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The human medial olivocochlear (MOC) reflex was assessed by observing the effects of contralateral acoustic stimulation (CAS) on the cochlear microphonic (CM) across a range of probe frequencies. A frequency-swept probe tone (125–4757 Hz, 90 dB SPL) was presented in two directions (up sweep and down sweep) to normal-hearing young adults. This study assessed MOC effects on the CM in individual participants using a statistical approach that calculated minimum detectable changes in magnitude and phase based on CM signal-to-noise ratio (SNR). Significant increases in CM magnitude, typically 1–2 dB in size, were observed for most participants from 354 to 1414 Hz, where the size and consistency of these effects depended on participant, probe frequency, sweep direction, and SNR. CAS-related phase lags were also observed, consistent with CM-based MOC studies in laboratory animals. Observed effects on CM magnitude and phase were in the opposite directions of reported effects on otoacoustic emissions (OAEs). OAEs are sensitive to changes in the motility of outer hair cells located near the peak region of the traveling wave, while the effects of CAS on the CM likely originate from MOC-related changes in the conductance of outer hair cells located in the basal tail of the traveling wave. Thus, MOC effects on the CM are complementary to those observed for OAEs. [ABSTRACT FROM AUTHOR]

The encoding of acoustic stimuli requires precise neuron timing. Auditory neurons in the cochlear nucleus (CN) and brainstem are well suited for accurate analysis of fast acoustic signals, given their physiological specializations of fast membrane time constants, fast axonal conduction, and reliable synaptic transmission. The medial olivocochlear (MOC) neurons that provide efferent inhibition of the cochlea reside in the ventral brainstem and participate in these fast neural circuits. However, their modulation of cochlear function occurs over time scales of a slower nature. This suggests the presence of mechanisms that reduce MOC inhibition of cochlear function. To determine how monaural excitatory and inhibitory synaptic inputs integrate to affect the timing of MOC neuron activity, we developed a novel in vitro slice preparation (“wedge-slice”). The wedge-slice maintains the ascending auditory nerve root, the entire CN and projecting axons, while preserving the ability to perform visually guided patch-clamp electrophysiology recordings from genetically identified MOC neurons. The “in vivo-like” timing of the wedge-slice demonstrates that the inhibitory pathway accelerates relative to the excitatory pathway when the ascending circuit is intact, and the CN portion of the inhibitory circuit is precise enough to compensate for reduced precision in later synapses. When combined with machine learning PSC analysis and computational modeling, we demonstrate a larger suppression of MOC neuron activity when the inhibition occurs with in vivolike timing. This delay of MOC activity may ensure that the MOC system is only engaged by sustained background sounds, preventing a maladaptive hypersuppression of cochlear activity. [ABSTRACT FROM AUTHOR]

Hereditary congenital facial paresis type 1 (HCFP1) is an autosomal dominant disorder of absent or limited facial movement that maps to chromosome 3q21-q22 and is hypothesized to result from facial branchial motor neuron (FBMN) maldevelopment. In the present study, we report that HCFP1 results from heterozygous duplications within a neuron-specific GATA2 regulatory region that includes two enhancers and one silencer, and from noncoding single-nucleotide variants (SNVs) within the silencer. Some SNVs impair binding of NR2F1 to the silencer in vitro and in vivo and attenuate in vivo enhancer reporter expression in FBMNs. Gata2 and its effector Gata3 are essential for inner-ear efferent neuron (IEE) but not FBMN development. A humanized HCFP1 mouse model extends Gata2 expression, favors the formation of IEEs over FBMNs and is rescued by conditional loss of Gata3. These findings highlight the importance of temporal gene regulation in development and of noncoding variation in rare mendelian disease.

Efferent feedback to the mammalian cochlea includes cholinergic medial olivocochlear neurons (MOCs) that release ACh to hyperpolarize and shunt the voltage change that drives electromotility of outer hair cells (OHCs). Via brainstem connectivity, MOCs are activated by sound in a frequency- and intensity-dependent manner, thereby reducing the amplification of cochlear vibration provided by OHC electromotility. Among other roles, this efferent feedback protects the cochlea from acoustic trauma. Lesion studies, as well as a variety of genetic mouse models, support the hypothesis of efferent protection from acoustic trauma. Genetic knockout and gain-of-function knockin of the unique a9a10-containing nicotinic acetylcholine receptor (nAChR) in hair cells show that acoustic protection correlates with the efficacy of cholinergic inhibition of OHCs. This protective effect was replicated by viral transduction of the gain-of-function a9L9'T nAChR into a9-knockout mice. Continued progress with "efferent gene therapy" will require a reliable method for visualizing nAChR expression in cochlear hair cells. To that end, mice expressing HA-tagged a9 or a10 nAChRs were generated using CRISPR technology. This progress will facilitate continued study of the hair cell nAChR as a therapeutic target to prevent hearing loss and potentially to ameliorate associated pathologies such as hyperacusis. [ABSTRACT FROM AUTHOR]

