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ELife Mar 2024Mammals harbor a limited number of sound-receptor hair cells (HCs) that cannot be regenerated after damage. Thus, investigating the underlying molecular mechanisms that...
Mammals harbor a limited number of sound-receptor hair cells (HCs) that cannot be regenerated after damage. Thus, investigating the underlying molecular mechanisms that maintain HC survival is crucial for preventing hearing impairment. Intriguingly, or HCs form initially but then rapidly degenerate, whereas HCs degenerate considerably later. However, the transcriptional cascades involving Pou4f3, Gfi1, and Rbm24 remain undescribed. Here, we demonstrate that expression is completely repressed in HCs but unaltered in HCs, and further that the expression of both POU4F3 and GFI1 is intact in HCs. Moreover, by using in vivo mouse transgenic reporter assays, we identify three enhancers to which POU4F3 binds. Lastly, through in vivo genetic testing of whether Rbm24 restoration alleviates the degeneration of HCs, we show that ectopic Rbm24 alone cannot prevent HCs from degenerating. Collectively, our findings provide new molecular and genetic insights into how HC survival is regulated.
Topics: Animals; Mice; Animals, Genetically Modified; Transcription Factors; Genetic Therapy; Hair Cells, Auditory; Sound; Mammals; Homeodomain Proteins; Transcription Factor Brn-3C; DNA-Binding Proteins; RNA-Binding Proteins
PubMed: 38483314
DOI: 10.7554/eLife.90025 -
International Journal of Molecular... Feb 2024In mammalian hearing, type-I afferent auditory nerve fibers comprise the basis of the afferent auditory pathway. They are connected to inner hair cells of the cochlea...
In mammalian hearing, type-I afferent auditory nerve fibers comprise the basis of the afferent auditory pathway. They are connected to inner hair cells of the cochlea via specialized ribbon synapses. Auditory nerve fibers of different physiological types differ subtly in their synaptic location and morphology. Low-spontaneous-rate auditory nerve fibers typically connect on the modiolar side of the inner hair cell, while high-spontaneous-rate fibers are typically found on the pillar side. In aging and noise-damaged ears, this fine-tuned balance between auditory nerve fiber populations can be disrupted and the functional consequences are currently unclear. Here, using immunofluorescent labeling of presynaptic ribbons and postsynaptic glutamate receptor patches, we investigated changes in synaptic morphology at three different tonotopic locations along the cochlea of aging gerbils compared to those of young adults. Quiet-aged gerbils showed about 20% loss of afferent ribbon synapses. While the loss was random at apical, low-frequency cochlear locations, at the basal, high-frequency location it almost exclusively affected the modiolar-located synapses. The subtle differences in volumes of pre- and postsynaptic elements located on the inner hair cell's modiolar versus pillar side were unaffected by age. This is consistent with known physiology and suggests a predominant, age-related loss in the low-spontaneous-rate auditory nerve population in the cochlear base, but not the apex.
Topics: Animals; Gerbillinae; Cochlea; Synapses; Cochlear Nerve; Hair Cells, Auditory, Inner
PubMed: 38473985
DOI: 10.3390/ijms25052738 -
Scientific Reports Mar 2024Sensory neurons are afferent neurons in sensory systems that convert stimuli and transmit information to the central nervous system as electrical signals. Primary...
Sensory neurons are afferent neurons in sensory systems that convert stimuli and transmit information to the central nervous system as electrical signals. Primary afferent neurons that are affected by non-noxious and noxious stimuli are present in the dorsal root ganglia (DRG), and the DRG sensory neurons are used as an in vitro model of the nociceptive response. However, DRG derived from mouse or rat give a low yield of neurons, and they are difficult to culture. To help alleviate this problem, we characterized human induced pluripotent stem cell (hiPSC) derived sensory neurons. They can solve the problems of interspecies differences and supply stability. We investigated expressions of sensory neuron related proteins and genes, and drug responses by Multi-Electrode Array (MEA) to analyze the properties and functions of sensory neurons. They expressed nociceptor, mechanoreceptor and proprioceptor related genes and proteins. They constitute a heterogeneous population of their subclasses. We confirmed that they could respond to both noxious and non-noxious stimuli. We showed that histamine inhibitors reduced histamine-induced neuronal excitability. Furthermore, incubation with a ProTx-II and Nav1.7 inhibitor reduced the spontaneous neural activity in hiPSC-derived sensory neurons. Their responsiveness was different from each drug. We have demonstrated that hiPSC-derived sensory neurons combined with MEA are good candidates for drug discovery studies where DRG in vitro modeling is necessary.
