The mesencephalic trigeminal nucleus (MTN) contains trigeminal proprioceptive neurons, a unique class of primary sensory neurons with centrally located cell bodies and a developmental origin distinct from that of peripheral ganglion-derived spinal proprioceptors. MTN neurons have long been recognized for their morphological heterogeneity, but their functions were traditionally viewed as confined to the jaw jerk reflex and oromotor control, reflecting their predominant innervation of jaw-closing muscles. Recent single-cell transcriptomic studies have provided new insight into MTN neurons by uncovering molecular determinants of proprioceptive identity, revealing discrete transcriptional programs that underlie their developmental trajectories and functional specialization. While some subsets of MTN neurons share features with Group Ia and II proprioceptors, they are distinguished by characteristic molecular signatures, including the absence of Runx3 , differential Ntrk2 and Ntrk3 expression, and broader transcriptional features that are not observed in classical spinal counterparts. Accumulating evidence also supports a functional role for MTN neurons in the behavioral transition from suckling to mastication during the weaning period in mammals. In this review, we integrate anatomical, molecular, and functional perspectives to refine the proprioceptive identity of MTN neurons and highlight their implications for sensorimotor maturation and developmental disorders.

The sense of smell is maintained by regenerating olfactory sensory neurons (OSNs) from basal stem cells in the olfactory epithelium (OE). Acute inflammation destroys OSNs, causing hyposmia and anosmia, but activates basal cells. Manipulation of signaling pathways to promote basal cell proliferation and neuroregeneration would reveal novel therapeutic targets for smell deficits. We found that ciliary neurotrophic factor (CNTF) from horizontal basal cells (HBCs, quiescent stem cells) promotes neuroregeneration and functional recovery following methimazole-induced acute injury. Moreover, inhibition of focal adhesion kinase (FAK) upregulates CNTF in naïve OE. Here, we show that the small molecule FAK inhibitor increased CNTF expression in cultured primary HBCs isolated from methimazole-treated mice. Although methimazole-induced CNTF did not seem to be through FAK signaling, inducible cre-lox knockout of FAK in HBCs in mice further increased CNTF expression, as well as Mash1, a marker for globose basal cells (GBCs, neuronal progenitors), and GBC proliferation. Moreover, intranasal aspiration, but not systemic treatment, of a water-soluble pharmacological FAK inhibitor (FAK14) 3 days following methimazole, dose-dependently increased CNTF and Mash1 expression, and GBC proliferation. Intranasal FAK14 also enhanced methimazole-induced regeneration of new OSNs in CNTF+/+, but not in CNTF-/-, mice, demonstrating that FAK14 boosts neuroregeneration through additional CNTF following acute inflammation. Finally, intranasal FAK14 instillation following methimazole improved the functional recovery of smell. This study identifies the therapeutic potential of intranasal application of FAK inhibitors to enhance olfactory neuroregeneration and function following injury.

P2X2/3 receptors as a potential target for cancer pain treatment.

Chronic cough is a prevalent and debilitating condition that significantly impairs quality of life and remains a therapeutic challenge owing to the limited efficacy and unfavorable adverse effect profiles of existing treatments. In recent years, a deeper understanding of the neurobiology of the cough reflex has unveiled the pivotal role of purinergic signaling in the pathophysiology of cough hypersensitivity. Extracellular adenosine triphosphate, released in response to airway inflammation and irritation, activates the P2X3 and P2X2/3 receptors on vagal sensory nerves, triggering and sensitizing the cough reflex. This has led to the emergence of P2X3 receptor antagonists as a promising new class of targeted therapies. This comprehensive review of the pathophysiology of chronic cough focuses on the role of purinergic signaling, with an examination of the preclinical and clinical evidence supporting the efficacy of P2X3 antagonists, such as gefapixant, in reducing cough frequency. Furthermore, we discuss the clinical and safety considerations of these novel drugs, including the main challenge of taste-related adverse effects, and explore future perspectives, such as the development of more selective molecules and the identification of biomarkers to guide personalized treatment strategies. The advent of purinergic receptor modulation marks a significant milestone in the management of chronic cough, offering new hope for patients with this refractory condition.