Background: Postoperative ileus (POI) remains a common phenomenon following loop ileostomy closure. Our aim was to determine whether preoperative physiological stimulation (PPS) of the efferent limb reduced POI incidence. Methods: A PRISMA-compliant meta-analysis searching PubMed, EMBASE and CENTRAL databases was performed. The last search was carried out on 30 January 2023. All randomized studies comparing PPS versus no stimulation were included. The primary endpoint was POI incidence. Secondary endpoints included the time to first passage of flatus/stool, time to resume oral diet, need for nasogastric tube (NGT) placement postoperatively, length of stay (LOS) and other complications. Random effects models were used to calculate pooled effect size estimates. Trial sequential analyses (TSA) were also performed. Results: Three randomized studies capturing 235 patients (116 PPS, 119 no stimulation) were included. On random effects analysis, PPS was associated with a quicker time to resume oral diet (MD − 1.47 days, 95% CI − 2.75 to − 0.19, p = 0.02), shorter LOS (MD − 1.47 days, 95% CI − 2.47 to − 0.46, p = 0.004) (MD − 1.41 days, 95% CI − 2.32 to − 0.50, p = 0.002, I2 = 56%) and fewer other complications (OR 0.42, 95% CI 0.18 to 1.01, p = 0.05). However, there was no difference in POI incidence (OR 0.35, 95% CI 0.10 to 1.21, p = 0.10), the requirement for NGT placement (OR 0.50, 95% CI 0.21 to 1.20, p = 0.12) or time to first passage of flatus/stool (MD − 0.60 days, 95% CI − 1.95 to 0.76, p = 0.39). TSA revealed imprecise estimates for all outcomes (except LOS) and further studies are warranted to meet the required information threshold. Conclusions: PPS prior to stoma closure may reduce LOS and postoperative complications albeit without a demonstrable beneficial effect on POI. Further high-powered studies are required to confirm or refute these findings. [ABSTRACT FROM AUTHOR]

Background: Postoperative ileus (POI) remains a common phenomenon following loop ileostomy closure. Our aim was to determine whether preoperative physiological stimulation (PPS) of the efferent limb reduced POI incidence. Methods: A PRISMA-compliant meta-analysis searching PubMed, EMBASE and CENTRAL databases was performed. The last search was carried out on 30 January 2023. All randomized studies comparing PPS versus no stimulation were included. The primary endpoint was POI incidence. Secondary endpoints included the time to first passage of flatus/stool, time to resume oral diet, need for nasogastric tube (NGT) placement postoperatively, length of stay (LOS) and other complications. Random effects models were used to calculate pooled effect size estimates. Trial sequential analyses (TSA) were also performed. Results: Three randomized studies capturing 235 patients (116 PPS, 119 no stimulation) were included. On random effects analysis, PPS was associated with a quicker time to resume oral diet (MD − 1.47 days, 95% CI − 2.75 to − 0.19, p = 0.02), shorter LOS (MD − 1.47 days, 95% CI − 2.47 to − 0.46, p = 0.004) (MD − 1.41 days, 95% CI − 2.32 to − 0.50, p = 0.002, I2 = 56%) and fewer other complications (OR 0.42, 95% CI 0.18 to 1.01, p = 0.05). However, there was no difference in POI incidence (OR 0.35, 95% CI 0.10 to 1.21, p = 0.10), the requirement for NGT placement (OR 0.50, 95% CI 0.21 to 1.20, p = 0.12) or time to first passage of flatus/stool (MD − 0.60 days, 95% CI − 1.95 to 0.76, p = 0.39). TSA revealed imprecise estimates for all outcomes (except LOS) and further studies are warranted to meet the required information threshold. Conclusions: PPS prior to stoma closure may reduce LOS and postoperative complications albeit without a demonstrable beneficial effect on POI. Further high-powered studies are required to confirm or refute these findings. [ABSTRACT FROM AUTHOR]

Efferent feedback to the mammalian cochlea includes cholinergic medial olivocochlear neurons (MOCs) that release ACh to hyperpolarize and shunt the voltage change that drives electromotility of outer hair cells (OHCs). Via brainstem connectivity, MOCs are activated by sound in a frequency- and intensity-dependent manner, thereby reducing the amplification of cochlear vibration provided by OHC electromotility. Among other roles, this efferent feedback protects the cochlea from acoustic trauma. Lesion studies, as well as a variety of genetic mouse models, support the hypothesis of efferent protection from acoustic trauma. Genetic knockout and gain-of-function knockin of the unique α9α10-containing nicotinic acetylcholine receptor (nAChR) in hair cells show that acoustic protection correlates with the efficacy of cholinergic inhibition of OHCs. This protective effect was replicated by viral transduction of the gain-of-function α9L9’T nAChR into α9-knockout mice. Continued progress with “efferent gene therapy” will require a reliable method for visualizing nAChR expression in cochlear hair cells. To that end, mice expressing HA-tagged α9 or α10 nAChRs were generated using CRISPR technology. This progress will facilitate continued study of the hair cell nAChR as a therapeutic target to prevent hearing loss and potentially to ameliorate associated pathologies such as hyperacusis.

