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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 -
Korean Circulation Journal May 2024Trigger and functional substrate are related to the tone of autonomic nervous system, and the role of the autonomic nerve is more significant in paroxysmal atrial... (Review)
Review
Trigger and functional substrate are related to the tone of autonomic nervous system, and the role of the autonomic nerve is more significant in paroxysmal atrial fibrillation (AF) compared to non-paroxysmal AF. We have several options for neuromodulation to help to manage patients with AF. Neuromodulation targets can be divided into efferent and afferent pathways. On the efferent side, block would be an intuitive approach. However, permanent block is hard to achieve due to completeness of the procedure and reinnervation issues. Temporary block such as botulinum toxin injection into ganglionated plexi would be a possible option for post-cardiac surgery AF. Low-level subthreshold stimulation could also prevent AF, but the invasiveness of the procedure is the barrier for the general use. On the afferent side, block is also an option. Various renal denervation approaches are currently under investigation. Auditory vagus nerve stimulation is one of the representative low-level afferent stimulation methods. This technique is noninvasive and easy to apply, so it has the potential to be widely utilized if its efficacy is confirmed.
PubMed: 38654454
DOI: 10.4070/kcj.2024.0050 -
Brain and Behavior Apr 2024To explore the changes in the cerebral microstructure of patients with noise-induced hearing loss (NIHL) using diffusion tensor imaging (DTI).
OBJECTIVE
To explore the changes in the cerebral microstructure of patients with noise-induced hearing loss (NIHL) using diffusion tensor imaging (DTI).
METHOD
Overall, 122 patients with NIHL (mild [MP, n = 79], relatively severe patients [including moderate and severe; RSP, n = 32], and undetermined [lost to follow-up, n = 11]) and 84 healthy controls (HCs) were enrolled. All clinical data, including age, education level, hearing threshold, occupation type, noise exposure time, and some scale scores (including the Mini-Mental State Examination [MMSE], tinnitus handicap inventory [THI], and Hamilton Anxiety Scale [HAMA]), were collected and analyzed. All participants underwent T1WI3DFSPGR and DTI, and tract-based spatial statistics and region of interest (ROI) analysis were used for assessment.
RESULTS
The final sample included 71 MP, 28 RSP, and 75 HCs. The HAMA scores of the three groups were significantly different (p < .05). The noise exposure times, hearing thresholds, and HAMA scores of the MP and RSP were significantly different (p < .05). The noise exposure time was positively correlated with the hearing threshold and negatively correlated with the HAMA scores (p < .05), whereas the THI scores were positively correlated with the hearing threshold (p < .05). DTI analysis showed that all DTI parameters (fractional anisotropy [FA], axial diffusivity [AD], mean diffusivity [MD], and radial diffusivity [RD]) were significantly different in the left inferior longitudinal fasciculus (ILF) and left inferior fronto-occipital fasciculus (IFOF) for the three groups (p < .05). In addition, the FA values were significantly lower in the bilateral corticospinal tract (CST), right fronto-pontine tract (FPT), right forceps major, left superior longitudinal fasciculus (temporal part) (SLF), and left cingulum (hippocampus) (C-H) of the MP and RSP than in those of the HCs (p < .05); the AD values showed diverse changes in the bilateral CST, left IFOF, right anterior thalamic radiation, right external capsule (EC), right SLF, and right superior cerebellar peduncle (SCP) of the MP and RSP relative to those of the HC (p < .05). However, there were no significant differences among the bilateral auditory cortex ROIs of the three groups (p > .05). There was a significant negative correlation between the FA and HAMA scores for the left IFOF/ILF, right FPT, left SLF, and left C-H for the three groups (p < .05). There was a significant positive correlation between the AD and HAMA scores for the left IFOF/ILF and right EC of the three groups (p < .05). There were significantly positive correlations between the RD/MD and HAMA scores in the left IFOF/ILF of the three groups (p < .05). There was a significant negative correlation between the AD in the right SCP and noise exposure time of the MP and RSP groups (p < .05). The AD, MD, and RD in the left ROI were significantly positively correlated with hearing threshold in the MP and RSP groups (p < .05), whereas FA in the right ROI was significantly positively correlated with the HAMA scores for the three groups (p < .05).
CONCLUSION
The changes in the white matter (WM) microstructure may be related to hearing loss caused by noise exposure, and the WM structural abnormalities in patients with NIHL were mainly located in the syndesmotic fibers of the temporooccipital region, which affected the auditory and language pathways. This confirmed that the auditory pathways have abnormal structural connectivity in patients with NIHL.
Topics: Humans; Diffusion Tensor Imaging; Male; Female; Adult; Middle Aged; Hearing Loss, Noise-Induced; White Matter; Brain
PubMed: 38648388
DOI: 10.1002/brb3.3479