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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 Nov 2023During social interactions, we continuously integrate current and previous information over varying timescales to infer other people's action intentions. Motor cognition...
During social interactions, we continuously integrate current and previous information over varying timescales to infer other people's action intentions. Motor cognition theories argue for a hierarchical organization of goal-directed actions based on temporal scales. Accordingly, transient motor primitives are represented at lower levels of the hierarchy, a combination of primitives building motor sequences at subordinate levels, and more stable overarching action goals at superordinate levels. A neural topography of hierarchal timescales for information accumulation was previously shown in the visual and auditory domains. However, whether such a temporal hierarchy can also account for observed goal-directed action representations in motor pathways remains to be determined. Thus, the current study examined the neural architecture underlying the processing of observed goal-directed actions using inter-subject correlation (ISC) of fMRI activity. Observers (n = 24) viewed sequential hand movements presented in their intact order or piecewise scrambled at three timescales pertaining to goal-directed action evolution (Primitives: ± 1.5 s, Sub-Goals: ± 4 s, and High-Goals: ± 10 s). The results revealed differential intrinsic temporal capacities for integrating goal-directed action information across brain areas engaged in action observation. Longer timescales (> ± 10 s) were found in the posterior parietal and dorsal premotor compared to the ventral premotor (± 4 s) and anterior parietal (± 1.5 s) cortex. Moreover, our results revealed a hemispheric bias with more extended timescales in the right MT+, primary somatosensory, and early visual cortices compared to their homotopic regions in the left hemisphere. Our findings corroborate a hierarchical neural mapping of observed actions based on temporal scales of goals and provide further support for a ubiquitous time-dependent neural organization of information processing across multiple modalities.
Topics: Humans; Goals; Psychomotor Performance; Brain Mapping; Cerebral Cortex; Brain; Magnetic Resonance Imaging
PubMed: 37952024
DOI: 10.1038/s41598-023-46917-z -
Asian Journal of Pharmaceutical Sciences Jul 2023Alzheimer's disease (AD) is a typical neurodegenerative disease that leads to irreversible neuronal degeneration, and effective treatment remains elusive due to the...
Alzheimer's disease (AD) is a typical neurodegenerative disease that leads to irreversible neuronal degeneration, and effective treatment remains elusive due to the unclear mechanism. We utilized biocompatible mesenchymal stem cell-derived extracellular vesicles as carriers loaded with the CB2 target medicine AM1241 (EVs-AM1241) to protect against neurodegenerative progression and neuronal function in AD model mice. According to the results, EVs-AM1241 were successfully constructed and exhibited better bioavailability and therapeutic effects than bare AM1241. The Morris water maze (MWM) and fear conditioning tests revealed that the learning and memory of EVs-AM1241-treated model mice were significantly improved. electrophysiological recording of CA1 neurons indicated enhanced response to an auditory conditioned stimulus following fear learning. Immunostaining and Western blot analysis showed that amyloid plaque deposition and amyloid β (Aβ)-induced neuronal apoptosis were significantly suppressed by EVs-AM1241. Moreover, EVs-AM1241 increased the number of neurons and restored the neuronal cytoskeleton, indicating that they enhanced neuronal regeneration. RNA sequencing revealed that EVs-AM1241 facilitated Aβ phagocytosis, promoted neurogenesis and ultimately improved learning and memory through the calcium-Erk signaling pathway. Our study showed that EVs-AM1241 efficiently reversed neurodegenerative pathology and enhanced neurogenesis in model mice, indicating that they are very promising particles for treating AD.
PubMed: 37645682
DOI: 10.1016/j.ajps.2023.100835 -
The Journal of Neuroscience : the... Jul 2023One of the most striking aspects of the sensory epithelium of the mammalian cochlea, the organ of Corti (OC), is the presence of precise boundaries between sensory and...