Auditory experience plays a critical role in hearing development. Developmental auditory deprivation because of otitis media, a common childhood disease, produces long-standing changes in the central auditory system, even after the middle ear pathology is resolved. The effects of sound deprivation because of otitis media have been mostly studied in the ascending auditory system but remain to be examined in the descending pathway that runs from the auditory cortex to the cochlea via the brainstem. Alterations in the efferent neural system could be important because the descending olivocochlear pathway influences the neural representation of transient sounds in noise in the afferent auditory system and is thought to be involved in auditory learning. Here, we show that the inhibitory strength of the medial olivocochlear efferents is weaker in children with a documented history of otitis media relative to controls; both boys and girls were included in the study. In addition, children with otitis media history required a higher signal-to-noise ratio on a sentence-in-noise recognition task than controls to achieve the same criterion performance level. Poorer speech-in-noise recognition, a hallmark of impaired central auditory processing, was related to efferent inhibition, and could not be attributed to the middle ear or cochlear mechanics. [ABSTRACT FROM AUTHOR]

Cholinergic circuits in the central nervous system are vulnerable to age-related functional decline, but it is not known if aging impacts cholinergic signaling in the vestibular sensory organs, which are critically important to balance maintenance and visual gaze stability. We have previously shown cholinergic neurotransmission between vestibular efferent terminals and type II mechanosensory hair cells requires the alpha9 (Chrna9) nicotinic receptor subunit. Homozygous knockout of the alpha9 subunit causes vestibulo-ocular reflex adaptation deficits that mirror those observed in aged mice. This prompted examination of cholinergic signaling in the vestibular sensory organs of aged mice. We confirmed older (>24 months) mice had impaired performance in a balance beam task compared to young (3–4 months) adult mice. While there was no qualitative loss of cholinergic axon varicosities in the crista ampullaris of old mice, qPCR analysis revealed reduced expression of nicotinic receptor subunit genes Chrna1 , Chrna9 , and Chrna10 in the cristae of old relative to young mice. Functionally, single-cell patch clamp recordings taken from type II vestibular hair cells exposed to acetylcholine show reduced conductance through alpha9/10 subunit-containing nicotinic receptors in older mice, despite preserved passive membrane properties and voltage-activated conductances. These findings suggest that cholinergic signaling in the peripheral vestibular sensory organs is vulnerable to aging processes, manifesting in dynamic molecular and functional age-related changes. Given the importance of these organs to our everyday activities, and the dramatic increase in fall incidence in the older, further investigation into the mechanisms of altered peripheral vestibular function in older humans is warranted. [ABSTRACT FROM AUTHOR]

In 1985, Bill Brownell and colleagues published the remarkable observation that cochlear outer hair cells (OHCs) express voltage-driven mechanical motion: electromotility. They proposed OHC electromotility as the mechanism for the elusive "cochlear amplifier" required to explain the sensitivity of mammalian hearing. The finding and hypothesis stimulated an explosion of experiments that have transformed our understanding of cochlear mechanics and physiology, the evolution of hair cell structure and function, and audiology. Here, we bring together examples of current research that illustrate the continuing impact of the discovery of OHC electromotility. [ABSTRACT FROM AUTHOR]

Brainstem olivocochlear neurons (OCNs) modulate the earliest stages of auditory processing through feedback projections to the cochlea and have been shown to influence hearing and protect the ear from sound-induced damage. Here, we used single-nucleus sequencing, anatomical reconstructions, and electrophysiology to characterize murine OCNs during postnatal development, in mature animals, and after sound exposure. We identified markers for known medial (MOC) and lateral (LOC) OCN subtypes, and show that they express distinct cohorts of physiologically relevant genes that change over development. In addition, we discovered a neuropeptide-enriched LOC subtype that produces Neuropeptide Y along with other neurotransmitters. Throughout the cochlea, both LOC subtypes extend arborizations over wide frequency domains. Moreover, LOC neuropeptide expression is strongly upregulated days after acoustic trauma, potentially providing a sustained protective signal to the cochlea. OCNs are therefore poised to have diffuse, dynamic effects on early auditory processing over timescales ranging from milliseconds to days.

The aim of this study was to compare the reliability of the medial olivocochlear reflex (MOCR) between men and women. The strength of the MOCR was measured in terms of the suppression of transiently evoked otoacoustic emissions (TEOAEs) by contralateral acoustic stimulation (CAS). The difference between TEOAEs with and without CAS (white noise) was calculated as raw decibel TEOAE suppression as well as normalized TEOAE suppression expressed in percent. In each subject, sets of measurements were performed twice. Reliability was evaluated by calculating the intraclass correlation coefficient, the standard error of measurement, and the minimum detectable change (MDC). The study included 40 normally hearing subjects (20 men; 20 women). The estimates of MOCR for both genders were similar. Nevertheless, the reliability of the MOCR was poorer in men, with an MDC around twice that of women. This can be only partially attributed to slightly lower signal-to-noise ratios (SNRs) in men, since we used strict procedures calling for high SNRs (around 20 dB on average). Furthermore, even when we compared subgroups with similar SNRs, there was still lower MOCR reliability in men.

