Sensory Neurons Research Articles

Near-infrared photobiomodulation therapy on HD10.6 human sensory neurons cell culture.

We investigated the molecular effects of near-infrared photobiomodulation therapy (PBMT) on HD10.6 human sensory neuron cell cultures. This study explores the utility of PBMT in modulating the functionality of sensory neurons in vitro with a potential translational effect on analgesia, a significant concern in clinical settings, particularly in pediatrics where non-invasive treatments are crucial. HD10.6 human sensory neuron cell model was employed in the study. The 800 and 970 PBMT was tested on the cells and mitochondria related parameters and TRP channel functionality were evaluated after irradiation. We found that PBMT affects mitochondrial dynamics and reduces oxidative stress, influenced calcium ion flow, pivotal in nociception signaling, and modified the expression of TRPV1 and TRPA1 receptors post-irradiation. This study observed a potential impact of PBMT on sensory neurons through various cellular mechanisms. These findings may contribute to the understanding of PBMT's mechanistic effects on human sensory neurons, not yet explored in in-vitro model, pointing to its potential utility as a supportive treatment for non-invasive pain management in pediatric care.

RNA helicase MOV10 suppresses fear memory and dendritic arborization and regulates microtubule dynamics in hippocampal neurons

BackgroundRNA helicase MOV10 is highly expressed in postnatal brain and associates with FMRP and AGO2, suggesting a role in translation regulation in learning and memory.ResultsWe generated a brain-specific knockout mouse (Mov10 Deletion) with greatly reduced MOV10 expression in cortex and hippocampus. Behavior testing revealed enhanced fear memory, similar to that observed in a mouse with reduced brain microRNA production, supporting MOV10’s reported role as an AGO2 cofactor. Cultured hippocampal neurons have elongated distal dendrites, a reported feature of augmin/HAUS over-expression in Drosophila da sensory neurons. In mitotic spindle formation, HAUS is antagonized by the microtubule bundling protein NUMA1. Numa1 mRNA is a MOV10 CLIP target and is among the genes significantly decreased in Mov10 Deletion hippocampus. Restoration of NUMA1 expression and knockdown of HAUS rescued phenotypes of the Mov10 Deletion hippocampal neurons.ConclusionsThis is the first evidence of translation regulation of NUMA1 by MOV10 as a control point in dendritogenesis.

New generation capsaicin-diclofenac containing, silicon-based transdermal patch provides prolonged analgesic effect in acute and chronic pain models.

Pain is one of the major public health burdens worldwide, however, conventional analgesics are often ineffective. Capsaicin -the active compound of Capsicum species, being responsible for their pungency - has been part of traditional medicine long ago. Capsaicin is a natural agonist of the Transient Receptor Potential Vanilloid 1 receptor - localized on capsaicin-sensitive sensory neurons and strongly involved in pain transmission -, and has been in focus of analgesic drug research for many years. In this study, we aimed to develop a sustained release transdermal patch (transdermal therapeutic system, TTS) combining the advantages of low-concentration capsaicin and diclofenac embedded in an innovative structure, as well as to perform complex preclinical investigations of its analgesic effect. Drug delivery properties of the TTS were investigated with Franz cell and flow-through cell tests. Analgesic effect of the TTS was examined in in vivo models of acute postoperative and inflammatory, chronic neuropathic and osteoarthritic pain. Modified silicone polymer matrix-based TTS containing low-concentration capsaicin and diclofenac has been developed, releasing both compounds according to zero-order kinetics. Moreover, capsaicin and diclofenac facilitated the liberation of each other. Combined TTS significantly reduced acute postoperative and inflammatory pain, as well as chronic neuropathic and osteoarthritic pain. Interestingly, in acute postoperative and chronic osteoarthritic pain, capsaicin prolonged and potentiated the pain-relieving effect of diclofenac. New generation combined low-concentration capsaicin-diclofenac containing TTS can be an effective therapeutic tool in acute and chronic pain states involving neuropathic and inflammatory components.

First-in-human study of epidural spinal cord stimulation in individuals with spinal muscular atrophy.