Topics: Humans; Rats; Mice; Animals; Induced Pluripotent Stem Cells; Histamine; Sensory Receptor Cells; Ganglia, Spinal
PubMed: 38472288
DOI: 10.1038/s41598-024-55602-8 -
The Journal of Neuroscience : the... Apr 2024Following peripheral nerve injury, denervated tissues can be reinnervated via regeneration of injured neurons or collateral sprouting of neighboring uninjured afferents...
Following peripheral nerve injury, denervated tissues can be reinnervated via regeneration of injured neurons or collateral sprouting of neighboring uninjured afferents into denervated territory. While there has been substantial focus on mechanisms underlying regeneration, collateral sprouting has received less attention. Here, we used immunohistochemistry and genetic neuronal labeling to define the subtype specificity of sprouting-mediated reinnervation of plantar hindpaw skin in the mouse spared nerve injury (SNI) model, in which productive regeneration cannot occur. Following initial loss of cutaneous afferents in the tibial nerve territory, we observed progressive centripetal reinnervation by multiple subtypes of neighboring uninjured fibers into denervated glabrous and hairy plantar skin of male mice. In addition to dermal reinnervation, CGRP-expressing peptidergic fibers slowly but continuously repopulated denervated epidermis, Interestingly, GFRα2-expressing nonpeptidergic fibers exhibited a transient burst of epidermal reinnervation, followed by a trend towards regression. Presumptive sympathetic nerve fibers also sprouted into denervated territory, as did a population of myelinated TrkC lineage fibers, though the latter did so inefficiently. Conversely, rapidly adapting Aβ fiber and C fiber low threshold mechanoreceptor (LTMR) subtypes failed to exhibit convincing sprouting up to 8 weeks after nerve injury in males or females. Optogenetics and behavioral assays in male mice further demonstrated the functionality of collaterally sprouted fibers in hairy plantar skin with restoration of punctate mechanosensation without hypersensitivity. Our findings advance understanding of differential collateral sprouting among sensory neuron subpopulations and may guide strategies to promote the progression of sensory recovery or limit maladaptive sensory phenomena after peripheral nerve injury.
Topics: Female; Mice; Male; Animals; Peripheral Nerve Injuries; Nerve Regeneration; Skin; Neurogenesis; Neurons, Afferent
PubMed: 38471780
DOI: 10.1523/JNEUROSCI.1494-23.2024 -
Cell Reports Mar 2024Primate hands house an array of mechanoreceptors and proprioceptors, which are essential for tactile and kinematic information crucial for daily motor action. While the...
Primate hands house an array of mechanoreceptors and proprioceptors, which are essential for tactile and kinematic information crucial for daily motor action. While the regulation of these somatosensory signals is essential for hand movements, the specific central nervous system (CNS) location and mechanism remain unclear. Our study demonstrates the attenuation of somatosensory signals in the cuneate nucleus during voluntary movement, suggesting significant modulation at this initial relay station in the CNS. The attenuation is comparable to the cerebral cortex but more pronounced than in the spinal cord, indicating the cuneate nuclei's role in somatosensory perception modulation during movement. Moreover, our findings suggest that the descending motor tract may regulate somatosensory transmission in the cuneate nucleus, enhancing relevant signals and suppressing unnecessary ones for the regulation of movement. This process of recurrent somatosensory modulation between cortical and subcortical areas could be a basic mechanism for modulating somatosensory signals to achieve active perception.
Topics: Animals; Hand; Medulla Oblongata; Spinal Cord; Touch; Primates; Somatosensory Cortex; Movement
PubMed: 38458194
DOI: 10.1016/j.celrep.2024.113884 -
Cureus Feb 2024The Bezold-Jarisch reflex (BJR) is an inhibitory reflex characterized by bradycardia, hypotension, and apnea originating from ventricular mechanoreceptors. BJR is an...
