens are detected and how that detection leads to the initiation of allergic immunity is poorly understood. In addition to the gastrointestinal tract, the barrier epithelium of the skin may also act as a site of food allergen sensitization. These barrier epithelia are densely innervated by sensory neurons, which respond to diverse physical environmental stimuli. Recent findings suggest that sensory neurons can directly detect a broad array of immunogens, including allergens, triggering sensory responses and the release of neuropeptides that influence immune cell function. Reciprocally, immune mediators modulate the activation or responsiveness of sensory neurons, forming neuroimmune feedback loops that may impact allergic immune responses. By utilizing cutaneous allergen exposure as a model, this review explores the pivotal role of sensory neurons in allergen detection and their dynamic bidirectional communication with the immune system, which ultimately orchestrates the type‐2 immune response. Furthermore, it sheds light on how peripheral signals are integrated within the central nervous system to coordinate hallmark features of allergic reactions. Drawing from this emerging evidence, we propose that atopy arises from a dysregulated neuroimmune circuit. [ABSTRACT FROM AUTHOR]

This article discusses the role of sensory neurons in tissue repair and regeneration, particularly in the context of diabetic and neuropathic conditions. The authors found that nociceptive sensory neurons release calcitonin gene-related peptide (CGRP) in response to acute injury, which modulates immune cells and creates an anti-inflammatory and pro-healing environment. However, in diabetic patients, there is a decrease in CGRP levels, which may contribute to impaired tissue healing. The authors propose that delivering engineered CGRP or CGRP analogues could be a potential therapeutic strategy to promote tissue healing in diabetic patients and other conditions where immune responses are dysfunctional. However, caution is needed when using CGRP inhibitors, as they may impair wound healing. Overall, this discovery has the potential to improve healing outcomes and enhance quality of life for patients with various conditions. [Extracted from the article]

Herpes zoster (HZ), resulting from the reactivation of the varicella‐zoster virus, is a significant disease. This study aimed to explore the factors influencing sensory neuron involvement in HZ at different locations and its association with postherpetic neuralgia (PHN). A total of 3143 cases were retrieved from an electronic medical record system, including 2676 cases of HZ and 467 cases of PHN. Gender, age, site of onset, past surgical history, and comorbidities were analyzed using a multifactorial logistic regression model. The results revealed correlations between age, gender, comorbidities (diabetes, coronary heart disease, percutaneous coronary intervention [PCI]), and sensory neuron involvement in HZ. Specifically, older age, female gender, and comorbid conditions such as diabetes/coronary heart disease were associated with sacral dorsal root ganglion (DRG) involvement, while PCI history was associated with lumbar DRG involvement. Additionally, sensory neuron involvement at different locations by HZ was linked to PHN. Furthermore, independent risk factors for PHN included thoracic DRG involvement, older age, and comorbidities (diabetes, surgical history, malignancy). It is crucial to prevent damage to the DRG, especially in individuals with comorbidities, through activities avoidance and active treatment, to minimize the occurrence of PHN. [ABSTRACT FROM AUTHOR]

Sensory neurons densely innervate the myocardium. The role of their sensing and response to acute and prolonged ischemia is largely unclear. In a cellular model of ischemia-reperfusion injury, the presence of sensory neurons increases cardiomyocyte survival. Here, after the exclusion of classical neurotransmitter release, and measurement of cytokine release, we modified the experiment from a direct co-culture of primary murine cardiomyocytes and sensory neurons to a transfer of the supernatant. Sensory neurons were exposed to ischemia and the resulting conditioned supernatant was transferred onto cardiomyocytes. This approach largely increased the tolerance of cardiomyocytes to ischemia and reperfusion. Towards the identification of the mechanism, it was demonstrated that after ten-fold dilution, the conditioned solution lost its protective effect. The effect remained after removal of extracellular vesicles by ultracentrifugation, and was not affected by exposure to protease activity, and fractionation pointed towards a hydrophilic agent. Solutions conditioned by HEK293t cells or 3T3 fibroblasts also increase cardiomyocyte survival, but to a lower degree. A metabolomic search identified 64 at least two-fold changed metabolites and lipids. Many of these could be identified and are involved in essential cellular functions. In the presented model for ischemia-reperfusion, sensory neurons secrete one or more cardioprotective substances that can improve cardiomyocyte survival. [ABSTRACT FROM AUTHOR]