Spinal muscular atrophy (SMA) is an inherited neurodegenerative disease causing motoneuron dysfunction, muscle weakness, fatigue and early mortality. Three new therapies can slow disease progression, enabling people to survive albeit with lingering motor impairments. Indeed, weakness and fatigue are still among patients' main concerns. Here we show that epidural spinal cord stimulation (SCS) improved motoneuron function, thereby increasing strength, endurance and gait quality, in three adults with type 3 SMA. Preclinical works demonstrated that SMA motoneurons show low firing rates because of a loss of excitatory input from primary sensory afferents. In the present study, we hypothesized that correcting this loss with electrical stimulation of the sensory afferents could improve motoneuron function. To test this hypothesis, we implanted three adults with SMA with epidural electrodes over the lumbosacral spinal cord, targeting sensory axons of the legs. We delivered SCS for 4 weeks, 2 h per day during motor tasks. Our intervention led to improvements in strength (up to +180%), gait quality (mean step length: +40%) and endurance (mean change in 6-minute walk test: +26 m), paralleled by increased motoneuron firing rates. These changes persisted even when SCS was turned OFF. Notably, no adverse events related to the stimulation were reported. ClinicalTrials.gov identifier: NCT05430113 .

Endoscopic blind limb reduction with septotomy for the treatment of candy cane syndrome after Roux-en-Y gastric bypass: Pilot feasibility study

AbstractCandy cane syndrome (CCS) refers to patients with a long and symptomatic blind afferent roux limb (BARL) after Roux-en-Y gastric bypass (RYGB). Revisional surgery is efficacious but can be cost prohibitive.We describe endoscopic blind limb reduction (EBLR), that converts the BARL into a “common channel” and eliminates food pooling, thereby improving symptoms. Patients that did not have a complete symptomatic response underwent a repeat EBLR or EBLR with septotomy (EBLR-S) based on residual BARL length.Five patients with CCS underwent the EBLR procedure. Mean age was 60.4 years, average BARL length 5.8 cm, and median Charlson comorbidity index was 3. Technical success was achieved in all five patients (100%). Symptom resolution was achieved in all five patients (100%). Two patients required a second procedure.EBLR may be a potentially safe, efficacious, and cost-effective alternative to surgery in patients with CCS. Further prospective studies are needed.

A pooled analysis of the side effects of non-invasive Transcutaneous Auricular Vagus Nerve Stimulation (taVNS)

IntroductionTranscutaneous auricular vagus nerve stimulation (taVNS) is a promising technique for modulating vagal afferent fibers non-invasively and has shown therapeutic potential in neurological, cognitive, and affective disorders. While previous research highlights its efficacy, the safety profile of taVNS has been less extensively examined.MethodsThis study therefore aimed to systematically investigate side effects of taVNS in a large pooled dataset consisting of n = 488 participants, utilizing a standardized questionnaire to assess ten reported side effects. Analyses included effects of stimulation type (interval vs. continuous), stimulation duration, stimulation intensity and participant characteristics (age and gender) as potential modulators.ResultsThe findings support the safety of taVNS, with minimal and mild side effects reported across participants (M = 1.86, SD = 1.36). Although participants receiving sham stimulation were 32.4% less likely to report unpleasant feelings compared to participants receiving taVNS, this effect was driven primarily by low-end ratings (specifically, a rating of 1, indicating not at all when experiencing the corresponding side effect), thus suggesting limited clinical relevance. Interval stimulation notably reduced the likelihood of some side effects, particularly for neck pain, dizziness and unpleasant feelings, suggesting potential for optimizing taVNS protocols. Stimulation intensity and duration showed few statistically significant, but clinically minimal (i.e., very small) effects.ConclusionOverall, these findings demonstrate a favorable safety profile of taVNS, with mostly mild and transient effects, supporting its use as a suitable non-invasive tool in both research and clinical applications.

Role of the calcium-sensing receptor in regulating vascular function.