The human medial olivocochlear (MOC) reflex was assessed by observing the effects of contralateral acoustic stimulation (CAS) on the cochlear microphonic (CM) across a range of probe frequencies. A frequency-swept probe tone (125-4757 Hz, 90 dB SPL) was presented in two directions (up sweep and down sweep) to normal-hearing young adults. This study assessed MOC effects on the CM in individual participants using a statistical approach that calculated minimum detectable changes in magnitude and phase based on CM signal-to-noise ratio (SNR). Significant increases in CM magnitude, typically 1-2 dB in size, were observed for most participants from 354 to 1414 Hz, where the size and consistency of these effects depended on participant, probe frequency, sweep direction, and SNR. CAS-related phase lags were also observed, consistent with CM-based MOC studies in laboratory animals. Observed effects on CM magnitude and phase were in the opposite directions of reported effects on otoacoustic emissions (OAEs). OAEs are sensitive to changes in the motility of outer hair cells located near the peak region of the traveling wave, while the effects of CAS on the CM likely originate from MOC-related changes in the conductance of outer hair cells located in the basal tail of the traveling wave. Thus, MOC effects on the CM are complementary to those observed for OAEs., (© 2024. The Author(s) under exclusive licence to Association for Research in Otolaryngology.)

Traditional cognitive linguistic theories acknowledge that human emotions are embodied, yet they fail to distinguish the dimensions that reflect the direction of neural signaling between the brain and body. Differences exist across languages and cultures in whether embodied emotions are conceptualized as afferent (feelings from the body) or efferent (enacted through the body). This important distinction has been neglected in academic discourse, arguably as a consequence of the 'lexical approach', and the dominance within the affective psychology of the cognitive and semantic models that overlook the role of interoception as an essential component of affective experience. Empirical and theoretical advances in human neuroscience are driving a reappraisal of the relationships between the mind, brain and body, with particular relevance to emotions. Allostatic (predictive) control of the internal bodily states is considered fundamental to the experience of emotions enacted through interoceptive sensory feelings and through the evoked physiological and physical actions mediated through efferent neural pathways. Embodied emotion concepts encompass these categorized outcomes of bidirectional brain–body interactions yet can be differentiated further into afferent or interoceptive and efferent or autonomic processes. Between languages, a comparison of emotion words indicates the dominance of afferent or interoceptive processes in how embodied emotions are conceptualized in Chinese, while efferent or autonomic processes feature more commonly in English. Correspondingly, in linguistic expressions of emotion, Chinese-speaking people are biased toward being more receptive, reflective, and adaptive, whereas native English speakers may tend to be more reactive, proactive, and interactive. Arguably, these distinct conceptual models of emotions may shape the perceived divergent values and 'national character' of Chinese- and English-speaking cultures. [ABSTRACT FROM AUTHOR]

The descending auditory system modulates the ascending system at every level. The final descending, or efferent, stage comprises lateral olivocochlear and medial olivocochlear (MOC) neurons. MOC somata in the ventral brainstem project axons to the cochlea to synapse onto outer hair cells (OHC), inhibiting OHC‐mediated cochlear amplification. MOC suppression of OHC function is implicated in cochlear gain control with changing sound intensity, detection of salient stimuli, attention and protection against acoustic trauma. Thus, sound excites MOC neurons to provide negative feedback of the cochlea. Sound also inhibits MOC neurons via medial nucleus of the trapezoid body (MNTB) neurons. However, MNTB–MOC synapses exhibit short‐term depression, suggesting reduced MNTB–MOC inhibition during sustained stimuli. Further, due to high rates of both baseline and sound‐evoked activity in MNTB neurons in vivo, MNTB–MOC synapses may be tonically depressed. To probe this, we characterized short‐term plasticity of MNTB–MOC synapses in mouse brain slices. We mimicked in vivo‐like temperature and extracellular calcium conditions, and in vivo‐like activity patterns of fast synaptic activation rates, sustained activation and prior tonic activity. Synaptic depression was sensitive to extracellular calcium concentration and temperature. During rapid MNTB axon stimulation, postsynaptic currents in MOC neurons summated but with concurrent depression, resulting in smaller, sustained currents, suggesting tonic inhibition of MOC neurons during rapid circuit activity. Low levels of baseline MNTB activity did not significantly reduce responses to subsequent rapid activity that mimics sound stimulation, indicating that, in vivo, MNTB inhibition of MOC neurons persists despite tonic synaptic depression. Key points: Inhibitory synapses from the medial nucleus of the trapezoid body (MNTB) onto medial olivocochlear (MOC) neurons exhibit short‐term plasticity that is sensitive to calcium and temperature, with enhanced synaptic depression occurring at higher calcium concentrations and at room temperature.High rates of background synaptic activity that mimic the upper limits of spontaneous MNTB activity cause tonic synaptic depression of MNTB–MOC synapses that limits further synaptic inhibition.High rates of activity at MNTB–MOC synapses cause synaptic summation with concurrent depression to yield a response with an initial large amplitude that decays to a tonic inhibition. [ABSTRACT FROM AUTHOR]