The Bezold-Jarisch reflex (BJR) is an inhibitory reflex characterized by bradycardia, hypotension, and apnea originating from ventricular mechanoreceptors. BJR is an uncommon but serious complication of neuraxial anesthesia. We present a case of a 33-year-old female undergoing combined spinal-epidural anesthesia prior to cesarean delivery who developed profound BJR, resulting in emergent actions. Within minutes of injection, she became severely bradycardic (HR: 17 bpm) and hypotensive (SBP: 30s mmHg) with bradypnea (RR: 6/min) and was treated with epinephrine. Fetal bradycardia prompted emergency cesarean section. Following delivery, the patient developed ventricular tachycardia, which was treated with intravenous fluids and cardiac monitoring. Both patient and neonate were discharged in stable condition on postoperative day four. This case illustrates the rapid maternal and fetal compromise associated with BJR during neuraxial anesthesia and the need for prompt recognition and treatment. Key steps include stopping anesthesia, intravenous fluid, left-lateral positioning, judicious vasopressors, fetal monitoring, and preparing for emergent delivery.
PubMed: 38449945
DOI: 10.7759/cureus.53643 -
Human Molecular Genetics May 2024Mutations in AIFM1, encoding for apoptosis-inducing factor (AIF), cause AUNX1, an X-linked neurologic disorder with late-onset auditory neuropathy (AN) and peripheral...
Mutations in AIFM1, encoding for apoptosis-inducing factor (AIF), cause AUNX1, an X-linked neurologic disorder with late-onset auditory neuropathy (AN) and peripheral neuropathy. Despite significant research on AIF, there are limited animal models with the disrupted AIFM1 representing the corresponding phenotype of human AUNX1, characterized by late-onset hearing loss and impaired auditory pathways. Here, we generated an Aifm1 p.R450Q knock-in mouse model (KI) based on the human AIFM1 p.R451Q mutation. Hemizygote KI male mice exhibited progressive hearing loss from P30 onward, with greater severity at P60 and stabilization until P210. Additionally, muscle atrophy was observed at P210. These phenotypic changes were accompanied by a gradual reduction in the number of spiral ganglion neuron cells (SGNs) at P30 and ribbons at P60, which coincided with the translocation of AIF into the nucleus starting from P21 and P30, respectively. The SGNs of KI mice at P210 displayed loss of cytomembrane integrity, abnormal nuclear morphology, and dendritic and axonal demyelination. Furthermore, the inner hair cells and myelin sheath displayed abnormal mitochondrial morphology, while fibroblasts from KI mice showed impaired mitochondrial function. In conclusion, we successfully generated a mouse model recapitulating AUNX1. Our findings indicate that disruption of Aifm1 induced the nuclear translocation of AIF, resulting in the impairment in the auditory pathway.
Topics: Animals; Humans; Male; Mice; Apoptosis Inducing Factor; Cell Nucleus; Disease Models, Animal; Gene Knock-In Techniques; Hair Cells, Auditory, Inner; Hearing Loss; Muscular Atrophy; Mutation; Protein Transport; Spiral Ganglion
PubMed: 38449065
DOI: 10.1093/hmg/ddae010 -
Nature Mar 2024Airway integrity must be continuously maintained throughout life. Sensory neurons guard against airway obstruction and, on a moment-by-moment basis, enact vital reflexes...
Airway integrity must be continuously maintained throughout life. Sensory neurons guard against airway obstruction and, on a moment-by-moment basis, enact vital reflexes to maintain respiratory function. Decreased lung capacity is common and life-threatening across many respiratory diseases, and lung collapse can be acutely evoked by chest wall trauma, pneumothorax or airway compression. Here we characterize a neuronal reflex of the vagus nerve evoked by airway closure that leads to gasping. In vivo vagal ganglion imaging revealed dedicated sensory neurons that detect airway compression but not airway stretch. Vagal neurons expressing PVALB mediate airway closure responses and innervate clusters of lung epithelial cells called neuroepithelial bodies (NEBs). Stimulating NEBs or vagal PVALB neurons evoked gasping in the absence of airway threats, whereas ablating NEBs or vagal PVALB neurons eliminated gasping in response to airway closure. Single-cell RNA sequencing revealed that NEBs uniformly express the mechanoreceptor PIEZO2, and targeted knockout of Piezo2 in NEBs eliminated responses to airway closure. NEBs were dispensable for the Hering-Breuer inspiratory reflex, which indicated that discrete terminal structures detect airway closure and inflation. Similar to the involvement of Merkel cells in touch sensation, NEBs are PIEZO2-expressing epithelial cells and, moreover, are crucial for an aspect of lung mechanosensation. These findings expand our understanding of neuronal diversity in the airways and reveal a dedicated vagal pathway that detects airway closure to help preserve respiratory function.