Skin is filled with a rich network of sensory neurons, and consequently skin interaction with, and perception of the external environment, is a continual phenomenon experienced by all people in society. For medical devices such as prosthetics, the mechanical interaction between skin and the device is an essential aspect for device function, but it must be minimized to ensure continued skin health, which is inherently intertwined with biological processes. Numerous factors influence the interface properties of skin. For example, hydration, which influences skin morphology and composition, in turn influencing skin mechanics that may lead to tissue inflammation and skin injury. Here, we review the current state-of-the-art in skin medical device tribology with a particular focus on skin-prosthetic interactions. We split this article into traditional approaches to skin friction and a biology-first approach to skin friction, with a paradigm shift of skin as an engineered material. The field of tribology has historically been an interdisciplinary field comprising engineers, chemists and physicists, but future developments are needed in skin biology to drive meaningful change. We envisage that the integration of both clinical and biological perspectives will drive future innovations towards improved medical device interactions with the skin, when paired with engineering perspectives.

Chronic type 2 inflammation is known to drive the neuroplasticity of both afferent and efferent vagal nerves innervating many organs. This results in increased neuronal density and sensitivity, possibly contributing to pathologies such as eczema and asthma. However, the mechanisms driving these neuronal changes, particularly in sensory pathways, remain poorly understood, and appropriate in vitro models for their study are lacking. Here, we describe the differentiation of sensory neurons from human pluripotent stem cells. The generation of sensory neurons was validated by verifying the expression of sensory neuron markers, such as β3-tubulin, PGP9.5, TRPV1, Nav1.8, and Piezo1/2, using immunofluorescence, flow cytometry, and RNA sequencing, as well as functional responsiveness to capsaicin using calcium imaging and spontaneous firing using a multi-electrode array. We exposed these hPSC-derived sensory neurons to TGF-β or type 2 cytokines IL-4 and IL-13, both of which play important roles in asthmatic airway remodeling. Both treatments induced neuroplasticity-related changes, such as increased network density and neuronal sensitivity in sensory neurons, albeit more strongly with TGF-β than with IL-4 + IL-13. Our results show robust and reproducible generation of functional hPSC-derived sensory neurons and their usability as a model to investigate the mechanisms underlying neuroplasticity. Furthermore, our findings support a role of TGF-β and type 2 cytokines in the development of neuroplasticity.

Recently, complementary and alternative medicine (CAM) has been actively employed for patients experiencing symptoms unresponsive to Western medical treatments like drug therapy. The natural compounds carotenoids and astaxanthin (AST) have demonstrated various beneficial biological actions for human health in several studies. Given their broad pharmacological activities and reduced toxicity, ASTs possess significant potential as resources for the development of natural analgesic drugs. Given recent studies showing that AST can modulate neuronal excitability, including nociceptive sensory transmission through voltage-gated Ca2+ channels and the n-methyl-D-aspartate (NMDA) glutamate receptor, and inhibit the cyclooxygenase-2 cascade, AST holds promise as a CAM, particularly as a therapeutic agent for nociceptive and pathological pain. Based on the in vivo research findings from our laboratory presented in this review, we have confirmed that carotenoid ASTs possess: (i) an intravenous anesthetic effect on both nociceptive and inflammatory pain comparable to existing analgesics such as ketamine; and (ii) an anti-inflammatory effect on chronic pain with an efficacy almost equivalent to that of the commonly used non-steroidal anti-inflammatory drug (NSAID) celecoxib. Therefore, these findings suggest that, as natural compounds, ASTs contribute to the relief of nociceptive and inflammatory pain, implying their potential for clinical application.

The vestibular system is a critical sensory modality required for coordinated movement, balance and our ability to interact with the surrounding environment. Vestibular sensory neurons provide the nervous system with information about head rotation and acceleration. However, the nervous system can also modify the activity of sensory neurons and hair cells via the actions of the efferent vestibular system (EVS). The function of the EVS has remained unknown partly because of an inability to target efferent vestibular neurons in a selective manner to understand their synaptic inputs and function during behaviour. Here, we present a novel method for the selective targeting and expression of flp-recombinase in EVS neurons. We take advantage of the dual expression of choline acetyl transferase (ChAT) and calcitonin gene related peptide (CGRP) in these neurons to develop an adeno-associated virus (AAV) that expresses a gene only in neurons with this intersectional expression. We use this system to map the monosynaptic inputs to EVS neurons and show inputs from distinct populations of brainstem and midbrain regions indicating a functional role as a multimodal processing center and integrator for the vestibular periphery. To demonstrate the applicability of our technology in behavioural assays, we performed a preliminary behaviour analysis (treadmill running and open field) in mice with disrupted EVS function. While more bespoke assays are required to ascertain EVS function/s, our viral method presents a novel tool for investigators examining the role of the vestibular system and its central circuits.