The body and brain are in constant two‐way communication. Driving this communication is a region in the lower brainstem: the dorsal vagal complex. Within the dorsal vagal complex, the caudal nucleus of the solitary tract (cNTS) is a major first stop for incoming information from the body to the brain carried by the vagus nerve. The anatomy of this region makes it ideally positioned to respond to signals of change in both emotional and bodily states. In turn, the cNTS controls the activity of regions throughout the brain that are involved in the control of both behaviour and physiology. This review is intended to help anyone with an interest in the cNTS. First, I provide an overview of the architecture of the cNTS and outline the wide range of neurotransmitters expressed in subsets of neurons in the cNTS. Next, in detail, I discuss the known inputs and outputs of the cNTS and briefly highlight what is known regarding the neurochemical makeup and function of those connections. Then, I discuss one group of cNTS neurons: glucagon‐like peptide‐1 (GLP‐1)‐expressing neurons. GLP‐1 neurons serve as a good example of a group of cNTS neurons, which receive input from varied sources and have the ability to modulate both behaviour and physiology. Finally, I consider what we might learn about other cNTS neurons from our study of GLP‐1 neurons and why it is important to remember that the manipulation of molecularly defined subsets of cNTS neurons is likely to affect physiology and behaviours beyond those monitored in individual experiments. [ABSTRACT FROM AUTHOR]

Abstract Background A long-standing debate concerns where in the processing hierarchy of the central nervous system (CNS) selective attention takes effect. In the auditory system, cochlear processes can be influenced via direct and mediated (by the inferior colliculus) projections from the auditory cortex to the superior olivary complex (SOC). Studies illustrating attentional modulations of cochlear responses have so far been limited to sound-evoked responses. The aim of the present study is to investigate intermodal (audiovisual) selective attention in humans simultaneously at the cortical and cochlear level during a stimulus-free cue-target interval. Results We found that cochlear activity in the silent cue-target intervals was modulated by a theta-rhythmic pattern (~ 6 Hz). While this pattern was present independently of attentional focus, cochlear theta activity was clearly enhanced when attending to the upcoming auditory input. On a cortical level, classical posterior alpha and beta power enhancements were found during auditory selective attention. Interestingly, participants with a stronger release of inhibition in auditory brain regions show a stronger attentional modulation of cochlear theta activity. Conclusions These results hint at a putative theta-rhythmic sampling of auditory input at the cochlear level. Furthermore, our results point to an interindividual variable engagement of efferent pathways in an attentional context that are linked to processes within and beyond processes in auditory cortical regions.

The vestibular end organs differ in terms of anatomical and physiological characteristics. Sensory modalities' stimuli including visual stimuli and vestibular sensation can influence these organs differently. This paper explores differences between vestibular responses to axial tilts in physical and virtual environments. Four passive whole-body movements (linear: up-down, and angular: yaw, pitch, and roll) were applied to twenty-seven healthy participants once using a hydraulic chair (physical) and once visually using a head-mounted display (virtual). Electrovestibulography (EVestG) was used as the outcome measure to investigate the magnitude of vestibular-response-change in both ears for physical and virtual stimuli. Three features including average action potential (AP) area, AP amplitude, and mean detected firing rate change were used as indices of response. The results show that for both physical and virtual stimuli (1) generally the pitch and roll tilts produce the largest EVestG changes compared to other tilts (2) roll and pitch tilt responses are not significantly different from each other and (3) right side and left side roll tilts' responses are not significantly different. The findings indicate although visually- and physically-induced vestibular responses are different in terms of afferent activity, visual stimuli can still result in distinct responses when exposed to different axial tilts. [ABSTRACT FROM AUTHOR]

The aim of this study was to compare the reliability of the medial olivocochlear reflex (MOCR) between men and women. The strength of the MOCR was measured in terms of the suppression of transiently evoked otoacoustic emissions (TEOAEs) by contralateral acoustic stimulation (CAS). The difference between TEOAEs with and without CAS (white noise) was calculated as raw decibel TEOAE suppression as well as normalized TEOAE suppression expressed in percent. In each subject, sets of measurements were performed twice. Reliability was evaluated by calculating the intraclass correlation coefficient, the standard error of measurement, and the minimum detectable change (MDC). The study included 40 normally hearing subjects (20 men; 20 women). The estimates of MOCR for both genders were similar. Nevertheless, the reliability of the MOCR was poorer in men, with an MDC around twice that of women. This can be only partially attributed to slightly lower signal-to-noise ratios (SNRs) in men, since we used strict procedures calling for high SNRs (around 20 dB on average). Furthermore, even when we compared subgroups with similar SNRs, there was still lower MOCR reliability in men. [ABSTRACT FROM AUTHOR]

The efferent auditory nervous system may be a potent force in shaping how the brain responds to behaviorally significant sounds. Previous human experiments using the frequency following response (FFR) have shown efferent-induced modulation of subcortical auditory function online and over short- and long-term time scales; however, a contemporary understanding of FFR generation presents new questions about whether previous effects were constrained solely to the auditory subcortex. The present experiment used sine-wave speech (SWS), an acoustically-sparse stimulus in which dynamic pure tones represent speech formant contours, to evoke FFRSWS. Due to the higher stimulus frequencies used in SWS, this approach biased neural responses toward brainstem generators and allowed for three stimuli (/bɔ/, /bu/, and /bo/) to be used to evoke FFRSWS before and after listeners in a training group were made aware that they were hearing a degraded speech stimulus. All SWS stimuli were rapidly perceived as speech when presented with a SWS carrier phrase, and average token identification reached ceiling performance during a perceptual training phase. Compared to a control group which remained naïve throughout the experiment, training group FFRSWS amplitudes were enhanced post-training for each stimulus. Further, linear support vector machine classification of training group FFRSWS significantly improved post-training compared to the control group, indicating that training-induced neural enhancements were sufficient to bolster machine learning classification accuracy. These results suggest that the efferent auditory system may rapidly modulate auditory brainstem representation of sounds depending on their context and perception as non-speech or speech. [ABSTRACT FROM AUTHOR]

