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BioRxiv : the Preprint Server For... Jun 2024The vestibular nerve is comprised of neuron sub-groups with diverse functions related to their intrinsic biophysical properties. This diversity is partly due to...
The vestibular nerve is comprised of neuron sub-groups with diverse functions related to their intrinsic biophysical properties. This diversity is partly due to differences in the types and numbers of low-voltage-gated potassium channels found in the neurons' membranes. Expression for some low-voltage gated ion channels like KCNQ4 is upregulated during early post-natal development; suggesting that ion channel composition and neuronal diversity may be shaped by hair cell activity. This idea is consistent with recent work showing that glutamatergic input from hair cells is necessary for the normal diversification auditory neurons. To test if biophysical diversity is similarly dependent on glutamatergic input in vestibular neurons, we examined the maturation of the vestibular epithelium and ganglion neurons in mice whose hair cell synapses lack glutamate. Despite lacking glutamatergic input, the knockout mice showed no notable balance deficits and crossed challenging balance beams with little difficulty. Immunolabeling of the vestibular epithelia showed normal development as indicated by an identifiable striolar zone with calyceal terminals labeled by molecular marker calretinin, and normal expression of KCNQ4 by the end of the second post-natal week. We found similar numbers of Type I and Type II hair cells in the knockout and wildtype animals, regardless of epithelial zone. Thus, the presumably quiescent Type II hair cells are not cleared from the epithelium. Patch-clamp recordings showed that biophysical diversity of vestibular ganglion neurons in the mice is comparable to that found in wildtype controls, with a similar range firing patterns at both immature and juvenile ages. However, our results suggest a subtle biophysical alteration to the largest ganglion cells (putative somata of central zone afferents); those in the knockout had smaller net conductance and were more excitable than those in the wild type. Thus, unlike in the auditory nerve, glutamatergic signaling is unnecessary for producing biophysical diversity in vestibular ganglion neurons. And yet, because the input signals from vestibular hair cells are complex and not solely reliant on quantal release of glutamate, whether diversity of vestibular ganglion neurons is simply hardwired or regulated by a more complex set of input signals remains to be determined.
PubMed: 38915604
DOI: 10.1101/2024.06.12.597464 -
Nature Communications Jun 2024Neuromuscular control of bionic arms has constantly improved over the past years, however, restoration of sensation remains elusive. Previous approaches to reestablish...
Neuromuscular control of bionic arms has constantly improved over the past years, however, restoration of sensation remains elusive. Previous approaches to reestablish sensory feedback include tactile, electrical, and peripheral nerve stimulation, however, they cannot recreate natural, intuitive sensations. Here, we establish an experimental biological sensorimotor interface and demonstrate its potential use in neuroprosthetics. We transfer a mixed nerve to a skeletal muscle combined with glabrous dermal skin transplantation, thus forming a bi-directional communication unit in a rat model. Morphological analyses indicate reinnervation of the skin, mechanoreceptors, NMJs, and muscle spindles. Furthermore, sequential retrograde labeling reveals specific sensory reinnervation at the level of the dorsal root ganglia. Electrophysiological recordings show reproducible afferent signals upon tactile stimulation and tendon manipulation. The results demonstrate the possibility of surgically creating an interface for both decoding efferent motor control, as well as encoding afferent tactile and proprioceptive feedback, and may indicate the way forward regarding clinical translation of biological communication pathways for neuroprosthetic applications.
Topics: Animals; Bionics; Rats; Muscle, Skeletal; Feedback, Sensory; Proprioception; Ganglia, Spinal; Mechanoreceptors; Muscle Spindles; Male; Female; Touch; Skin
PubMed: 38914540
DOI: 10.1038/s41467-024-49580-8 -
PloS One 2024In Drosophila coordinated proliferation of two neural stem cells, neuroblasts (NB) and neuroepithelial (NE) cells, is pivotal for proper larval brain growth that...
Multiple isoforms of the Activin-like receptor baboon differentially regulate proliferation and conversion behaviors of neuroblasts and neuroepithelial cells in the Drosophila larval brain.