Background: The identification of novel toxins from overlooked and taxonomically exceptional species bears potential for various pharmacological applications. The remipede Xibalbanus tulumensis, an underwater cave-dwelling crustacean, is the only crustacean for which a venom system has been described. Its venom contains several xibalbin peptides that have an inhibitor cysteine knot (ICK) scaffold. Results: Our screenings revealed that all tested xibalbin variants particularly inhibit potassium channels. Xib1 and xib13 with their eight-cysteine domain similar to spider knottins also inhibit voltage-gated sodium channels. No activity was noted on calcium channels. Expanding the functional testing, we demonstrate that xib1 and xib13 increase PKA-II and Erk1/2 sensitization signaling in nociceptive neurons, which may initiate pain sensitization. Our phylogenetic analysis suggests that xib13 either originates from the common ancestor of pancrustaceans or earlier while xib1 is more restricted to remipedes. The ten-cysteine scaffolded xib2 emerged from xib1, a result that is supported by our phylogenetic and machine learning-based analyses. Conclusions: Our functional characterization of synthesized variants of xib1, xib2, and xib13 elucidates their potential as inhibitors of potassium channels in mammalian systems. The specific interaction of xib2 with Kv1.6 channels, which are relevant to treating variants of epilepsy, shows potential for further studies. At higher concentrations, xib1 and xib13 activate the kinases PKA-II and ERK1/2 in mammalian sensory neurons, suggesting pain sensitization and potential applications related to pain research and therapy. While tested insect channels suggest that all probably act as neurotoxins, the biological function of xib1, xib2, and xib13 requires further elucidation. A novel finding on their evolutionary origin is the apparent emergence of X. tulumensis-specific xib2 from xib1. Our study is an important cornerstone for future studies to untangle the origin and function of these enigmatic proteins as important components of remipede but also other pancrustacean and arthropod venoms. [ABSTRACT FROM AUTHOR]

Chemotherapy-induced peripheral neuropathy (CIPN) is a disabling side effect of cancer chemotherapy that can often limit treatment options for cancer patients or have life-long neurodegenerative consequences that reduce the patient's quality of life. CIPN is caused by the detrimental actions of various chemotherapeutic agents on peripheral axons. Currently, there are no approved preventative measures or treatment options for CIPN, highlighting the need for the discovery of novel therapeutics and improving our understanding of disease mechanisms. In this study, we utilized human-induced pluripotent stem cell (hiPSC)-derived motor neurons as a platform to mimic axonal damage after treatment with vincristine, a chemotherapeutic used for the treatment of breast cancers, osteosarcomas, and leukemia. We screened a total of 1902 small molecules for neuroprotective properties in rescuing vincristine-induced axon growth deficits. From our primary screen, we identified 38 hit compounds that were subjected to secondary dose response screens. Six compounds showed favorable pharmacological profiles – AZD7762, A-674563, Blebbistatin, Glesatinib, KW-2449, and Pelitinib, all novel neuroprotectants against vincristine toxicity to neurons. In addition, four of these six compounds also showed efficacy against vincristine-induced growth arrest in human iPSC-derived sensory neurons. In this study, we utilized high-throughput screening of a large library of compounds in a therapeutically relevant assay. We identified several novel compounds that are efficacious in protecting different neuronal subtypes from the toxicity induced by a common chemotherapeutic agent, vincristine which could have therapeutic potential in the clinic. [ABSTRACT FROM AUTHOR]

Understanding the neural basis of infant social behaviors is crucial for elucidating the mechanisms of early social and emotional development. In this work, we report a specific population of somatostatin-expressing neurons in the zona incerta (ZISST) of preweaning mice that responds dynamically to social interactions, particularly those with their mother. Bidirectional neural activity manipulations in pups revealed that widespread connectivity of preweaning ZISST neurons to sensory, emotional, and cognitive brain centers mediates two key adaptive functions associated with maternal presence: the reduction of behavior distress and the facilitation of learning. These findings reveal a population of neurons in the infant mouse brain that coordinate the positive effects of the relationship with the mother on an infant's behavior and physiology. [ABSTRACT FROM AUTHOR]

Introduction: Damage to the corneal nerves can result in discomfort and chronic pain, profoundly impacting the quality of life of patients. Development of novel in vitro method is crucial to better understand corneal nerve regeneration and to find new treatments for the patients. Existing in vitro models often overlook the physiology of primary sensory neurons, for which the soma is separated from the nerve endings. Methods: To overcome this limitation, our novel model combines a compartmentalized microfluidic culture of trigeminal ganglion neurons from adult mice with live-imaging and automated 3D image analysis offering robust way to assess axonal regrowth after axotomy. Results: Physical axotomy performed by a two-second aspiration led to a reproducible 70% axonal loss and altered the phenotype of the neurons, increasing the number of substance P-positive neurons 72h post-axotomy. To validate our new model, we investigated axonal regeneration after exposure to pharmacological compounds. We selected various targets known to enhance or inhibit axonal regrowth and analyzed their basal expression in trigeminal ganglion cells by scRNAseq. NGF/GDNF, insulin, and Dooku-1 (Piezo1 antagonist) enhanced regrowth by 81, 74 and 157%, respectively, while Yoda-1 (Piezo1 agonist) had no effect. Furthermore, SARM1-IN-2 (Sarm1 inhibitor) inhibited axonal regrowth, leading to only 6% regrowth after 72h of exposure (versus 34% regrowth without any compound). Discussion: Combining compartmentalized trigeminal neuronal culture with advanced imaging and analysis allowed a thorough evaluation of the extent of the axotomy and subsequent axonal regrowth. This innovative approach holds great promise for advancing our understanding of corneal nerve injuries and regeneration and ultimately improving the quality of life for patients suffering from sensory abnormalities, and related conditions. [ABSTRACT FROM AUTHOR]