One of the most striking aspects of the sensory epithelium of the mammalian cochlea, the organ of Corti (OC), is the presence of precise boundaries between sensory and nonsensory cells at its medial and lateral edges. A particular example of this precision is the single row of inner hair cells (IHCs) and associated supporting cells along the medial (neural) boundary. Despite the regularity of this boundary, the developmental processes and genetic factors that contribute to its specification are poorly understood. In this study we demonstrate that (), which codes for a single-pass, transmembrane protein, is expressed before the development of the mouse organ of Corti in the row of cells that will form its medial border. Deletion of in mice of mixed sex leads to disruptions in boundary formation that manifest as ectopic inner hair cells and supporting cells. Genetic and pharmacological manipulations demonstrate that interacts with the Notch signaling pathway and strongly suggest that Lrrn1 normally acts to enhance Notch signaling across the medial boundary. This interaction is required to promote formation of the row of inner hair cells and suppress the conversion of adjacent nonsensory cells into hair cells and supporting cells. These results identify Lrrn1 as an important regulator of boundary formation and cellular patterning during development of the organ of Corti. Patterning of the developing mammalian cochlea into distinct sensory and nonsensory regions and the specification of multiple different cell fates within those regions are critical for proper auditory function. Here, we report that the transmembrane protein Leucine Rich Repeat Neuronal 1 (LRRN1) is expressed along the sharp medial boundary between the single row of mechanosensory inner hair cells (IHCs) and adjacent nonsensory cells. Formation of this boundary is mediated in part by Notch signaling, and loss of leads to disruptions in boundary formation similar to those caused by a reduction in Notch activity, suggesting that LRRN1 likely acts to enhance Notch signaling. Greater understanding of sensory/nonsensory cell fate decisions in the cochlea will help inform the development of regenerative strategies aimed at restoring auditory function.
Topics: Animals; Mice; Cell Differentiation; Cochlea; Hair Cells, Auditory; Hair Cells, Auditory, Inner; Leucine; Mammals; Membrane Proteins; Organ of Corti
PubMed: 37369584
DOI: 10.1523/JNEUROSCI.2141-22.2023 -
Frontiers in Cellular Neuroscience 2023Humans have six members of the ferlin protein family: dysferlin, myoferlin, otoferlin, fer1L4, fer1L5, and fer1L6. These proteins share common features such as multiple... (Review)
Review
Humans have six members of the ferlin protein family: dysferlin, myoferlin, otoferlin, fer1L4, fer1L5, and fer1L6. These proteins share common features such as multiple Ca-binding C2 domains, FerA domains, and membrane anchoring through their single C-terminal transmembrane domain, and are believed to play a key role in calcium-triggered membrane fusion and vesicle trafficking. Otoferlin plays a crucial role in hearing and vestibular function. In this review, we will discuss how we see otoferlin working as a Ca-dependent mechanical sensor regulating synaptic vesicle fusion at the hair cell ribbon synapses. Although otoferlin is also present in the central nervous system, particularly in the cortex and amygdala, its role in brain tissues remains unknown. Mutations in the OTOF gene cause one of the most frequent genetic forms of congenital deafness, DFNB9. These mutations produce severe to profound hearing loss due to a defect in synaptic excitatory glutamatergic transmission between the inner hair cells and the nerve fibers of the auditory nerve. Gene therapy protocols that allow normal rescue expression of otoferlin in hair cells have just started and are currently in pre-clinical phase. In parallel, studies have linked ferlins to cancer through their effect on cell signaling and development, allowing tumors to form and cancer cells to adapt to a hostile environment. Modulation by mechanical forces and Ca signaling are key determinants of the metastatic process. Although ferlins importance in cancer has not been extensively studied, data show that otoferlin expression is significantly associated with survival in specific cancer types, including clear cell and papillary cell renal carcinoma, and urothelial bladder cancer. These findings indicate a role for otoferlin in the carcinogenesis of these tumors, which requires further investigation to confirm and understand its exact role, particularly as it varies by tumor site. Targeting this protein may lead to new cancer therapies.
PubMed: 37538852
DOI: 10.3389/fncel.2023.1197611 -
Journal of Otology Jul 2023Misophonia is not investigated much from an audiological perspective. Our study aims to examine the processing of the auditory retro-cochlear pathways in individuals...
