-
Experimental Neurobiology Apr 2024In the auditory system, the spontaneous activity of cochlear inner hair cells (IHCs) is initiated by the release of ATP from inner supporting cells (ISCs). This ATP...
In the auditory system, the spontaneous activity of cochlear inner hair cells (IHCs) is initiated by the release of ATP from inner supporting cells (ISCs). This ATP release sets off a cascade, activating purinergic autoreceptors, opening of Ca-activated Cl channel TMEM16A, Cl efflux and osmotic cell shrinkage. Then, the shrunken ISCs efficiently regain their original volume, suggesting the existence of mechanisms for refilling Cland K, priming them for subsequent activity. This study explores the potential involvement of NKCCs (Na-K-Cl cotransporters) and KCCs (K-Cl cotransporters) in ISC spontaneous activity, considering their capability to transport both Cl and K ions across the cell membrane. Employing a combination of immunohistochemistry, pharmacological interventions, and shRNA experiment, we unveiled the pivotal role of NKCC1 in cochlear spontaneous activity. Immunohistochemistry revealed robust NKCC1 expression in ISCs, persisting until the 2nd postnatal week. Intriguingly, we observed a developmental shift in NKCC1 expression from ISCs to synaptophysin-positive efferent terminals at postnatal day 18, hinting at its potential involvement in modulating synaptic transmission during the post-hearing period. Experiments using bumetanide, a well-known NKCC inhibitor, supported the functional significance of NKCC1 in ISC spontaneous activity. Bumetanide significantly reduced the frequency of spontaneous extracellular potentials (sEP) and spontaneous optical changes (sOCs) in ISCs. NKCC1-shRNA experiments conducted in cultured cochlear tissues further supported these findings, demonstrating a substantial decrease in event frequency and area. Taken together, we revealed the role of NKCC1 in shaping the ISC spontaneous activity that govern auditory pathway development.
PubMed: 38724477
DOI: 10.5607/en24003 -
BioRxiv : the Preprint Server For... Apr 2024The stria vascularis (SV), part of the blood-labyrinth barrier, is an essential component of the inner ear that regulates the ionic environment required for hearing. SV...
SUMMARY
The stria vascularis (SV), part of the blood-labyrinth barrier, is an essential component of the inner ear that regulates the ionic environment required for hearing. SV degeneration disrupts cochlear homeostasis, leading to irreversible hearing loss, yet a comprehensive understanding of the SV, and consequently therapeutic availability for SV degeneration, is lacking. We developed a whole-tissue explant model from neonatal and adult mice to create a robust platform for SV research. We validated our model by demonstrating that the proliferative behaviour of the SV mimics SV providing a representative model and advancing high-throughput SV research. We also provided evidence for pharmacological intervention in our system by investigating the role of Wnt/β-catenin signaling in SV proliferation. Finally, we performed single-cell RNA sequencing from neonatal and adult mouse SV and revealed key genes and pathways that may play a role in SV proliferation and maintenance. Together, our results contribute new insights into investigating biological solutions for SV-associated hearing loss.
SIGNIFICANCE
Hearing loss impairs our ability to communicate with people and interact with our environment. This can lead to social isolation, depression, cognitive deficits, and dementia. Inner ear degeneration is a primary cause of hearing loss, and our study provides an in depth look at one of the major sites of inner ear degeneration: the stria vascularis. The stria vascularis and associated blood-labyrinth barrier maintain the functional integrity of the auditory system, yet it is relatively understudied. By developing a new model for the young and adult stria vascularis and using single cell RNA sequencing, our study provides a novel approach to studying this tissue, contributing new insights and widespread implications for auditory neuroscience and regenerative medicine.
HIGHLIGHTS
- We established an organotypic explant system of the neonatal and adult stria vascularis with an intact blood-labyrinth barrier. - Proliferation of the stria vascularis decreases with age , modelling its proliferative behaviour . - Pharmacological studies using our SV model open possibilities for testing injury paradigms and therapeutic interventions. - Inhibition of Wnt signalling decreases proliferation in neonatal stria vascularis.- We identified key genes and transcription factors unique to developing and mature SV cell types using single cell RNA sequencing.
PubMed: 38712156
DOI: 10.1101/2024.04.24.590986 -
BioRxiv : the Preprint Server For... May 2024Somatosensory neurons provide the nervous system with information about mechanical forces originating inside and outside the body. Here, we use connectomics to...