Peripheral nerve damage often leads to the onset of neuropathic pain (NeuP). This condition afflicts millions of people, significantly burdening healthcare systems and putting strain on families' financial well-being. Here, we will focus on the role of peripheral sensory neurons, specifically the Dorsal Root Ganglia neurons (DRG neurons) in the development of NeuP. After axotomy, DRG neurons activate regenerative signals of axons-soma communication to promote a gene program that activates an axonal branching and elongation processes. The results of a neuronal morphological cytoskeleton change are not always associated with functional recovery. Moreover, any axonal misstargeting may contribute to NeuP development. In this review, we will explore the epidemiology of NeuP and its molecular causes at the level of the peripheral nervous system and the target organs, with major focus on the neuronal crosstalk between intrinsic and extrinsic factors. Specifically, we will describe how failures in the neuronal regenerative program can exacerbate NeuP. [ABSTRACT FROM AUTHOR]

The red palm weevil (RPW), Rhynchophorus ferrugineus (Olivier), also known as the Asian palm weevil, is an invasive pest that causes widespread damage to palm trees around the globe. As pheromone communication is crucial for their mass attack and survival on palm trees, the olfactory concept of pest control strategies has been widely explored recently. We aim to understand the molecular basis of olfaction in RPW by studying one of the key olfactory proteins in insect pheromone communication, sensory neuron membrane proteins (SNMPs). SNMPs belong to the CD36 (cluster of differentiation 36) family that perform two distinct olfactory roles in insects, either in pheromone (odorant) transfer to the odorant receptors (SNMP1) or in the pheromone clearing process (SNMP2). In this study, we performed antennal transcriptomic screening and identified six SNMPs, mapping them on the R. ferrugineus genome, and confirmed four distinct SNMPs. Both SNMP1 proteins in RPW, viz., RferSNMPu1 and RferSNMPu2, were mapped onto the same scaffold in different loci in the RPW genome. To further understand the function of these proteins, we first classified them using phylogenetic analysis and checked their tissue-specific expression patterns. Further, we measured the relative transcript abundance of SNMPs in laboratory-reared, field-collected adults and pheromone-exposure experiments, ultimately identifying RferSNMPu1 as a potential candidate for functional analysis. We mapped RferSNMPu1 expression in the antennae and found that expression patterns were similar in both sexes. We used RNAi-based gene silencing to knockdown RferSNMPu1 and tested the changes in the RPW responses to aggregation pheromone compounds, 4-methyl-5-nonanol (ferrugineol) and 4-methyl-5-nonanone (ferrugineone), and a kairomone, ethyl acetate using electroantennogram (EAG) recordings. We found a significant reduction in the EAG recordings in the RferSNMPu1 knockdown strain of adult RPWs, confirming its potential role in pheromone detection. The structural modelling revealed the key domains in the RferSNMPu1 structure, which could likely be involved in pheromone detection based on the identified ectodomain tunnels. Our studies on RferSNMPu1 with a putative role in pheromone detection provide valuable insight into understanding the olfaction in R. ferrugineus as well as in other Curculionids, as SNMPs are under-explored in terms of its functional role in insect olfaction. Most importantly, RferSNMPu1 can be used as a potential target for the olfactory communication disruption in the R. ferrugineus control strategies. [ABSTRACT FROM AUTHOR]

Sensory neurons specialize in detecting and signaling the presence of diverse environmental stimuli. Neuronal injury or disease may undermine such signaling, diminishing the availability of crucial information. Can animals distinguish between a stimulus not being present and the inability to sense that stimulus in the first place? To address this question, we studied Caenorhabditis elegans nematode worms that lack gentle body touch sensation due to genetic mechanoreceptor dysfunction. We previously showed that worms can compensate for the loss of touch by enhancing their sense of smell, via an FLP-20 neuropeptide pathway. Here, we find that touch-deficient worms exhibit, in addition to sensory compensation, also cautious-like behavior, as if preemptively avoiding potential undetectable hazards. Intriguingly, these behavioral adjustments are abolished when the touch neurons are removed, suggesting that touch neurons are required for signaling the unavailability of touch information, in addition to their conventional role of signaling touch stimulation. Furthermore, we found that the ASE taste neurons, which similarly to the touch neurons, express the FLP-20 neuropeptide, exhibit altered FLP-20 expression levels in a touch-dependent manner, thus cooperating with the touch circuit. These results imply a novel form of neuronal signaling that enables C. elegans to distinguish between lack of touch stimulation and loss of touch sensation, producing adaptive behavioral adjustments that could overcome the inability to detect potential threats. Sensory loss deprives animals of important information. This study shows that Caenorhabditis elegans worms lacking touch sensation show cautious-like behaviors, indicating that the touch neurons provide not only information about the presence or absence of touch stimuli, but also about the unavailability of touch information. [ABSTRACT FROM AUTHOR]