Pain signaling via sensory neurons drives breast cancer progression through neuropeptide release and κ-opioid counter-regulation.

Bone healing is a tightly orchestrated, multiphase process that requires coordinated interactions between immune cells and skeletal cells. Sensory nerves act as intrinsic effectors of the inflammatory response, whose role in osteoimmunology during healing remains poorly defined. Using a bone healing model with sensory denervation, it's shown that sensory nerves protect bone repair by suppressing excessive osteoclastogenesis. During the acute inflammatory phase, sensory nerves are upstream regulators of macrophage activation. At the molecular level, calcitonin gene-related peptide (CGRP), a sensory neuron-derived neuropeptide, is identified to modulate macrophage activation by restricting key functions such as migration, phagocytosis, and pro-inflammatory cytokine production. Importantly, CGRP rapidly constrains adenosine triphosphate (ATP) synthesis and mitochondrial respiration in activating macrophages, accompanied bydownregulation of genes associated with oxidative phosphorylation and mitochondrial complex components. Following the metabolic alterations, macrophages exposed to CGRP show attenuated osteoclastogenic capacity, with decreased secretion of multiple key factors that support osteoclast differentiation and survival. Together, these findings indicate a neuro-immune-metabolic axis in bone healing, where sensory nerve-derived CGRP influences macrophage bioenergetics and thereby contributes to osteoimmunoligical regulation. It emphasizes the potential of incorporating sensory signals into therapeutic strategies, particularly those targeting immunometabolism in bone regeneration.

Sympathetic activation plays a role in heart failure (HF) development. Afferent renal nerve input may induce sympathoexcitation via the hypothalamic paraventricular nucleus (PVN), which projects to the rostral ventrolateral medulla, a center for sympathetic regulation. Central dendritic release of vasopressin from PVN neurons reportedly stimulates neighboring presympathetic neurons, causing sympathoexcitation. This study investigated whether afferent renal nerves contribute to hypertensive cardiac dysfunction and whether the afferent renal nerve-PVN axis mediates sympathoexcitation via central vasopressin using salt-loaded Dahl salt-sensitive rats, a model of hypertensive HF. Salt loading began at 6 weeks of age, with selective afferent renal denervation and total renal denervation performed at 9 weeks in Dahl salt-sensitive rats. HF phenotypes were examined at 16 weeks, while sympathomodulation by afferent renal denervation was assessed at 12 weeks, the pre-HF phase. At 16 weeks, afferent renal denervation and total renal denervation similarly improved left ventricular systolic dysfunction, reduced myocardial fibrosis and related mRNA levels, and lowered plasma norepinephrine levels without reducing blood pressure in hypertensive rats. At 12 weeks, afferent renal denervation attenuated the increase in plasma norepinephrine and presympathetic neuron activity in the PVN and rostral ventrolateral medulla in hypertensive rats, while decreasing vasopressin-producing PVN neuron activity. In acute experiments, afferent renal nerve stimulation increased sympathetic outflow, but vasopressin V1a and V1b receptor blockade in the PVN suppressed this sympathoexcitation in hypertensive rats. Afferent renal nerve input activates the sympathetic nervous system before left ventricular systolic dysfunction and contributes to hypertensive HF, with PVN vasopressin driving this sympathoexcitation.

Neuroinflammation and metabolic dysfunction drive nerve conduction deficits in diabetic neuropathy: Clinical and in silico insights.

Recent preclinical studies have shown that nicotinamide adenine dinucleotide (NAD+) plays a critical role in molecular mechanisms of axon degeneration, and reductions in NAD+ levels are associated with axonal degeneration. Nicotinamide riboside (NR) is a safe and widely available pyridine-nucleoside form of vitamin B3 and is an NAD+ precursor. To investigate if oral supplementation of synthetic NR can act as a therapeutic agent to prevent degeneration of small somatic sensory axons innervating the skin or promote regeneration of these same fibers in humans, we utilized a validated experimental model of cutaneous nerve degeneration and regeneration and conducted a placebo-controlled, double-blinded Phase 2 study. NR supplementation did not result in elevation of plasma NAD+ levels but resulted in a small increase in NAD+ in the skin samples. NR supplementation did not prevent capsaicin-induced degeneration of the epidermal sensory nerve fibers, and there was no difference in the amount of epidermal reinnervation at the 90-day visit. Although there was a small but statistically significant increase in the number of epidermal sensory nerve fibers at the 60-day visit, these results are preliminary and will need to be validated in larger studies. At present oral NR supplementation, at the doses used in this study, cannot be recommended to prevent neuropathy or to improve nerve regeneration.