Somatosensory neurons provide the nervous system with information about mechanical forces originating inside and outside the body. Here, we use connectomics to reconstruct and analyze neural circuits downstream of the largest somatosensory organ in the leg, the femoral chordotonal organ (FeCO). The FeCO has been proposed to support both proprioceptive sensing of the fly's femur-tibia joint and exteroceptive sensing of substrate vibrations, but it remains unknown which sensory neurons and central circuits contribute to each of these functions. We found that different subtypes of FeCO sensory neurons feed into distinct proprioceptive and exteroceptive pathways. Position- and movement-encoding FeCO neurons connect to local leg motor control circuits in the ventral nerve cord (VNC), indicating a proprioceptive function. In contrast, signals from the vibration-encoding FeCO neurons are integrated across legs and transmitted to auditory regions in the brain, indicating an exteroceptive function. Overall, our analyses reveal the structure of specialized circuits for processing proprioceptive and exteroceptive signals from the fly leg. They also demonstrate how analyzing patterns of synaptic connectivity can distill organizing principles from complex sensorimotor circuits.
PubMed: 38712128
DOI: 10.1101/2024.04.23.590808 -
Stem Cells Translational Medicine May 2024Loss of cochlear hair cells (HCs) leads to permanent hearing loss in mammals, and regenerative medicine is regarded as an ideal strategy for hearing recovery. Limited...
Loss of cochlear hair cells (HCs) leads to permanent hearing loss in mammals, and regenerative medicine is regarded as an ideal strategy for hearing recovery. Limited genetic and pharmaceutical approaches for HC regeneration have been established, and the existing strategies cannot achieve recovery of auditory function. A promising target to promote HC regeneration is MEK/ERK signaling because dynamic shifts in its activity during the critical stages of inner ear development have been observed. Here, we first showed that MEK/ERK signaling is activated specifically in supporting cells (SCs) after aminoglycoside-induced HC injury. We then selected 4 MEK/ERK signaling inhibitors, and PD0325901 (PD03) was found to induce the transdifferentiation of functional supernumerary HCs from SCs in the neonatal mammalian cochlear epithelium. We next found that PD03 facilitated the generation of HCs in inner ear organoids. Through genome-wide high-throughput RNA sequencing and verification, we found that the Notch pathway is the downstream target of MEK/ERK signaling. Importantly, delivery of PD03 into the inner ear induced mild HC regeneration in vivo. Our study thus reveals the importance of MEK/ERK signaling in cell fate determination and suggests that PD03 might serve as a new approach for HC regeneration.
PubMed: 38709826
DOI: 10.1093/stcltm/szae030 -
Frontiers in Integrative Neuroscience 2024Autistic individuals demonstrate greater variability and timing error in their motor performance than neurotypical individuals, likely due at least in part to atypical...
INTRODUCTION
Autistic individuals demonstrate greater variability and timing error in their motor performance than neurotypical individuals, likely due at least in part to atypical cerebellar characteristics and connectivity. These motor difficulties may differentially affect discrete as opposed to continuous movements in autistic individuals. Augmented auditory feedback has the potential to aid motor timing and variability due to intact auditory-motor pathways in autism and high sensitivity in autistic individuals to auditory stimuli.
METHODS
This experiment investigated whether there were differences in timing accuracy and variability in autistic adults as a function of task (discontinuous vs. continuous movements) and condition (augmented auditory feedback vs. no auditory feedback) in a synchronization-continuation paradigm. Ten autistic young adults aged 17-27 years of age completed the within-subjects study that involved drawing circles at 800 milliseconds intervals on a touch screen. In the discontinuous task, participants traced a series of discrete circles and paused at the top of each circle for at least 60 milliseconds. In the continuous task, participants traced the circles without pausing. Participants traced circles in either a non-auditory condition, or an auditory condition in which they heard a tone each time that they completed a circle drawing.
RESULTS
Participants had significantly better timing accuracy on the continuous timing task as opposed to the discontinuous task. Timing consistency was significantly higher for tasks performed with auditory feedback.
DISCUSSION
This research reveals that motor difficulties in autistic individuals affect discrete timing tasks more than continuous tasks, and provides evidence that augmented auditory feedback may be able to mitigate some of the timing variability present in autistic persons' movements. These results provide support for future investigation on the use of music-based therapies involving auditory feedback to address motor dysfunction in autistic individuals.