Functional expression of the calcium-sensing receptor (CaSR) in calcitropic tissues, for example, parathyroid glands and kidneys, is important for maintaining Ca2+ homeostasis. It is also established that the CaSR is present in tissues previously thought to be noncalcitropic and this review discusses the role of the CaSR in vascular function, focusing mainly on contractility but also outlining its role in cell proliferation and calcification. Stimulation of the CaSR by extracellular Ca2+ concentration ([Ca2+]o) on perivascular sensory nerves and vascular endothelial cells is associated with vasodilatation through the release of vasoactive substances and stimulation of IKCa channels and nitric oxide synthesis, respectively, which mediate endothelium-derived hyperpolarizations and activation of BKCa channels and KATP channels in vascular smooth muscle cells (VSMCs). CaSR-induced vasoconstrictions are mediated by the CaSR expressed in VSMCs, which are coupled to the Gq/11 protein-coupled pathway. In addition, the CaSR expressed on VSMCs also regulates proliferation and calcification. Consequently, the CaSR has been implicated in regulating systemic and pulmonary blood pressure and calcimimetics and calcilytics are potential therapeutic targets for cardiovascular diseases, such as hypertension, pulmonary artery hypertension, and atherosclerosis.

Single-cell transcriptomics reveals a compartmentalized antiviral interferon response in the nasal epithelium of mice.

Type III interferons (IFNs) primarily act on epithelial cells and protect against virus infection of the mucosa, whereas type I IFNs act more systemically. To date, it has been unknown which epithelial subtypes in the upper airways, the primary site for initial infection for most respiratory viruses, primarily rely on type III IFN or type I IFNs for antiviral protection. To address this question, we performed a single-cell transcriptomics analysis of the epithelial IFN-mediated response focusing on the upper airways of mice. This work identified nine distinct cell types derived from the olfactory epithelium and thirteen distinct cell types from the respiratory epithelium. Interestingly, type I IFNs induced a stronger antiviral transcriptional response than type III IFN in respiratory epithelial cells, whereas in olfactory epithelial cells, including sustentacular (SUS) and Bowman's gland cells (BGC), type III IFN was more dominant compared to type I IFN. SUS and BGC, which provide structural support and maintain the integrity of olfactory sensory neurons, were highly susceptible to infection with a mouse-adapted variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 MA20) but were protected against infection if the animals were prophylactically treated with type III IFN. These findings demonstrate a high degree of cell type heterogeneity in terms of interferon-mediated antiviral responses and reveal a potent role for type III IFNs in protecting the olfactory epithelium.IMPORTANCESARS-CoV-2 infects SUS and BGC in the olfactory epithelium, causing an impairment of structural support and integrity of olfactory sensory neurons that can result in severe olfactory dysfunctions. We observed an unexpected compartmentalization of the IFN-mediated transcriptional response within the airway epithelium, and we found that olfactory epithelial cells preferentially respond to type III IFN, which resulted in robust antiviral protection of SUS and BGC. Given the proximity of the olfactory epithelium to the central nervous system, we hypothesize that evolution favored a type III IFN-biased antiviral immune response in this tissue to limit inflammatory responses in the brain. Cell type-specific antiviral responses in the upper airways, triggered by the different types of IFNs, should be investigated in more detail and carefully taken into consideration during the development of IFN-based antivirals for clinical use.

Skull vibration induced nystagmus, velocity storage and self-stability

In this paper we give an introduction to the area, followed by brief reviews of the neural response to sound and vibration, and then the velocity storage integrator, before putting forward our hypothesis about the neural input to the velocity storage integrator. Finally we discuss some of the implications of our hypothesis. There are two pathways conveying neural information from the vestibular periphery (the semicircular canals and the otoliths) to central neural mechanisms—a direct and an indirect pathway. Within the indirect pathway there is a unique neural mechanism called the velocity storage integrator (VSI) which is part of a neural network generating prolonged nystagmus, afternystagmus and the sensation of self-motion and its converse self-stability. It is our hypothesis that only neural input from primary afferent neurons with irregular resting discharge projects in the direct pathway, whereas the primary afferent input in the indirect pathway consists of neurons with regular resting discharge. The basis for this hypothesis is that vibration is a selective stimulus for vestibular neurons with irregular resting discharge. 100 Hz mastoid vibration, while capable of generating nystagmus (skull vibration induced nystagmus SVIN), is ineffective in generating afternystagmus (in the condition of an encased labyrinth) which is a marker of the action of the VSI, leading to the conclusion that irregular afferents bypass the indirect pathway and the VSI. In order to present this hypothesis we review the evidence that irregular neurons are selectively activated by sound and vibration, whereas regular neurons are not so activated. There are close similarities between the temporal characteristics of the irregular afferent neural response to vibration and the temporal characteristics of SVIN. SVIN is a simple clinical indicator of whether a patient has an imbalance between the two vestibular labyrinths and our hypothesis ties SVIN to irregular primary vestibular neurons.