Physiological and psychophysical methods allow for an extended investigation of ascending (afferent) neural pathways from the ear to the brain in mammals, and their role in enhancing signals in noise. However, there is increased interest in descending (efferent) neural fibers in the mammalian auditory pathway. This efferent pathway operates via the olivocochlear system, modifying auditory processing by cochlear innervation and enhancing human ability to detect sounds in noisy backgrounds. Effective speech intelligibility may depend on a complex interaction between efferent time-constants and types of background noise. In this study, an auditory model with efferent-inspired processing provided the front-end to an automatic-speech-recognition system (ASR), used as a tool to evaluate speech recognition with changes in time-constants (50 to 2000 ms) and background noise type (unmodulated and modulated noise). With efferent activation, maximal speech recognition improvement (for both noise types) occurred for signal-to-noise ratios around 10 dB, characteristic of real-world speech-listening situations. Net speech improvement due to efferent activation (NSIEA) was smaller in modulated noise than in unmodulated noise. For unmodulated noise, NSIEA increased with increasing time-constant. For modulated noise, NSIEA increased for time-constants up to 200 ms but remained similar for longer time-constants, consistent with speech-envelope modulation times important to speech recognition in modulated noise. The model improves our understanding of the complex interactions involved in speech recognition in noise, and could be used to simulate the difficulties of speech perception in noise as a consequence of different types of hearing loss.

The efferent auditory nervous system may be a potent force in shaping how the brain responds to behaviorally significant sounds. Previous human experiments using the frequency following response (FFR) have shown efferent-induced modulation of subcortical auditory function online and over short- and long-term time scales; however, a contemporary understanding of FFR generation presents new questions about whether previous effects were constrained solely to the auditory subcortex. The present experiment used sine-wave speech (SWS), an acoustically-sparse stimulus in which dynamic pure tones represent speech formant contours, to evoke FFRSWS. Due to the higher stimulus frequencies used in SWS, this approach biased neural responses toward brainstem generators and allowed for three stimuli (/bɔ/, /bu/, and /bo/) to be used to evoke FFRSWSbefore and after listeners in a training group were made aware that they were hearing a degraded speech stimulus. All SWS stimuli were rapidly perceived as speech when presented with a SWS carrier phrase, and average token identification reached ceiling performance during a perceptual training phase. Compared to a control group which remained naïve throughout the experiment, training group FFRSWS amplitudes were enhanced post-training for each stimulus. Further, linear support vector machine classification of training group FFRSWS significantly improved post-training compared to the control group, indicating that training-induced neural enhancements were sufficient to bolster machine learning classification accuracy. These results suggest that the efferent auditory system may rapidly modulate auditory brainstem representation of sounds depending on their context and perception as non-speech or speech.

During development, inner hair cells (IHCs) in the mammalian cochlea are unresponsive to acoustic stimuli but instead exhibit spontaneous activity. During this same period, neurons originating from the medial olivocochlear complex (MOC) transiently innervate IHCs, regulating their firing pattern which is crucial for the correct development of the auditory pathway. Although the MOC-IHC is a cholinergic synapse, previous evidence indicates the widespread presence of gamma-aminobutyric acid (GABA) signaling markers, including presynaptic GABA B receptors (GABA B R). In this study, we explore the source of GABA by optogenetically activating either cholinergic or GABAergic fibers. The optogenetic stimulation of MOC terminals from GAD;ChR2-eYFP and ChAT;ChR2-eYFP mice evoked synaptic currents in IHCs that were blocked by α-bungarotoxin. This suggests that GABAergic fibers release ACh and activate α9α10 nicotinic acetylcholine receptors (nAChRs). Additionally, MOC cholinergic fibers release not only ACh but also GABA, as the effect of GABA on ACh response amplitude was prevented by applying the GABA B -R blocker (CGP 36216). Using optical neurotransmitter detection and calcium imaging techniques, we examined the extent of GABAergic modulation at the single synapse level. Our findings suggest heterogeneity in GABA modulation, as only 15 out of 31 recorded synaptic sites were modulated by applying the GABA B R specific antagonist, CGP (100-200 μM). In conclusion, we provide compelling evidence that GABA and ACh are co-released from at least a subset of MOC terminals. In this circuit, GABA functions as a negative feedback mechanism, locally regulating the extent of cholinergic inhibition at certain efferent-IHC synapses during an immature stage., Competing Interests: The authors declare no competing financial interests.