PubMed: 38690085
DOI: 10.3389/fnint.2024.1379208 -
International Journal of Molecular... Apr 2024Hearing loss represents a multifaceted and pervasive challenge that deeply impacts various aspects of an individual's life, spanning psychological, emotional, social,... (Review)
Review
Hearing loss represents a multifaceted and pervasive challenge that deeply impacts various aspects of an individual's life, spanning psychological, emotional, social, and economic realms. Understanding the molecular underpinnings that orchestrate hearing loss remains paramount in the quest for effective therapeutic strategies. This review aims to expound upon the physiological, biochemical, and molecular aspects of hearing loss, with a specific focus on its correlation with diabetes. Within this context, phytochemicals have surfaced as prospective contenders in the pursuit of potential adjuvant therapies. These compounds exhibit noteworthy antioxidant and anti-inflammatory properties, which hold the potential to counteract the detrimental effects induced by oxidative stress and inflammation-prominent contributors to hearing impairment. Furthermore, this review offers an up-to-date exploration of the diverse molecular pathways modulated by these compounds. However, the dynamic landscape of their efficacy warrants recognition as an ongoing investigative topic, inherently contingent upon specific experimental models. Ultimately, to ascertain the genuine potential of phytochemicals as agents in hearing loss treatment, a comprehensive grasp of the molecular mechanisms at play, coupled with rigorous clinical investigations, stands as an imperative quest.
Topics: Oxidative Stress; Humans; Phytochemicals; Hearing Loss, Sensorineural; Animals; Antioxidants; Hair Cells, Auditory; Cell Death; Anti-Inflammatory Agents
PubMed: 38673858
DOI: 10.3390/ijms25084272 -
Life (Basel, Switzerland) Apr 2024Age-related hearing loss (ARHL) is a complex communication disorder that affects the cochlea and central auditory pathway. The goal of this study is to characterize this...
BACKGROUND
Age-related hearing loss (ARHL) is a complex communication disorder that affects the cochlea and central auditory pathway. The goal of this study is to characterize this type of hearing loss and to identify non-invasive, inexpensive, and quick tests to detect ARHL among elderly adults, seeking to preserve quality of life and reduce the burden on healthcare systems.
METHODS
An observational, prospective study is conducted with >55-year-old subjects divided into the following groups: normal range (Group A), detected but not treated (Group B), and detected and treated (Group C). During follow-up, Speech Spatial Qualities (SSQ12), and Hearing Handicap Inventory in the Elderly Screening test (HHIE-S) questionnaires were assessed, along with hearing levels (hearing thresholds at 4 kHz were studied in more depth), and a series of tests and questionnaires to assess balance, cognitive level, level of dependence, and depression.
RESULTS
A total of 710 patients were included in this study. The duration of hearing loss (11.8 yr. in Group B and 21.0 yr. in Group C) and average time-to-treatment for Group C (14.1 yr.) are both protracted. Both of the used questionnaires show statistically significant differences among the groups, revealing greater handicaps for Group C. Audiometry performed at 4 kHz shows how hearing loss progresses with age, finding differences between men and women. There is a correlation between time-to-treatment in Group C and the cognitive test DSST (-0.26; = 0.003).
CONCLUSIONS
HHIE-S, SSQ12, and 4 kHz audiometry are sensitive and feasible tests to implement in screening programs.
PubMed: 38672742
DOI: 10.3390/life14040471 -
Hearing Research Jun 2024We recently reported that the central nucleus of the inferior colliculus (the auditory midbrain) is innervated by glutamatergic pyramidal cells originating not only in...