PURPOSE
Misophonia is not investigated much from an audiological perspective. Our study aims to examine the processing of the auditory retro-cochlear pathways in individuals with misophonia.
METHODS
A cross-sectional study was conducted among university students who had misophonia. The revised Amsterdam Misophonia Scale was used to determine the severity of misophonia. Participants were divided into mild and moderate-severe misophonia and compared with the healthy control group. Auditory Brainstem Response testing was recorded from all the individuals with misophonia. The absolute latency, amplitude, inter-peak latency difference, and inter-rate latency difference were compared between the groups.
RESULTS
One-way ANOVA result showed no significant difference in all the parameters of auditory brainstem response between the groups. These results are suggestive of normal brainstem processing in individuals with misophonia.
CONCLUSIONS
The study concludes that the auditory pathway up to brainstem areas is intact in individuals with misophonia. Further studies are essential on a larger population for generalizing the results.
PubMed: 37497334
DOI: 10.1016/j.joto.2023.05.006 -
Cell Death & Disease Jun 2023Wolfram syndrome (WS) is a rare neurodegenerative disorder encompassing diabetes mellitus, diabetes insipidus, optic atrophy, hearing loss (HL) as well as neurological...
Wolfram syndrome (WS) is a rare neurodegenerative disorder encompassing diabetes mellitus, diabetes insipidus, optic atrophy, hearing loss (HL) as well as neurological disorders. None of the animal models of the pathology are presenting with an early onset HL, impeding the understanding of the role of Wolframin (WFS1), the protein responsible for WS, in the auditory pathway. We generated a knock-in mouse, the Wfs1 line, presenting a human mutation leading to severe deafness in affected individuals. The homozygous mice showed a profound post-natal HL and vestibular syndrome, a collapse of the endocochlear potential (EP) and a devastating alteration of the stria vascularis and neurosensory epithelium. The mutant protein prevented the localization to the cell surface of the Na/KATPase β1 subunit, a key protein for the maintenance of the EP. Overall, our data support a key role of WFS1 in the maintenance of the EP and the stria vascularis, via its binding partner, the Na/KATPase β1 subunit.
Topics: Animals; Humans; Mice; Adenosine Triphosphatases; Cell Membrane; Deafness; Epithelium; Wolfram Syndrome
PubMed: 37386014
DOI: 10.1038/s41419-023-05912-y -
Arquivos de Neuro-psiquiatria Oct 2023Multiple sclerosis (MS) is an inflammatory demyelinating disease. Auditory evoked potential studies have demonstrated conduction and neural processing deficits in adults...
BACKGROUND
Multiple sclerosis (MS) is an inflammatory demyelinating disease. Auditory evoked potential studies have demonstrated conduction and neural processing deficits in adults with MS, but little is known about the electrophysiological responses in children and adolescents.
OBJECTIVE
to evaluate the central auditory pathway with brainstem auditory evoked potentials (BAEP) and long-latency auditory evoked potentials (LLAEP) in children and adolescents with MS.
METHODS
The study comprised 17 individuals with MS, of both sexes, aged 9 to 18 years, and 17 healthy volunteers, matched for age and sex. All individuals had normal hearing and no middle ear impairments. They were assessed with click-BAEP and LLAEP through oddball paradigm and tone-burst stimuli.
RESULTS
Abnormal responses were observed in 60% of electrophysiologic assessments of individuals with MS. In BAEP, 58.82% of MS patients had abnormal responses, with longer wave V latency and therefore longer III-V and I-V interpeak latencies than healthy volunteers. In LLAEP, 52.94% of MS patients had abnormal responses. Although statistical differences were found only in P2-N2 amplitude, MS patients had longer latencies and smaller amplitudes than healthy volunteers in all components.
CONCLUSION
Children and adolescents with MS had abnormal BAEP responses, with delayed neural conduction between the cochlear nucleus and the lateral lemniscus. Also, abnormal LLAEP results suggest a decrease in neural processing speed and auditory sensory discrimination response.