Ca2+ signaling is a major contributor to sensory hair cell function in the cochlea. Oncomodulin (OCM) is a Ca2+ binding protein (CaBP) preferentially expressed in outer hair cells (OHCs) of the cochlea and few other specialized cell types. Here, we expand on our previous reports and show that OCM delays hearing loss in mice of two different genetic backgrounds: CBA/CaJ and C57Bl/6J. In both backgrounds, genetic disruption of Ocm leads to early progressive hearing loss as measured by auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE). In both strains, loss of Ocm reduced hearing across lifetime (hearing span) by more than 50% relative to wild type (WT). Even though the two WT strains have very different hearing spans, OCM plays a considerable and similar role within their genetic environment to regulate hearing function. The accelerated age-related hearing loss (ARHL) of the Ocm KO illustrates the importance of Ca2+ signaling in maintaining hearing health. Manipulation of OCM and Ca2+ signaling may reveal important clues to the systems of function/dysfunction that lead to ARHL. [ABSTRACT FROM AUTHOR]

Xenopus laevis has a lateral line mechanosensory system throughout its full life cycle, and a previous study on prefeeding stage tadpoles revealed that it may play a role in motor responses to both water suction and water jets. Here, we investigated the physiology of the anterior lateral line system in newly hatched tadpoles and the motor outputs induced by its activation in response to brief suction stimuli. High-speed videoing showed tadpoles tended to turn and swim away when strong suction was applied close to the head. The lateral line neuromasts were revealed by using DASPEI staining, and their inactivation with neomycin eliminated tadpole motor responses to suction. In immobilized preparations, suction or electrically stimulating the anterior lateral line nerve reliably initiated swimming but the motor nerve discharges implicating turning was observed only occasionally. The same stimulation applied during ongoing fictive swimming produced a halting response. The anterior lateral line nerve showed spontaneous afferent discharges at rest and increased activity during stimulation. Efferent activities were only recorded during tadpole fictive swimming and were largely synchronous with the ipsilateral motor nerve discharges. Finally, calcium imaging identified neurons with fluorescence increase time-locked with suction stimulation in the hindbrain and midbrain. A cluster of neurons at the entry point of the anterior lateral line nerve in the dorsolateral hindbrain had the shortest latency in their responses, supporting their potential sensory interneuron identity. Future studies need to reveal how the lateral line sensory information is processed by the central circuit to determine tadpole motor behavior. NEW & NOTEWORTHY We studied Xenopus tadpole motor responses to anterior lateral line stimulation using high-speed videos, electrophysiology and calcium imaging. Activating the lateral line reliably started swimming. At high stimulation intensities, turning was observed behaviorally but suitable motor nerve discharges were seen only occasionally in immobilized tadpoles. Suction applied during swimming produced a halting response. We analyzed afferent and efferent activities of the tadpole anterior lateral line nerve and located sensory interneurons using calcium imaging. [ABSTRACT FROM AUTHOR]

Vertebrate hair cell (HC) systems are innervated by efferent fibers that modulate their response to external stimuli. In mammals, the best studied efferent-HC synapse, the cholinergic medial olivocochlear (MOC) efferent system, makes direct synaptic contacts with HCs. The net effect of MOC activity is to hyperpolarize HCs through the activation of α9α10 nicotinic cholinergic receptors (nAChRs) and the subsequent activation of Ca2+-dependent SK2 potassium channels. A serious obstacle in research on many mammalian sensory systems in their native context is that their constituent neurons are difficult to access even in newborn animals, hampering circuit observation, mapping, or controlled manipulation. By contrast, fishes and amphibians have a superficial and accessible mechanosensory system, the lateral line (LL), which circumvents many of these problems. LL responsiveness is modulated by efferent neurons which aid to distinguish between external and self-generated stimuli. One component of the LL efferent system is cholinergic and its activation inhibits LL afferent activity, similar to what has been described for MOC efferents. The zebrafish (Danio rerio) has emerged as a powerful model system for studying human hearing and balance disorders, since LL HC are structurally and functionally analogous to cochlear HCs, but are optically and pharmacologically accessible within an intact specimen. Complementing mammalian studies, zebrafish have been used to gain significant insights into many facets of HC biology, including mechanotransduction and synaptic physiology as well as mechanisms of both hereditary and acquired HC dysfunction. With the rise of the zebrafish LL as a model in which to study auditory system function and disease, there has been an increased interest in studying its efferent system and evaluate the similarity between mammalian and piscine efferent synapses. Advances derived from studies in zebrafish include understanding the effect of the LL efferent system on HC and afferent activity, and revealing that an α9-containing nAChR, functionally coupled to SK channels, operates at the LL efferent synapse. In this review, we discuss the tools and findings of these recent investigations into zebrafish efferent-HC synapse, their commonalities with the mammalian counterpart and discuss several emerging areas for future studies. [ABSTRACT FROM AUTHOR]

The medial olivocochlear (MOC) reflex provides efferent feedback from the brainstem to cochlear outer hair cells. Physiologic studies have demonstrated that the MOC reflex is involved in "unmasking" of signals-in-noise at the level of the auditory nerve; however, its functional importance in human hearing remains unclear. This study examined relationships between pre-neural measurements of MOC reflex strength (click-evoked otoacoustic emission inhibition; CEOAE) and neural measurements of speech-in-noise encoding (speech frequency following response; sFFR) in four conditions (Quiet, Contralateral Noise, Ipsilateral Noise, and Ipsilateral + Contralateral Noise). Three measures of CEOAE inhibition (amplitude reduction, effective attenuation, and input-output slope inhibition) were used to quantify pre-neural MOC reflex strength. Correlations between pre-neural MOC reflex strength and sFFR "unmasking" (i.e. response recovery from masking effects with activation of the MOC reflex in time and frequency domains) were assessed. 18 young adults with normal hearing. sFFR unmasking effects were insignificant, and there were no correlations between pre-neural MOC reflex strength and sFFR unmasking in the time or frequency domain. Our results do not support the hypothesis that the MOC reflex is involved in speech-in-noise neural encoding, at least for features that are represented in the sFFR at the SNR tested. [ABSTRACT FROM AUTHOR]