Background: Lucilia cuprina (Wiedemann, 1830) (Diptera: Calliphoridae) is the main causative agent of flystrike of sheep in Australia and New Zealand. Female flies lay eggs in an open wound or natural orifice, and the developing larvae eat the host's tissues, a condition called myiasis. To improve our understanding of host-seeking behavior, we quantified gene expression in male and female antennae based on their behavior. Methods: A spatial olfactometer was used to evaluate the olfactory response of L. cuprina mated males and gravid females to fresh or rotting beef. Antennal RNA-Seq analysis was used to identify sensory receptors differentially expressed between groups. Results: Lucilia cuprina females were more attracted to rotten compared to fresh beef (> fivefold increase). However, males and some females did not respond to either type of beef. RNA-Seq analysis was performed on antennae dissected from attracted females, non-attracted females and males. Transcripts encoding sensory receptors from 11 gene families were identified above a threshold (≥ 5 transcript per million) including 49 ATP-binding cassette transporters (ABCs), two ammonium transporters (AMTs), 37 odorant receptors (ORs), 16 ionotropic receptors (IRs), 5 gustatory receptors (GRs), 22 odorant-binding proteins (OBPs), 9 CD36-sensory neuron membrane proteins (CD36/SNMPs), 4 chemosensory proteins (CSPs), 4 myeloid lipid-recognition (ML) and Niemann-Pick C2 disease proteins (ML/NPC2), 2 pickpocket receptors (PPKs) and 3 transient receptor potential channels (TRPs). Differential expression analyses identified sex-biased sensory receptors. Conclusions: We identified sensory receptors that were differentially expressed between the antennae of both sexes and hence may be associated with host detection by female flies. The most promising for future investigations were as follows: an odorant receptor (LcupOR46) which is female-biased in L. cuprina and Cochliomyia hominivorax Coquerel, 1858; an ABC transporter (ABC G23.1) that was the sole sensory receptor upregulated in the antennae of females attracted to rotting beef compared to non-attracted females; a female-biased ammonia transporter (AMT_Rh50), which was previously associated with ammonium detection in Drosophila melanogaster Meigen, 1830. This is the first report suggesting a possible role for ABC transporters in L. cuprina olfaction and potentially in other insects. [ABSTRACT FROM AUTHOR]

The efficient coding approach proposes that neural systems represent as much sensory information as biological constraints allow. It aims at formalizing encoding as a constrained optimal process. A different approach, that aims at formalizing decoding, proposes that neural systems instantiate a generative model of the sensory world. Here, we put forth a normative framework that characterizes neural systems as jointly optimizing encoding and decoding. It takes the form of a variational autoencoder: sensory stimuli are encoded in the noisy activity of neurons to be interpreted by a flexible decoder; encoding must allow for an accurate stimulus reconstruction from neural activity. Jointly, neural activity is required to represent the statistics of latent features which are mapped by the decoder into distributions over sensory stimuli; decoding correspondingly optimizes the accuracy of the generative model. This framework yields in a family of encoding-decoding models, which result in equally accurate generative models, indexed by a measure of the stimulus-induced deviation of neural activity from the marginal distribution over neural activity. Each member of this family predicts a specific relation between properties of the sensory neurons—such as the arrangement of the tuning curve means (preferred stimuli) and widths (degrees of selectivity) in the population—as a function of the statistics of the sensory world. Our approach thus generalizes the efficient coding approach. Notably, here, the form of the constraint on the optimization derives from the requirement of an accurate generative model, while it is arbitrary in efficient coding models. Moreover, solutions do not require the knowledge of the stimulus distribution, but are learned on the basis of data samples; the constraint further acts as regularizer, allowing the model to generalize beyond the training data. Finally, we characterize the family of models we obtain through alternate measures of performance, such as the error in stimulus reconstruction. We find that a range of models admits comparable performance; in particular, a population of sensory neurons with broad tuning curves as observed experimentally yields both low reconstruction stimulus error and an accurate generative model that generalizes robustly to unseen data. Author summary: Our brain represents the sensory world in the activity of populations of neurons. Two theories have addressed the nature of these representations. The first theory—efficient coding—posits that neurons encode as much information as possible about sensory stimuli, subject to resource constraints such as limits on energy consumption. The second one—generative modeling—focuses on decoding, and is organized around the idea that neural activity plays the role of a latent variable from which sensory stimuli can be simulated. Our work subsumes the two approaches in a unifying framework based on the mathematics of variational autoencoders. Unlike in efficient coding, which assumes full knowledge of stimulus statistics, here representations are learned from examples, in a joint optimization of encoding and decoding. This new framework yields a range of optimal representations, corresponding to different models of neural selectivity and reconstruction performances, depending on the resource constraint. The form of the constraint is not arbitrary but derives from the optimization framework, and its strength tunes the ability of the model to generalize beyond the training example. Central to the approach, and to the nature of the representations it implies, is the interplay of encoding and decoding, itself central to brain processing. [ABSTRACT FROM AUTHOR]