Topics: Male; Adult; Female; Humans; Child; Adolescent; Auditory Pathways; Multiple Sclerosis; Evoked Potentials, Auditory; Evoked Potentials, Auditory, Brain Stem; Hearing Tests
PubMed: 37852288
DOI: 10.1055/s-0043-1775985 -
Brazilian Journal of Otorhinolaryngology 2024Our study aimed to verify the evidence of auditory training employed in the audiological treatment of tinnitus in adults and older adults. (Review)
Review
OBJECTIVES
Our study aimed to verify the evidence of auditory training employed in the audiological treatment of tinnitus in adults and older adults.
METHODS
Scoping review based on a search for articles in journals available in MEDLINE (PubMed), Embase (Elsevier), LILACS (BVS), and Cochrane Library. Titles and abstracts of the retrieved articles were assessed by peers, following the eligibility criteria; they were afterward read in full text, and the references were hand searched in the results found. Studies' level of evidence was classified into very high (Level A+), high (Level A), moderate (Level B), limited (Level C), low (Level D), or very low (Level D-) based on the Critically Appraised Topics.
RESULTS
2160 records were identified in the searching stage and 15 studies were eligible for data extraction. Study design, sample characterization, auditory training tasks, sound stimuli, outcome measures, and results were extracted. Frequency discrimination training was the most frequent strategy, followed by auditory attentional skills training and multisensory training. Almost all studies with daily auditory training sessions reported significant benefits demonstrated in at least one outcome measure. Studies that used auditory discrimination training and attentional auditory skill stimulation to treat tinnitus obtained quality evidence levels ranging from limited to high (C‒A) and studies that applied multisensory training or attentional training combined with counseling and passive listening in tinnitus patients reached a high-quality evidence level (A).
CONCLUSION
Recent studies had higher levels of evidence and considered attentional factors and multisensory pathways in auditory training strategies.
Topics: Aged; Humans; Acoustic Stimulation; Attention; Auditory Perception; Tinnitus; Adult
PubMed: 38006725
DOI: 10.1016/j.bjorl.2023.101361 -
BioRxiv : the Preprint Server For... Dec 2023Sensory perception is dynamic, quickly adapting to sudden shifts in environmental or behavioral context. Though decades of work have established that these dynamics are...
UNLABELLED
Sensory perception is dynamic, quickly adapting to sudden shifts in environmental or behavioral context. Though decades of work have established that these dynamics are mediated by rapid fluctuations in sensory cortical activity, we have a limited understanding of the brain regions and pathways that orchestrate these changes. Neurons in the orbitofrontal cortex (OFC) encode contextual information, and recent data suggest that some of these signals are transmitted to sensory cortices. Whether and how these signals shape sensory encoding and perceptual sensitivity remains uncertain. Here, we asked whether the OFC mediates context-dependent changes in auditory cortical sensitivity and sound perception by monitoring and manipulating OFC activity in freely moving animals under two behavioral contexts: passive sound exposure and engagement in an amplitude modulation (AM) detection task. We found that the majority of OFC neurons, including the specific subset that innervate the auditory cortex, were strongly modulated by task engagement. Pharmacological inactivation of the OFC prevented rapid context-dependent changes in auditory cortical firing, and significantly impaired behavioral AM detection. Our findings suggest that contextual information from the OFC mediates rapid plasticity in the auditory cortex and facilitates the perception of behaviorally relevant sounds.
SIGNIFICANCE STATEMENT
Sensory perception depends on the context in which stimuli are presented. For example, perception is enhanced when stimuli are informative, such as when they are important to solve a task. Perceptual enhancements result from an increase in the sensitivity of sensory cortical neurons; however, we do not fully understand how such changes are initiated in the brain. Here, we tested the role of the orbitofrontal cortex (OFC) in controlling auditory cortical sensitivity and sound perception. We found that OFC neurons change their activity when animals perform a sound detection task. Inactivating OFC impairs sound detection and prevents task-dependent increases in auditory cortical sensitivity. Our findings suggest that the OFC controls contextual modulations of the auditory cortex and sound perception.
PubMed: 38187685
DOI: 10.1101/2023.12.18.570797