In Drosophila coordinated proliferation of two neural stem cells, neuroblasts (NB) and neuroepithelial (NE) cells, is pivotal for proper larval brain growth that ultimately determines the final size and performance of an adult brain. The larval brain growth displays two phases based on behaviors of NB and NEs: the first one in early larval stages, influenced by nutritional status and the second one in the last larval stage, promoted by ecdysone signaling after critical weight checkpoint. Mutations of the baboon (babo) gene that produces three isoforms (BaboA-C), all acting as type-I receptors of Activin-type transforming growth factor β (TGF-β) signaling, cause a small brain phenotype due to severely reduced proliferation of the neural stem cells. In this study we show that loss of babo function severely affects proliferation of NBs and NEs as well as conversion of NEs from both phases. By analyzing babo-null and newly generated isoform-specific mutants by CRISPR mutagenesis as well as isoform-specific RNAi knockdowns in a cell- and stage-specific manner, our data support differential contributions of the isoforms for these cellular events with BaboA playing the major role. Stage-specific expression of EcR-B1 in the brain is also regulated primarily by BaboA along with function of the other isoforms. Blocking EcR function in both neural stem cells results in a small brain phenotype that is more severe than baboA-knockdown alone. In summary, our study proposes that the Babo-mediated signaling promotes proper behaviors of the neural stem cells in both phases and achieves this by acting upstream of EcR-B1 expression in the second phase.
Topics: Animals; Drosophila Proteins; Larva; Protein Isoforms; Neural Stem Cells; Cell Proliferation; Brain; Neuroepithelial Cells; Drosophila melanogaster; Signal Transduction; Activin Receptors
PubMed: 38913612
DOI: 10.1371/journal.pone.0305696 -
Translational Vision Science &... Jun 2024To assess longitudinal reproducibility of metrics of foveal density (peak cone density [PCD], cone density centroid [CDC], and 80th percentile centroid area) in...
PURPOSE
To assess longitudinal reproducibility of metrics of foveal density (peak cone density [PCD], cone density centroid [CDC], and 80th percentile centroid area) in participants with normal vision.
METHODS
Participants (n = 19; five male and 14 female) were imaged at two time points (average interval of 3.2 years) using an adaptive optics scanning light ophthalmoscope (AOSLO). Foveally centered regions of interest (ROIs) were extracted from AOSLO montages. Cone coordinate matrices were semiautomatically derived for each ROI, and cone mosaic metrics were calculated.
RESULTS
On average, there were no significant changes in cone mosaic metrics between visits. The average ± SD PCD was 187,000 ± 20,000 cones/mm2 and 189,000 ± 21,700 cones/mm2 for visits 1 and 2, respectively (P = 0.52). The average ± SD density at the CDC was 183,000 ± 19,000 cones/mm2 and 184,000 ± 20,800 cones/mm2 for visits 1 and 2, respectively (P = 0.78). The average ± SD 80th percentile isodensity contour area was 15,400 ± 1800 µm2 and 15,600 ± 1910 µm2 for visits 1 and 2, respectively (P = 0.57).
CONCLUSIONS
Foveal cone mosaic density metrics were highly reproducible in the cohort examined here, although further study is required in more diverse populations.
TRANSLATIONAL RELEVANCE
Determination of the normative longitudinal changes in foveal cone topography is key for evaluating longitudinal measures of foveal cone topography in patients with progressive retinal dystrophies.
Topics: Humans; Retinal Cone Photoreceptor Cells; Male; Fovea Centralis; Female; Adult; Reproducibility of Results; Middle Aged; Cell Count; Young Adult; Ophthalmoscopy; Tomography, Optical Coherence; Visual Acuity
PubMed: 38913007
DOI: 10.1167/tvst.13.6.18 -
JCI Insight May 2024Peripheral nerve injury-induced neuronal hyperactivity in the dorsal root ganglion (DRG) participates in neuropathic pain. The calcium-activated potassium channel...
Peripheral nerve injury-induced neuronal hyperactivity in the dorsal root ganglion (DRG) participates in neuropathic pain. The calcium-activated potassium channel subfamily N member 1 (KCNN1) mediates action potential afterhyperpolarization (AHP) and gates neuronal excitability. However, the specific contribution of DRG KCNN1 to neuropathic pain is not yet clear. We report that chronic constriction injury (CCI) of the unilateral sciatic nerve or unilateral ligation of the fourth lumbar nerve produced the downregulation of Kcnn1 mRNA and KCNN1 protein in the injured DRG. This downregulation was partially attributed to a decrease in DRG estrogen-related receptor gamma (ESRRG), a transcription factor, which led to reduced binding to the Kcnn1 promoter. Rescuing this downregulation prevented CCI-induced decreases in total potassium voltage currents and AHP currents, reduced excitability in the injured DRG neurons, and alleviated CCI-induced development and maintenance of nociceptive hypersensitivities, without affecting locomotor function and acute pain. Mimicking the CCI-induced DRG KCNN1 downregulation resulted in augmented responses to mechanical, heat, and cold stimuli in naive mice. Our findings indicate that ESRRG-controlled downregulation of DRG KCNN1 is likely essential for the development and maintenance of neuropathic pain. Thus, KCNN1 may serve as a potential target for managing this disorder.