Eugenol (EUG) is a bioactive monoterpenoid used as an analgesic, preservative, and flavoring agent. Our new data show EUG as a voltage-gated Na+ channel (VGSC) inhibitor, comparable but not identical to lidocaine (LID). EUG inhibits both total and only TTX-R voltage-activated Na+ currents (INa) recorded from VGSCs naturally expressed on dorsal root ganglion sensory neurons in rats. Inhibition is quick, fully reversible, and dose-dependent. Our biophysical and pharmacological analyses showed that EUG and LID inhibit VGSCs with different mechanisms. EUG inhibits VGSCs with a dose–response relationship characterized by a Hill coefficient of 2, while this parameter for the inhibition by LID is 1. Furthermore, in a different way from LID, EUG modified the voltage dependence of both the VGSC activation and inactivation processes and the recovery from fast inactivated states and the entry to slow inactivated states. In addition, we suggest that EUG, but not LID, interacts with VGSC pre-open–closed states, according to our data. [ABSTRACT FROM AUTHOR]

Microtubule associated proteins (MAPs) are widely expressed in the central nervous system, and have established roles in cell proliferation, myelination, neurite formation, axon specification, outgrowth, dendrite, and synapse formation. We report eleven individuals from seven families harboring predicted pathogenic biallelic, de novo, and heterozygous variants in the NAV3 gene, which encodes the microtubule positive tip protein neuron navigator 3 (NAV3). All affected individuals have intellectual disability (ID), microcephaly, skeletal deformities, ocular anomalies, and behavioral issues. In mouse brain, Nav3 is expressed throughout the nervous system, with more prominent signatures in postmitotic, excitatory, inhibiting, and sensory neurons. When overexpressed in HEK293T and COS7 cells, pathogenic variants impaired NAV3 ability to stabilize microtubules. Further, knocking-down nav3 in zebrafish led to severe morphological defects, microcephaly, impaired neuronal growth, and behavioral impairment, which were rescued with co-injection of WT NAV3 mRNA and not by transcripts encoding the pathogenic variants. Our findings establish the role of NAV3 in neurodevelopmental disorders, and reveal its involvement in neuronal morphogenesis, and neuromuscular responses. neuron navigator-3 (NAV3) is involved in neuronal morphogenesis, vision, and neuromuscular responses, and the biallelic/mono-allelic variants of NAV3 are causative of a spectrum of neurodevelopmental disorders [ABSTRACT FROM AUTHOR]

The purpose of this study was to investigate the effect of dietary sesame oil and ginger oil supplements on the dorsal root ganglia following a sciatic nerve crush model in male Wistar albino rats. Crush injury models have been done by means of graded forceps (50 Newton). The animals were given a daily sesame oil (4 ml/kg/day) and ginger oil (400 mg/kg/day) via oral gavage for a period of 28 days. Dorsal root ganglia from the L5 levels were harvested. Processing of tissues was done for electron microscopy and light microscopy. Immunohistochemical staining with active caspase-3 antibody and qualitative ultrastructural analyses of tissues were made by a light and a transmission electron microscope, respectively. The results showed that crush injury leads to remarkable ultrastructural changes in sensory neurons, such as swollen mitochondria, disruption of cristae structure, glial cell proliferation and, consequently, phagocytosis of the damaged neuron. These ultrastructural changes were less evident in the treated groups, and both natural compounds reduced the expression of activated caspase-3, which may also affect ultrastructural changes. The application of the natural products sesame oil and ginger oil may represent a supportive approach to the protection of sensory neurons against the destructive effects of peripheral nerve crush injury. [ABSTRACT FROM AUTHOR]