Adaptation with naturalistic textures in macaque V1 and V2.

Adaptation affects neuronal responsivity and selectivity throughout the visual hierarchy. However, because most prior studies have tailored stimuli to a single brain area of interest, we have a poor understanding of how exposure to a particular image alters responsivity and tuning at different stages of visual processing. Here we assess how adaptation with naturalistic textures alters neuronal responsivity and selectivity in primary visual cortex (V1) and area V2 of macaque monkeys. Neurons in both areas respond to textures, but V2 neurons are sensitive to higher-order image statistics which do not strongly modulate V1 responsivity. We tested the specificity of adaptation in each area with textures and spectrally-matched 'noise' stimuli. Adaptation reduced responsivity in both V1 and V2, but only in V2 was the reduction dependent on the presence of higher-order texture statistics. Despite this specificity, the texture information provided by single neurons and populations was reduced after adaptation, in both V1 and V2. Our results suggest that adaptation effects for a given feature are induced at the stage of processing that tuning for that feature first arises and that stimulus-specific adaptation effects need not result in improved sensory encoding.Significance statement Nearly all sensory neurons adapt to recent input. However, how the adjustment triggered by a particular input is distributed across brain areas and how these changes contribute to sensory processing are poorly understood. Here we explore adaptation with naturalistic textures, for which neurons in primary visual cortex and area V2 have differing selectivity. Adaptation reduced responsivity in both areas, but the effects in V2 alone depended on the presence of the higher-level texture statistics to which V2 neurons are sensitive. Though prior work with simpler stimuli has argued that stimulus-specific adaptation improves stimulus discriminability, we found adaptation reduced texture information. Thus, adaptation need not improve visual encoding, suggesting its effects may serve some other purpose.

Potentiation of visualized exosomal miR-1306-3p from primary sensory neurons contributes to chronic visceral pain via spinal P2X3 receptors.

Exosomes served as "communicators" to exchange information among different cells in the nervous system. Our previous study demonstrated that the enhanced spinal synaptic transmission contributed to chronic visceral pain in irritable bowel syndrome. However, the underlying mechanism of primary sensory neuron (PSN)-derived exosomes on spinal transmission remains unclear. In this study, an exosome visualization method was established to specifically track exosomes derived from PSNs in CD63-GFPf/+ (green fluorescent protein) mice. Neonatal maternal deprivation (NMD) was adopted to induce chronic visceral pain in CD63-GFPf/+ male mice. The exosome visualization technology demonstrated that NMD increased visible PSN-derived exosomes in the spinal dorsal horn, enhanced spinal synaptic transmission, and led to visceral pain in CD63-GFPf/+ male mice. The PSN-derived exosomal miR-1306-3p sorted from spinal dorsal horn activated P2X3R, enhanced spinal synaptic transmission, and led to visceral pain in NMD mice. Moreover, upregulation of Rab27a in dorsal root ganglia mediated the increased release of PSN-derived exosomes, and intrathecal injection of siR-Rab27a reduced visible PSN-derived exosomes in spinal cord, suppressed spinal synaptic transmission, and alleviated visceral pain in NMD mice. This and future studies would reveal the detailed mechanisms of PSN-derived exosomes and provide a potential target for clinical treatment of chronic visceral pain in patients with irritable bowel syndrome.

Mapping Protein Distribution in the Canine Photoreceptor Sensory Cilium and Calyceal Processes by Ultrastructure Expansion Microscopy.