Paclitaxel impairs mitochondrial dynamics in human sensory-like neuron cells.

Axon guidance deficits in a human sensory-like neuron model of Fabry disease.

Recovery after axotomy of a peripheral nerve is dependent on regrowth of axons from the point of injury to distal sensorimotor tissues and can be complicated by nerve branching. Little is known about regeneration of sensory axons that encounter branch points distal to injuries. The experiments reported here focused on this question and sought to assess the fidelity of sensory axon regeneration, where fidelity is defined as an axon that originally innervated a distal branch of the sciatic nerve regenerated into that same distal branch after injury, with serial retrograde labeling. Rats with segmental sciatic nerve injuries were treated with linear or branched grafts, with retrograde labels injected into the peroneal and sural branches of the sciatic nerve prior to injury and 12 weeks after. Lumbar dorsal root ganglia 4 and 5 were collected after 12 weeks and were imaged to determine the fidelity of sensory axon regeneration. Results show that the fidelity of sensory regeneration into these two branches differed by the branch and the graft type. Interestingly, the fidelity of sensory axon reinnervation was greater into the peroneal nerve, which is a mixed sensorimotor nerve, compared to the sural nerve, which is a sensory nerve. This occurred in both graft types and suggests that the fidelity of sensory regeneration is improved into mixed branches distal to the PNI compared to sensory branches and supports why regeneration of segmental branched defects may be superior using anatomically matching branched grafts.

Sensory and autonomic nerves supply the sinonasal mucosa and contribute to chronic rhinitis, rhinosinusitis, and craniofacial pain. While posterior and posterolateral nasal nerves have been studied anatomically and histologically, nerves supplying the anterolateral nasal wall (ALNW) have been incompletely studied. The purpose of this cadaveric study was to investigate the ALNW's nerve supply. Sixteen fresh cadaver heads were dissected. First, six heads underwent unilateral ALNW dissection to harvest nerves coursing through the bony ALNW, and these were termed anterior nasal nerves (ANNs). Specimens were formalin-fixed, sectioned, and stained with hematoxylin and eosin, as well as for sensory or autonomic neuropeptides and enzymes. Nerve biomarker presence/absence was recorded. Next, 10 heads (20 sides) were utilized for ALNW mucosal area measurement and dissections. Bilateral subperiosteal dissections were performed to count nerves coursing from the ALNW and anterior portion of the inferior turbinate (IT). Of the six ANNs analyzed immunohistochemically, sensory and autonomic nerve markers were identified in each ANN. The other 10 cadavers all had ANNs coursing from the bony ALNW, with significantly more ANNs coursing through the bony ALNW superior to the IT-ALNW mucosal junction (p = 0.001). ANNs were identified in all cadavers, with more supplying the ALNW than the anterior portion of the IT. Sensory and autonomic nerve markers were identified in the ANNs. Future studies should explore the relative contributions of sensory versus autonomic dysfunction in different rhinologic conditions, and whether these aberrations differentially affect the anterior versus posterior nasal cavities.

The heart-brain axis forms an important physiological network, which is increasingly gaining recognition due to its involvement in cardiac function under steady-state conditions and pathological modifications of the heart in cardiovascular disease. Neurological disorders are known to affect cardiac function by propagating structural alterations in the heart. On the other hand, cardiovascular events have detrimental effects on the central nervous system affecting several brain regions, such as the hippocampus, which is important for cognition. Several anatomical regions of the brain, such as cortical and subcortical forebrain structures, regulate cardiovascular functions via the autonomic nervous system. The sympathetic and parasympathetic nervous systems, which are parts of the autonomic nervous system, play a crucial role in cardiovascular health. Cardiovascular disease, such as myocardial infarction (MI), activates the sympathetic nervous system, leading to exaggerated cardiac remodeling and subsequent arrhythmias. MI also alters afferent sensory neurons affecting nociceptive neurotransmission. This review focuses on the significance of the heart-brain axis and summarizes recent studies in this arena.

Contribution of proneurotrophin-3 to nerve trauma-induced neuropathic pain through promoting TrkC-mediated increase of CCL2 in primary sensory neurons.

EAE models of neuropathic pain in multiple sclerosis do not require pertussis toxin.