Topics: Animals; Female; Male; Mice; Epithelial Cells; Lung; Mechanoreceptors; Parvalbumins; Reflex; Respiration; Sensory Receptor Cells; Vagus Nerve; Lung Compliance; Respiratory Mechanics
PubMed: 38448588
DOI: 10.1038/s41586-024-07144-2 -
Frontiers in Bioengineering and... 2024There is a growing need for sensing materials that can provide multiple sensing capabilities for wearable devices, implantable sensors, and diagnostics tools. As complex...
There is a growing need for sensing materials that can provide multiple sensing capabilities for wearable devices, implantable sensors, and diagnostics tools. As complex human physiology requires materials that can simultaneously detect and respond to slow and fast pressure fluctuations. Mimicking the slow adaptive (SA) and fast adaptive (FA) mechanoreceptors in skin can lead to the development of dual sensing electrospun polymer nanocomposites for biomedical applications. These dual sensing nanocomposites can provide simultaneous sensing of both slow and fast pressure fluctuations, making them ideal for applications such as monitoring vital signs, detecting a wider range of movements and pressures. Here we develop a novel dual sensing PVDF-HFP-based nanocomposite that combines the advantages of capacitive and piezoelectric properties through controling electrospinning environment and processing parameters, polymer solution composition, and addition of nucleating agents such as Carbon Black (CB) to enhance the crystalline development of β-phase, fibre thickness, and morphology. The developed PVDF-HFP/CB nanocomposite presents and response to both slow and fast pressure fluctuations with high capacitance (5.37 nF) and output voltage (1.51 V) allowing for accurate and reliable measurements.
PubMed: 38444647
DOI: 10.3389/fbioe.2024.1322753 -
Journal of Neuroengineering and... Mar 2024The regulation of gait is critical to many activities of everyday life. When walking, somatosensory information obtained from mechanoreceptors throughout body is... (Review)
Review
BACKGROUND
The regulation of gait is critical to many activities of everyday life. When walking, somatosensory information obtained from mechanoreceptors throughout body is delivered to numerous supraspinal networks and used to execute the appropriate motion to meet ever-changing environmental and task demands. Aging and age-related conditions oftentimes alter the supraspinal sensorimotor control of walking, including the responsiveness of the cortical brain regions to the sensorimotor inputs obtained from the peripheral nervous system, resulting in diminished mobility in the older adult population. It is thus important to explicitly characterize such supraspinal sensorimotor elements of walking, providing knowledge informing novel rehabilitative targets. The past efforts majorly relied upon mental imagery or virtual reality to study the supraspinal control of walking. Recent efforts have been made to develop magnetic resonance imaging (MRI)-compatible devices simulating specific somatosensory and/or motor aspects of walking. However, there exists large variance in the design and functionality of these devices, and as such inconsistent functional MRI (fMRI) observations.
METHODS
We have therefore completed a systematic review to summarize current achievements in the development of these MRI-compatible devices and synthesize available imaging results emanating from studies that have utilized these devices.
RESULTS
The device design, study protocol and neuroimaging observations of 26 studies using 13 types of devices were extracted. Three of these devices can provide somatosensory stimuli, eight motor stimuli, and two both types of stimuli. Our review demonstrated that using these devices, fMRI data of brain activation can be successfully obtained when participants remain motionless and experience sensorimotor stimulation during fMRI acquisition. The activation in multiple cortical (e.g., primary sensorimotor cortex) and subcortical (e.g., cerebellum) regions has been each linked to these types of walking-related sensorimotor stimuli.
CONCLUSION
The observations of these publications suggest the promise of implementing these devices to characterize the supraspinal sensorimotor control of walking. Still, the evidence level of these neuroimaging observations was still low due to small sample size and varied study protocols, which thus needs to be confirmed via studies with more rigorous design.
Topics: Humans; Aged; Walking; Magnetic Resonance Imaging; Gait; Neuroimaging; Aging
PubMed: 38443983
DOI: 10.1186/s12984-024-01323-y