Photoreceptors are highly polarized sensory neurons, possessing a unique ciliary structure known as the photoreceptor sensory cilium (PSC). Vertebrates have two subtypes of photoreceptors: rods, which are responsible for night vision, and cones, which enable daylight vision and color perception. Despite the identification of functional and morphological differences between these subtypes, ultrastructural analysis of the PSC molecular architecture between rods and cones is still lacking. This study employed ultrastructure expansion microscopy (U-ExM) to characterize the PSC molecular architecture in canine retina. Canine neuroretinas (5-mm punches) were fixed in paraformaldehyde solution for either short or long durations. Additionally, 20-µm-thick cryosections from frozen archival retinal tissues fixed using the longer protocol were analyzed. A U-ExM protocol previously developed for mouse retina was adapted to these canine tissues with a battery of specific antibodies that label the various compartments of the PSC. We demonstrated that U-ExM is applicable to both non-frozen and cryopreserved retinal tissues processed with standard paraformaldehyde fixation. Using this validated U-ExM protocol, we revealed the molecular localization of numerous ciliopathy-related proteins in canine photoreceptors. Furthermore, we identified significant architectural differences in the PSC, ciliary rootlet, and calyceal processes between canine rods and cones. U-ExM is a powerful tool for studying the PSC molecular architecture using frozen archival retinas that are processed following standard paraformaldehyde fixation and embedding protocols. The findings gained from this study pave the way for a better understanding of alterations in the molecular architecture of the PSC in canine models of retinal ciliopathies.

Disrupted Mitochondrial Dynamics Impair Corneal Epithelial Healing in Neurotrophic Keratopathy

Neurotrophic keratopathy (NK) is a degenerative corneal disease characterized by impaired corneal sensitivity and epithelial repair that is often linked to sensory nerve dysfunction. To establish a clinically relevant model and explore the mechanisms underlying NK pathogenesis, we developed a novel mouse model through partial transection of the ciliary nerve. This approach mimics the progressive nature of NK, reproducing key clinical features such as corneal epithelial defects, reduced sensitivity, diminished tear secretion, and delayed wound healing. Using this model, we investigated how disruptions in mitochondrial dynamics contribute to corneal epithelial dysfunction and impaired repair in NK. Our findings revealed substantial disruptions in mitochondrial dynamics, including reduced expression of fusion proteins (OPA1), downregulation of fission regulators (FIS1 and MFF), and impaired mitochondrial transport, as evidenced by decreased expression of Rhot1 and Kif5b. Additionally, the downregulation of mitophagy-related genes (Pink1 and Prkn) contributed to the accumulation of dysfunctional mitochondria, leading to DNA damage and impaired corneal epithelial repair. These mitochondrial abnormalities were accompanied by increased γH2AX staining, indicative of DNA double-strand breaks and cellular stress. This study highlights the pivotal role of mitochondrial dynamics in corneal epithelial health and repair, suggesting that therapeutic strategies aimed at restoring mitochondrial function, enhancing mitophagy, and mitigating oxidative stress may offer promising avenues for treating NK.

Piezo2 in sensory neurons regulates systemic and adipose tissue metabolism.

Systemic metabolism ensures energy homeostasis through inter-organ crosstalk regulating thermogenic adipose tissue. Unlike the well-described inductive role of the sympathetic system, the inhibitory signal ensuring energy preservation remains poorly understood. Here, we show that, via the mechanosensor Piezo2, sensory neurons regulate morphological and physiological properties of brown and beige fat and prevent systemic hypermetabolism. Targeting runt-related transcription factor 3 (Runx3)/parvalbumin (PV) sensory neurons in independent genetic mouse models resulted in a systemic metabolic phenotype characterized by reduced body fat and increased insulin sensitivity and glucose tolerance. Deletion of Piezo2 in PV sensory neurons reproduced the phenotype, protected against high-fat-diet-induced obesity, and caused adipose tissue browning and beiging, likely driven by elevated norepinephrine levels. Finding that brown and beige fat are innervated by Runx3/PV sensory neurons expressing Piezo2 suggests a model in which mechanical signals, sensed by Piezo2 in sensory neurons, protect energy storage and prevent a systemic hypermetabolic phenotype.

Deficiency of KIF15 contributes to oxaliplatin-induced cold hypersensitivity by limiting annexin A2 and enhancing TRPA1 localization in DRG neuronal membrane.