Topics: Animals; Neuralgia; Ganglia, Spinal; Mice; Down-Regulation; Sensory Receptor Cells; Male; Peripheral Nerve Injuries; Mice, Inbred C57BL; Sciatic Nerve; Disease Models, Animal; Intermediate-Conductance Calcium-Activated Potassium Channels; Action Potentials
PubMed: 38912580
DOI: 10.1172/jci.insight.180085 -
Frontiers in Physiology 2024The neuropeptides kisspeptin, neurokinin B, and dynorphin A are imperative for the pulsatile secretion of gonadotropin-releasing hormone and luteinizing hormone to...
The neuropeptides kisspeptin, neurokinin B, and dynorphin A are imperative for the pulsatile secretion of gonadotropin-releasing hormone and luteinizing hormone to ultimately regulate reproductive cyclicity. A population of neurons co-expressing these neuropeptides, KNDy neurons, within the arcuate nucleus of the hypothalamus (ARC) are positioned to integrate energy status from afferent neuronal and glial cells. We hypothesized that KNDy-expressing neurons in the ARC of mature ewes are influenced by energy balance. To test this hypothesis, ovary-intact, mature ewes were fed to lose, maintain, or gain body weight and hypothalamic tissue harvested during the luteal phase of the estrous cycle. Fluorescent, multiplex immunohistochemistry with direct antibody conjugation was employed to identify and quantify neurons expressing a single neuropeptide, as well as for the first time report co-expression of kisspeptin, neurokinin B, and dynorphin A protein in the ARC. Previous reports using this population of ewes demonstrated that concentrations of insulin and leptin differed between ewes fed to achieve different body weights and that ewes fed to gain body weight had increased concentrations of progesterone. Moreover, within this population of ewes tanycyte density and cellular penetration into the ARC was increased in ewes fed to gain body weight. Within the current report we have revealed that the number of neurons in the ARC expressing kisspeptin, neurokinin B, and dynorphin A protein was increased in ewes fed to gain body weight. Moreover, the number of KNDy neurons in the ARC expressing all three neuropeptides within a single neuron was decreased in ewes fed to lose body weight and increased in ewes fed to gain body weight when compared to ewes fed to maintain body weight. The cumulative findings of this experimental model suggest that expression of kisspeptin, neurokinin B, and dynorphin A protein in the ARC during the luteal phase of the estrous cycle are influenced by energy balance-induced alterations in circulating concentrations of progesterone that drive changes in morphology and density of tanycytes to ultimately regulate central perception of global energy status. Moreover, these results demonstrate that changes in KNDy neurons within the ARC occur as an adaptation to energy balance, potentially regulated divergently by metabolic milieu via proopiomelanocortin afferents.
PubMed: 38911326
DOI: 10.3389/fphys.2024.1372944 -
Science Advances Jun 2024Sensory neurons in the dorsal root ganglion (DRG) and trigeminal ganglion (TG) are specialized to detect and transduce diverse environmental stimuli to the central...
Sensory neurons in the dorsal root ganglion (DRG) and trigeminal ganglion (TG) are specialized to detect and transduce diverse environmental stimuli to the central nervous system. Single-cell RNA sequencing has provided insights into the diversity of sensory ganglia cell types in rodents, nonhuman primates, and humans, but it remains difficult to compare cell types across studies and species. We thus constructed harmonized atlases of the DRG and TG that describe and facilitate comparison of 18 neuronal and 11 non-neuronal cell types across six species and 31 datasets. We then performed single-cell/nucleus RNA sequencing of DRG from both human and the highly regenerative axolotl and found that the harmonized atlas also improves cell type annotation, particularly of sparse neuronal subtypes. We observed that the transcriptomes of sensory neuron subtypes are broadly similar across vertebrates, but the expression of functionally important neuropeptides and channels can vary notably. The resources presented here can guide future studies in comparative transcriptomics, simplify cell-type nomenclature differences across studies, and help prioritize targets for future analgesic development.