Lympho-epithelial Kazal-type-related inhibitor (LEKTI) is a serine protease inhibitor consisting of multiple domains. A loss of function mutation is described in Netherton patients that show severe symptoms of atopic lesions and itch. LEKTI domain 6 (LD6) has shown strong serine protease-inhibitory action in in vitro assays and thus it was tested in vitro and in vivo for potential anti-inflammatory action in models of atopic skin disease. Human skin equivalents were treated with LD6 and an inflammatory reaction was challenged by kallikrein-related endopeptidase 5 (KLK5). Furthermore, LD6 was tested on dorsal root ganglia cells stimulated with KLK5, SLIGRL and histamine by calcium imaging. The effect of topically administered LD6 (0.4–0.8%) in lipoderm was compared to a topical formulation of betamethasone-diproprionate (0.1%) in a therapeutic setting on atopic dermatitis-like lesions in NC/Nga mice sensitized to house dust mite antigen. Endpoints were clinical scoring of the mice as well as determination of scratching behaviour. KLK5 induced an upregulation of CXCL-8, CCL20 and IL-6 in skin equivalents. This upregulation was reduced by pre-incubation with LD6. KLK5 as well as histamine induced calcium influx in a population of neurons. LD6 significantly reduced the calcium response to both stimuli. When administered onto lesional skin of NC/Nga mice, both LD6 and betamethasone-dipropionate significantly reduced the inflammatory reaction. The effect on itch behaviour was less pronounced. Topical administration of LD6 might be a new therapeutic option for treatment of lesional atopic skin. • LEKTI domain 6 reduces activation of sensory neurons provoked by proteases. • LEKTI domain 6 reduces activation of sensory neurons provoked by histamine. • LEKTI domain 6 reduces the inflammatory response in skin constructs. • LEKTI domain 6 reduces the inflammatory response in a murine atopic dermatitis model. [ABSTRACT FROM AUTHOR]

Different stimuli can potentially activate overlapping populations of neurons in the brain. How does the brain maintain information about multiple items? Here, we describe a new theory: neurons might switch back and forth between encoding each item across time. Recent statistical advances have allowed neurophysiology studies to probe for such activity fluctuations, generating support for this theory and opening intriguing new research directions. Many open questions remain, such as the time scale of activity fluctuations, the manner in which they are coordinated across (and read out from) neural ensembles, and the implications for perceptual binding, neural oscillations, and cognitive processes like attention, memory, and thought. Our ability to perceive multiple objects is mysterious. Sensory neurons are broadly tuned, producing potential overlap in the populations of neurons activated by each object in a scene. This overlap raises questions about how distinct information is retained about each item. We present a novel signal switching theory of neural representation, which posits that neural signals may interleave representations of individual items across time. Evidence for this theory comes from new statistical tools that overcome the limitations inherent to standard time-and-trial-pooled assessments of neural signals. Our theory has implications for diverse domains of neuroscience, including attention, figure binding/scene segregation, oscillations, and divisive normalization. The general concept of switching between functions could also lend explanatory power to theories of grounded cognition. [ABSTRACT FROM AUTHOR]

Frequent itching and incessant scratching are commonly observed in various chronic inflammatory skin conditions, including atopic dermatitis and psoriasis. The persistent and prolonged nature of pruritus can worsen one's quality of life. Keratinocytes (KCs), the predominant cells of the epidermis, have been confirmed to interact with sensory neurons and immune cells and be involved in chronic skin inflammatory diseases associated with pruritus. Initially, KCs and sensory neurons form a unique synapse‐like connection within the epidermis, serving as the structural foundation for their interaction. Additionally, several receptors, including toll‐like receptors and protease‐activated receptor 2, expressed on KCs, become activated in an inflammatory milieu. On the one hand, activated KCs are sources of pro‐inflammatory cytokines and neurotrophic factors, such as adenosine triphosphate, thymic stromal lymphopoietin, and nerve growth factor, which directly or indirectly participate in stimulating sensory neurons, thereby contributing to the itch sensations. On the other hand, KCs also function as primary transducers alongside intraepidermal nerve endings, directly initiating pruritic responses. This review summarizes the current literature and highlights the critical role of KCs in the development and persistence of chronic itch in inflammatory skin disorders. [ABSTRACT FROM AUTHOR]