Effective treatments for oxaliplatin-induced cold hypersensitivity remain a significant clinical challenge, primarily due to gaps in our understanding of the underlying pathophysiology. Our previous studies have indicated that kinesin-12 (KIF15) is expressed in neurons, suggesting its potential involvement in neurodevelopment and neuronal plasticity. However, its role in mediating chemotherapy-induced pain in primary sensory neurons has not yet been reported. In this study, we found that KIF15-knockout (Kif15-KO) mice showed an increase in cold sensitivity, with this heightened cold hypersensitivity being dependent on the accumulation of the TRP ankyrin 1 (TRPA1) channel on the cell membrane. We further demonstrated that in a model of oxaliplatin-induced peripheral neuropathy (OIPN), KIF15 expression was markedly reduced, coinciding with an increase in TRPA1 membrane localization and a physical interaction between KIF15 and Annexin A2 in peripheral sensory neurons. This suggests a mechanistic link where the loss of KIF15 disrupts the function of Annexin A2, enhancing the localization of TRPA1 on the cell membrane of dorsal root ganglion (DRG) neurons, thereby contributing to cold hypersensitivity. Our results offer a new understanding of the molecular mechanisms underlying chemotherapy-induced cold hypersensitivity, highlighting KIF15 as a key regulator and a potential therapeutic target for conditions like OIPN.

Upregulation of the neuropeptide receptor calcitonin receptor-like in the spinal cord via MLL2 in a mouse model of paclitaxel-induced peripheral neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a prevalent and severe side effect affecting cancer patients undergoing paclitaxel treatment. Growing evidence underscores the pivotal role of calcitonin-related peptide (CGRP) in the development of CIPN. Repeated administration of paclitaxel induces alterations in CGRP release from sensory neurons within the dorsal root ganglia (DRG). The density of the CGRP receptor is most prominent in the dorsal horn of the spinal cord, where it overlaps with the distribution of CGRP. However, the impact of chemotherapy treatment on expression of the CGRP receptor in the spinal cord remains unclear, as well as the potential therapeutic benefits of a CGRP receptor antagonist in an animal model of CIPN. Using a mouse model of paclitaxel-induced mechanical hypersensitivity, we show upregulation of Calcitonin receptor-like receptor (Calcrl) mRNA expression in the spinal cord, an event that occurred in association with upregulation of the H3K4 methyltransferase MLL2. This effect of repeated paclitaxel administration was also linked to an increase in the recruitment of MLL2, thereby enhancing levels of the active mark H3K4me2 at the Calcrl promoter. Furthermore, administration of the CGRP receptor antagonist BIBN4096 mitigated mechanical and cold hypersensitivity in paclitaxel-treated mice. Together, these observations suggest the CGRP receptor in the spinal cord as a potential target for reducing paclitaxel-induced neuropathic pain in animal models.

Oxaliplatin reversibly and differentially affects electrogenic activity of small IB4(+) of male and female rat sensory neurons.

Oxaliplatin-induced peripheral neuropathy (OIPN) is a prevalent drug side effect with unclear molecular mechanism and sex differences. We report that a 48-hour exposure of 1 µg·mL-1 oxaliplatin potently and reversibly increased the excitability of IB4(+) male and female nociceptors. In females, oxaliplatin augmented spontaneous and tonic activity, increased the overshoot and amplitude of action potentials, depolarized the membrane potential, reduced the rheobase, and raised the firing frequency, primarily due to the depolarization of KV currents and a mild up-regulation of TTX-resistant (TTX-r) NaV currents. In males, oxaliplatin reduced the rheobase, augmented the firing frequency, and prolonged the action potential peak time, mediated by increased TTX-r NaV currents, hyperpolarization of their activation curve, and a faster recovery from inactivation. Oxaliplatin also up-regulated TRPV1 currents in male and female IB4(+) nociceptors and augmented TRPA1 responses in male IB4(+) neurons. These findings highlight NaV1.8, TRPV1, and TRPA1 as therapeutic targets to mitigate OIPN and validate the use of long-term nociceptor cultures as preclinical models for studying peripheral neuropathies.

Vascular dysfunction is at the onset of oxaliplatin-induced peripheral neuropathy symptoms in mice.