We recently reported that the central nucleus of the inferior colliculus (the auditory midbrain) is innervated by glutamatergic pyramidal cells originating not only in auditory cortex (AC), but also in multiple 'non-auditory' regions of the cerebral cortex. Here, in anaesthetised rats, we used optogenetics and electrical stimulation, combined with recording in the inferior colliculus to determine the functional influence of these descending connections. Specifically, we determined the extent of monosynaptic excitation and the influence of these descending connections on spontaneous activity in the inferior colliculus. A retrograde virus encoding both green fluorescent protein (GFP) and channelrhodopsin (ChR2) injected into the central nucleus of the inferior colliculus (ICc) resulted in GFP expression in discrete groups of cells in multiple areas of the cerebral cortex. Light stimulation of AC and primary motor cortex (M1) caused local activation of cortical neurones and increased the firing rate of neurones in ICc indicating a direct excitatory input from AC and M1 to ICc with a restricted distribution. In naïve animals, electrical stimulation at multiple different sites within M1, secondary motor, somatosensory, and prefrontal cortices increased firing rate in ICc. However, it was notable that stimulation at some adjacent sites failed to influence firing at the recording site in ICc. Responses in ICc comprised singular spikes of constant shape and size which occurred with a short, and fixed latency (∼ 5 ms) consistent with monosynaptic excitation of individual ICc units. Increasing the stimulus current decreased the latency of these spikes, suggesting more rapid depolarization of cortical neurones, and increased the number of (usually adjacent) channels on which a monosynaptic spike was seen, suggesting recruitment of increasing numbers of cortical neurons. Electrical stimulation of cortical regions also evoked longer latency, longer duration increases in firing activity, comprising multiple units with spikes occurring with significant temporal jitter, consistent with polysynaptic excitation. Increasing the stimulus current increased the number of spikes in these polysynaptic responses and increased the number of channels on which the responses were observed, although the magnitude of the responses always diminished away from the most activated channels. Together our findings indicate descending connections from motor, somatosensory and executive cortical regions directly activate small numbers of ICc neurones and that this in turn leads to extensive polysynaptic activation of local circuits within the ICc.
Topics: Animals; Inferior Colliculi; Somatosensory Cortex; Optogenetics; Electric Stimulation; Auditory Cortex; Motor Cortex; Auditory Pathways; Synapses; Male; Neurons; Rats, Sprague-Dawley; Green Fluorescent Proteins; Female; Channelrhodopsins; Rats
PubMed: 38670009
DOI: 10.1016/j.heares.2024.109009 -
BioRxiv : the Preprint Server For... Apr 2024Autism spectrum disorder (ASD) is characterized by a complex etiology, with genetic determinants significantly influencing its manifestation. Among these, the gene...
Autism spectrum disorder (ASD) is characterized by a complex etiology, with genetic determinants significantly influencing its manifestation. Among these, the gene emerges as a pivotal player, crucially involved in both glial and neuronal functionality. This study elucidates the underexplored roles of in oligodendrocytes, and its subsequent impact on myelination and auditory neural processes. The results reveal a nuanced interplay between oligodendrocytes and axons, where deletion causes alterations in the intricate process of myelination. This disruption, in turn, instigates changes in axonal properties and neuronal activities at the single cell level. Furthermore, oligodendrocyte-specific deletion compromises the integrity of neural circuitry within auditory pathways, leading to auditory hypersensitivity-a common sensory abnormality observed in ASD. Through transcriptional profiling, we identified alterations in the expression of myelin-associated genes, highlighting the cellular consequences engendered by deletion. In summary, the findings provide unprecedented insights into the pathway from deletion in oligodendrocytes to sensory abnormalities in ASD, underscoring the integral role of -mediated myelination in auditory responses. This research thereby provides novel insights into the intricate tapestry of genetic and cellular interactions inherent in ASD.
PubMed: 38659965
DOI: 10.1101/2024.04.15.589242 -
Cell Reports May 2024The mammalian brain can store and retrieve memories of related events as distinct memories and remember common features of those experiences. How it computes this...
The mammalian brain can store and retrieve memories of related events as distinct memories and remember common features of those experiences. How it computes this function remains elusive. Here, we show in rats that recent memories of two closely timed auditory fear events share overlapping neuronal ensembles in the basolateral amygdala (BLA) and are functionally linked. However, remote memories have reduced neuronal overlap and are functionally independent. The activity of parvalbumin (PV)-expressing neurons in the BLA plays a crucial role in forming separate remote memories. Chemogenetic blockade of PV preserves individual remote memories but prevents their segregation, resulting in reciprocal associations. The hippocampus drives this process through specific excitatory connections with BLA GABAergic interneurons. These findings provide insights into the neuronal mechanisms that minimize the overlap between distinct remote memories and enable the retrieval of related memories separately.
Topics: Animals; Hippocampus; Rats; Male; Amygdala; Parvalbumins; Basolateral Nuclear Complex; Interneurons; Memory; Fear; GABAergic Neurons; Neurons; Neural Pathways
PubMed: 38656872
DOI: 10.1016/j.celrep.2024.114151