Microtubule-based kinesin motor proteins are crucial for intracellular transport, but their hyperactivation can be detrimental for cellular functions. This study investigated the impact of a constitutively active ciliary kinesin mutant, OSM-3CA, on sensory cilia in C. elegans. Surprisingly, we found that OSM-3CA was absent from cilia but underwent disposal through membrane abscission at the tips of aberrant neurites. Neighboring glial cells engulf and eliminate the released OSM-3CA, a process that depends on the engulfment receptor CED-1. Through genetic suppressor screens, we identified intragenic mutations in the OSM-3CA motor domain and mutations inhibiting the ciliary kinase DYF-5, both of which restored normal cilia in OSM-3CA-expressing animals. We showed that conformational changes in OSM-3CA prevent its entry into cilia, and OSM-3CA disposal requires its hyperactivity. Finally, we provide evidence that neurons also dispose of hyperactive kinesin-1 resulting from a clinic variant associated with amyotrophic lateral sclerosis, suggesting a widespread mechanism for regulating hyperactive kinesins. Synopsis: Hyperactivation of kinesins has been linked to neurodegenerative conditions. This study shows that a hyperactive version of OSM-3, a member of kinesin-2 superfamily that drives anterograde intraflagellar transport in C. elegans, is expelled from neurons for degradation in glial cells. Hyperactive OSM-3CA kinesin is absent from cilia and forms dynamic puncta within the neurites of sensory neurons. OSM-3CA puncta are ejected from sensory neurons and engulfed by neighboring cephalic sheath glia cells in a manner dependent of the phagocytic receptor CED-1. Mutations that reduce OSM-3CA activity or increase its microtubule binding protect OSM-3CA and restore normal cilia. ALS-linked hyperactive kinesin-1 is also expelled from neurons when ectopically expressed in C. elegans. Phagocytic receptor CED-1 enables glial uptake and subsequent degradation of hyperactive kinesins in C. elegans. [ABSTRACT FROM AUTHOR]

Skin denervation has been shown to cause remission of psoriatic lesions in patients, which can reappear if reinnervation occurs. This effect can be induced by the activation of dendritic cells through sensory innervation. However, a direct effect of nerves on the proliferation of keratinocytes involved in the formation of psoriatic plaques has not been investigated. We developed, by tissue engineering, a model of psoriatic skin made of patient skin cells that showed increased keratinocyte proliferation and epidermal thickness compared to healthy controls. When this model was treated with CGRP, a neuropeptide released by sensory neurons, an increased keratinocyte proliferation was observed in the psoriatic skin model, but not in the control. When a sensory nerve network was incorporated in the psoriatic model and treated with capsaicin to induce neuropeptide release, an increase of keratinocyte proliferation was confirmed, which was blocked by a CGRP antagonist while no difference was noticed in the innervated healthy control. We showed that sensory neurons can participate directly to keratinocyte hyperproliferation in the formation of psoriatic lesions through the release of CGRP, independently of the immune system. Our unique tissue-engineered innervated psoriatic skin model could be a valuable tool to better understand the mechanism by which nerves may modulate psoriatic lesion formation in humans. This study shows that keratinocytes extracted from patients' psoriatic skin retain, at least in part, the disease phenotype. Indeed, when combined in a 3D model of tissue-engineered psoriatic skin, keratinocytes exhibited a higher proliferation rate, and produced a thicker epidermis than a healthy skin control. In addition, their hyperproliferation was aggravated by a treatment with CGRP, a neuropeptide released by sensory nerves. In a innervated model of tissue-engineered psoriatic skin, an increase in keratinocyte hyperproliferation was also observed after inducing neurons to release neuropeptides. This effect was prevented by concomitant treatment with an antagonist to CGRP. Thus, this study shows that sensory nerves can directly participate to affect keratinocyte hyperproliferation in psoriasis through CGRP release. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract Background Human induced pluripotent stem cell (iPSC)-derived peripheral sensory neurons present a valuable tool to model human diseases and are a source for applications in drug discovery and regenerative medicine. Clinically, peripheral sensory neuropathies can result in maladies ranging from a complete loss of pain to severe painful neuropathic disorders. Sensory neurons are located in the dorsal root ganglion and are comprised of functionally diverse neuronal types. Low efficiency, reproducibility concerns, variations arising due to genetic factors and time needed to generate functionally mature neuronal populations from iPSCs remain key challenges to study human nociception in vitro. Here, we report a detailed functional characterization of iPSC-derived sensory neurons with an accelerated differentiation protocol (“Anatomic” protocol) compared to the most commonly used small molecule approach (“Chambers” protocol). Anatomic’s commercially available RealDRG™ were further characterized for both functional and expression phenotyping of key nociceptor markers. Methods Multiple iPSC clones derived from different reprogramming methods, genetics, age, and somatic cell sources were used to generate sensory neurons. Manual patch clamp was used to functionally characterize both control and patient-derived neurons. High throughput techniques were further used to demonstrate that RealDRGs™ derived from the Anatomic protocol are amenable to high throughput technologies for disease modelling. Results The Anatomic protocol rendered a purer culture without the use of mitomycin C to suppress non-neuronal outgrowth, while Chambers differentiations yielded a mix of cell types. Chambers protocol results in predominantly tonic firing when compared to Anatomic protocol. Patient-derived nociceptors displayed higher frequency firing compared to control subject with both, Chambers and Anatomic differentiation approaches, underlining their potential use for clinical phenotyping as a disease-in-a-dish model. RealDRG™ sensory neurons show heterogeneity of nociceptive markers indicating that the cells may be useful as a humanized model system for translational studies. Conclusions We validated the efficiency of two differentiation protocols and their potential application for functional assessment and thus understanding the disease mechanisms from patients suffering from pain disorders. We propose that both differentiation methods can be further exploited for understanding mechanisms and development of novel treatments in pain disorders.