Oxaliplatin-induced peripheral neuropathy (OIPN) is an adverse side effect of this chemotherapy used for gastrointestinal cancers. The continuous pain experienced by OIPN patients often results in the reduction or discontinuation of chemotherapy, thereby affecting patient survival. Several pathogenic mechanisms involving sensory neurons were shown to participate in the occurrence of OIPN symptoms. However, the dysfunction of the blood-nerve barrier as a source of nerve alteration had not been thoroughly explored. To characterise the vascular contribution to OIPN symptoms, we undertook two comparative transcriptomic analyses of mouse purified brain and sciatic nerve blood vessels (BVs) and nerve BVs after oxaliplatin or control administration. These analyses reveal distinct molecular landscapes between brain and nerve BVs and the up-regulation of transcripts involved in vascular contraction after oxaliplatin treatment. Anatomical examination of the nerve yet shows the preservation of BV architecture in the acute OIPN mouse model, although treated mice exhibit both neuropathic symptoms and enhanced vasoconstriction reflected by hypoxia. Moreover, vasodilators significantly reduce oxaliplatin-induced neuropathic symptoms and endoneurial hypoxia, establishing the key involvement of nerve blood flow in OIPN.

Glucagon-Like Peptide-1 Links Ingestion, Homeostasis, and the Heart.

Glucagon-like peptide-1 (GLP-1), a hormone released from enteroendocrine cells in the distal small and large intestines in response to nutrients and other stimuli, not only controls eating and insulin release, but is also involved in drinking control as well as renal and cardiovascular functions. Moreover, GLP-1 functions as a central nervous system peptide transmitter, produced by preproglucagon (PPG) neurons in the hindbrain. Intestinal GLP-1 inhibits eating by activating vagal sensory neurons directly, via GLP-1 receptors (GLP-1Rs), but presumably also indirectly, by triggering the release of serotonin from enterochromaffin cells. GLP-1 enhances glucose-dependent insulin release via a vago-vagal reflex and by direct action on beta cells. Finally, intestinal GLP-1 acts on the kidneys to modulate electrolyte and water movements, and on the heart, where it provides numerous benefits, including anti-inflammatory, antiatherogenic, and vasodilatory effects, as well as protection against ischemia/reperfusion injury and arrhythmias. Hindbrain PPG neurons receive multiple inputs and project to many GLP-1R-expressing brain areas involved in reward, autonomic functions, and stress. PPG neuron-derived GLP-1 is involved in the termination of large meals and is implicated in the inhibition of water intake. This review details GLP-1's roles in these interconnected systems, highlighting recent findings and unresolved issues, and integrating them to discuss the physiological and pathological relevance of endogenous GLP-1 in coordinating these functions. As eating poses significant threats to metabolic, fluid, and immune homeostasis, the body needs mechanisms to mitigate these challenges while sustaining essential nutrient intake. Endogenous GLP-1 plays a crucial role in this "ingestive homeostasis."

BoNT/Action beyond neurons.

Botulinum neurotoxin type A (BoNT/A) has expanded its therapeutic uses beyond neuromuscular disorders to include treatments for various pain syndromes and neurological conditions. Originally recognized for blocking acetylcholine release at neuromuscular junctions, BoNT/A's effects extend to both peripheral and central nervous systems. Its ability to undergo retrograde transport allows BoNT/A to modulate synaptic transmission and reduce pain centrally, influencing neurotransmitter systems beyond muscle control. BoNT/A also interacts with glial cells, such as Schwann cells, satellite glial cells, astrocytes, microglia, and oligodendrocytes. Schwann cells, key to peripheral nerve regeneration, are directly influenced by BoNT/A, which promotes their proliferation and enhances remyelination. Satellite glial cells, involved in sensory neuron regulation, show reduced glutamate release in response to BoNT/A, aiding in pain relief. In the CNS, BoNT/A modulates astrocyte activity, reducing excitotoxicity and inflammation, which is relevant in conditions like epilepsy. Microglia, the CNS's immune cells, shift from a pro-inflammatory to a neuroprotective state when treated with BoNT/A, enhancing tissue repair. Additionally, BoNT/A promotes oligodendrocyte survival and remyelination, especially after spinal cord injury. Overall, BoNT/A's ability to target both neurons and glial cells presents a multifaceted therapeutic strategy for neurological disorders, pain management, and CNS repair. Further research is necessary to fully elucidate its mechanisms and optimize its clinical application.