Topics: Animals; Humans; Ganglia, Spinal; Trigeminal Ganglion; Transcriptome; Single-Cell Analysis; Sensory Receptor Cells; Species Specificity; Mice; Atlases as Topic; Gene Expression Profiling; Rats
PubMed: 38905344
DOI: 10.1126/sciadv.adj9173 -
Frontiers in Neural Circuits 2024The olfactory epithelium (OE) is directly exposed to environmental agents entering the nasal cavity, leaving OSNs prone to injury and degeneration. The causes of... (Review)
Review
The olfactory epithelium (OE) is directly exposed to environmental agents entering the nasal cavity, leaving OSNs prone to injury and degeneration. The causes of olfactory dysfunction are diverse and include head trauma, neurodegenerative diseases, and aging, but the main causes are chronic rhinosinusitis (CRS) and viral infections. In CRS and viral infections, reduced airflow due to local inflammation, inflammatory cytokine production, release of degranulated proteins from eosinophils, and cell injury lead to decreased olfactory function. It is well known that injury-induced loss of mature OSNs in the adult OE causes massive regeneration of new OSNs within a few months through the proliferation and differentiation of progenitor basal cells that are subsequently incorporated into olfactory neural circuits. Although normal olfactory function returns after injury in most cases, prolonged olfactory impairment and lack of improvement in olfactory function in some cases poses a major clinical problem. Persistent inflammation or severe injury in the OE results in morphological changes in the OE and respiratory epithelium and decreases the number of mature OSNs, resulting in irreversible loss of olfactory function. In this review, we discuss the histological structure and distribution of the human OE, and the pathogenesis of olfactory dysfunction associated with CRS and viral infection.
Topics: Humans; Olfactory Mucosa; Olfaction Disorders; Olfactory Receptor Neurons; Sinusitis; Rhinitis; Animals
PubMed: 38903957
DOI: 10.3389/fncir.2024.1406218 -
International Journal of Medical... 2024Synuclein family members (Snca, Sncb, and Scng) are expressed in the retina, but their precise locations and roles are poorly understood. We performed an extensive...
Synuclein family members (Snca, Sncb, and Scng) are expressed in the retina, but their precise locations and roles are poorly understood. We performed an extensive analysis of the single-cell transcriptome in healthy and injured retinas to investigate their expression patterns and roles. We observed the expression of all synuclein family members in retinal ganglion cells (RGCs), which remained consistent across species (human, mouse, and chicken). We unveiled differential expression of Snca across distinct clusters (highly expressed in most), while Sncb and Sncg displayed uniform expression across all clusters. Further, we observed a decreased expression in RGCs following traumatic axonal injury. However, the proportion of α-Syn-positive RGCs in all RGCs and α-Syn-positive intrinsically photosensitive retinal ganglion cells (ipRGCs) in all ipRGCs remained unaltered. Lastly, we identified changes in communication patterns preceding cell death, with particular significance in the pleiotrophin-nucleolin (Ptn-Ncl) and neural cell adhesion molecule signaling pathways, where communication differences were pronounced between cells with varying expression levels of Snca. Our study employs an innovative approach using scRNA-seq to characterize synuclein expression in health retinal cells, specifically focusing on RGC subtypes, advances our knowledge of retinal physiology and pathology.
Topics: Animals; Retinal Ganglion Cells; Humans; Mice; alpha-Synuclein; gamma-Synuclein; beta-Synuclein; Chickens; Transcriptome; Single-Cell Analysis; Retina; Neoplasm Proteins
PubMed: 38903914
DOI: 10.7150/ijms.95598 -
Nature Communications Jun 2024Psoriasis is an immune-mediated skin disease associated with neurogenic inflammation, but the underlying molecular mechanism remains unclear. We demonstrate here that...
Psoriasis is an immune-mediated skin disease associated with neurogenic inflammation, but the underlying molecular mechanism remains unclear. We demonstrate here that acid-sensing ion channel 3 (ASIC3) exacerbates psoriatic inflammation through a sensory neurogenic pathway. Global or nociceptor-specific Asic3 knockout (KO) in female mice alleviates imiquimod-induced psoriatic acanthosis and type 17 inflammation to the same extent as nociceptor ablation. However, ASIC3 is dispensable for IL-23-induced psoriatic inflammation that bypasses the need for nociceptors. Mechanistically, ASIC3 activation induces the activity-dependent release of calcitonin gene-related peptide (CGRP) from sensory neurons to promote neurogenic inflammation. Botulinum neurotoxin A and CGRP antagonists prevent sensory neuron-mediated exacerbation of psoriatic inflammation to similar extents as Asic3 KO. In contrast, replenishing CGRP in the skin of Asic3 KO mice restores the inflammatory response. These findings establish sensory ASIC3 as a critical constituent in psoriatic inflammation, and a promising target for neurogenic inflammation management.
Topics: Animals; Acid Sensing Ion Channels; Female; Mice, Knockout; Psoriasis; Mice; Calcitonin Gene-Related Peptide; Sensory Receptor Cells; Skin; Imiquimod; Mice, Inbred C57BL; Disease Models, Animal; Inflammation; Neurogenic Inflammation; Humans; Nociceptors; Interleukin-23
PubMed: 38902277
DOI: 10.1038/s41467-024-49577-3