Insulin-like growth factor-1 (IGF-1) is a polypeptide hormone with a ubiquitous distribution in numerous tissues and with various functions in both neuronal and non-neuronal cells. IGF-1 provides trophic support for many neurons of both the central and peripheral nervous systems. In the central nervous system (CNS), IGF-1R signaling regulates brain development, increases neuronal firing and modulates synaptic transmission. IGF-1 and IGF-IR are not only expressed in CNS neurons but also in sensory dorsal root ganglion (DRG) nociceptive neurons that convey pain signals. DRG nociceptive neurons express a variety of receptors and ion channels that are essential players of neuronal excitability, notably the ligand-gated cation channel TRPV1 and the voltage-gated M-type K+ channel, which, respectively, triggers and dampens sensory neuron excitability. Although many lines of evidence suggest that IGF-IR signaling contributes to pain sensitivity, its possible modulation of TRPV1 and M-type K+ channel remains largely unexplored. In this study, we examined the impact of IGF-1R signaling on DRG neuron excitability and its modulation of TRPV1 and M-type K+ channel activities in cultured rat DRG neurons. Acute application of IGF-1 to DRG neurons triggered hyper-excitability by inducing spontaneous firing or by increasing the frequency of spikes evoked by depolarizing current injection. These effects were prevented by the IGF-1R antagonist NVP-AEW541 and by the PI3Kinase blocker wortmannin. Surprisingly, acute exposure to IGF-1 profoundly inhibited both the TRPV1 current and the spike burst evoked by capsaicin. The Src kinase inhibitor PP2 potently depressed the capsaicin-evoked spike burst but did not alter the IGF-1 inhibition of the hyperexcitability triggered by capsaicin. Chronic IGF-1 treatment (24 h) reduced the spike firing evoked by depolarizing current injection and upregulated the M-current density. In contrast, chronic IGF-1 markedly increased the spike burst evoked by capsaicin. In all, our data suggest that IGF-1 exerts complex effects on DRG neuron excitability as revealed by its dual and opposite actions upon acute and chronic exposures. [ABSTRACT FROM AUTHOR]

Zygaenoidea is a superfamily of lepidopterans containing many venomous species, including the Limacodidae (nettle caterpillars) and Megalopygidae (asp caterpillars). Venom proteomes have been recently documented for several species from each of these families, but further data are required to understand the evolution of venom in Zygaenoidea. In this study, we examined the 'electric' caterpillar from North-Eastern Australia, a limacodid caterpillar densely covered in venomous spines. We used DNA barcoding to identify this caterpillar as the larva of the moth Comana monomorpha (Turner, 1904). We report the clinical symptoms of C. monomorpha envenomation, which include acute pain, and erythema and oedema lasting for more than a week. Combining transcriptomics of venom spines with proteomics of venom harvested from the spine tips revealed a venom markedly different in composition from previously examined limacodid venoms that are rich in peptides. In contrast, the venom of C. monomorpha is rich in aerolysin-like proteins similar to those found in venoms of asp caterpillars (Megalopygidae). Consistent with this composition, the venom potently permeabilises sensory neurons and human neuroblastoma cells. This study highlights the diversity of venom composition in Limacodidae. [ABSTRACT FROM AUTHOR]

Acoel flatworms have played a relevant role in classical (and current) discussions on the evolutionary origin of bilaterian animals. This is mostly derived from the apparent simplicity of their body architectures. This tenet has been challenged over the last couple of decades, mostly because detailed studies of their morphology and the introduction of multiple genomic technologies have unveiled a complexity of cell types, tissular arrangements and patterning mechanisms that were hidden below this 'superficial' simplicity. One tissue that has received a particular attention has been the nervous system (NS). The combination of ultrastructural and single cell methodologies has revealed unique cellular diversity and developmental trajectories for most of their neurons and associated sensory systems. Moreover, the great diversity in NS architectures shown by different acoels offers us with a unique group of animals where to study key aspects of neurogenesis and diversification od neural systems over evolutionary time. In this review we revisit some recent developments in the characterization of the acoel nervous system structure and the regulatory mechanisms that contribute to their embryological development. We end up by suggesting some promising avenues to better understand how this tissue is organized in its finest cellular details and how to achieve a deeper knowledge of the functional roles that genes and gene networks play in its construction. [ABSTRACT FROM AUTHOR]