Vection is defined as an illusory self-motion sensation induced in stationary observers that can be experienced in a real/virtual world. Vection, as a result of immersion in virtual reality (VR) environments, can subsequently lead to a sense of inability to maintain postural control and cause cybersickness symptoms. The multisensory integration of visual and vestibular (balance) information plays a vital role in vection. The etiology of vection perception, as well as, the vestibular response change while experiencing vection is poorly understood. This study explores vestibular response change following vection in 20 individuals (10 females, 26.45 ± 4.40 (SD) years). Vection was induced in participants using an immersive VR roller-coaster. The vestibular response was measured simultaneously using a noninvasive method called Electrovestibulography (EVestG). The detected field potentials and the time intervals between the field potentials were extracted from the recorded EVestG signals corresponding to four segments of the VR roller-coaster trajectory namely Stationary, Up movement, Down movement, and slopes and turns (Mix). The results show that the Stationary segment is significantly different (P < 0.05) from other dynamic segments when the average field potential of the right and left ear are subtracted. Furthermore, the Stationary segment shows longer time intervals between field potentials compared to those of the other segments in the right ear. These observations suggest that the combined effect of the visually induced sensation of self-motion together with a concurrent/co-occurring stress/anxiety factor can affect the vestibular activity in an excitatory way. Increased excitatory vestibular activity implies increased feeling of imbalance and more likelihood of experiencing cybersickness by the participants. [ABSTRACT FROM AUTHOR]

Ca2+ signaling is a major contributor to sensory hair cell function in the cochlea. Oncomodulin (OCM) is a Ca2+ binding protein (CaBP) preferentially expressed in outer hair cells (OHCs) of the cochlea and few other specialized cell types. Here, we expand on our previous reports and show that OCM delays hearing loss in mice of two different genetic backgrounds: CBA/CaJ and C57Bl/6J. In both backgrounds, genetic disruption of Ocm leads to early progressive hearing loss as measured by auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE). In both strains, loss of Ocm reduced hearing across lifetime (hearing span) by more than 50% relative to wild type (WT). Even though the two WT strains have very different hearing spans, OCM plays a considerable and similar role within their genetic environment to regulate hearing function. The accelerated age-related hearing loss (ARHL) of the Ocm KO illustrates the importance of Ca2+ signaling in maintaining hearing health. Manipulation of OCM and Ca2+ signaling may reveal important clues to the systems of function/dysfunction that lead to ARHL.

Vertebrate hair cell (HC) systems are innervated by efferent fibers that modulate their response to external stimuli. In mammals, the best studied efferent-HC synapse, the cholinergic medial olivocochlear (MOC) efferent system, makes direct synaptic contacts with HCs. The net effect of MOC activity is to hyperpolarize HCs through the activation of α9α10 nicotinic cholinergic receptors (nAChRs) and the subsequent activation of Ca2+-dependent SK2 potassium channels. A serious obstacle in research on many mammalian sensory systems in their native context is that their constituent neurons are difficult to access even in newborn animals, hampering circuit observation, mapping, or controlled manipulation. By contrast, fishes and amphibians have a superficial and accessible mechanosensory system, the lateral line (LL), which circumvents many of these problems. LL responsiveness is modulated by efferent neurons which aid to distinguish between external and self-generated stimuli. One component of the LL efferent system is cholinergic and its activation inhibits LL afferent activity, similar to what has been described for MOC efferents. The zebrafish (Danio rerio) has emerged as a powerful model system for studying human hearing and balance disorders, since LL HC are structurally and functionally analogous to cochlear HCs, but are optically and pharmacologically accessible within an intact specimen. Complementing mammalian studies, zebrafish have been used to gain significant insights into many facets of HC biology, including mechanotransduction and synaptic physiology as well as mechanisms of both hereditary and acquired HC dysfunction. With the rise of the zebrafish LL as a model in which to study auditory system function and disease, there has been an increased interest in studying its efferent system and evaluate the similarity between mammalian and piscine efferent synapses. Advances derived from studies in zebrafish include understanding the effect of the LL efferent system on HC and afferent activity, and revealing that an α9-containing nAChR, functionally coupled to SK channels, operates at the LL efferent synapse. In this review, we discuss the tools and findings of these recent investigations into zebrafish efferent-HC synapse, their commonalities with the mammalian counterpart and discuss several emerging areas for future studies.

Activity in each brain region is shaped by the convergence of ascending and descending axonal pathways, and the balance and characteristics of these determine the neural output. The medial olivocochlear (MOC) efferent system is part of a reflex arc that critically controls auditory sensitivity. Multiple central pathways contact MOC neurons, raising the question of how a reflex arc could be engaged by diverse inputs. We examined functional properties of synapses onto brainstem MOC neurons from ascending (ventral cochlear nucleus, VCN) and descending (inferior colliculus, IC) sources in mice using an optogenetic approach. We found that these pathways exhibited opposing forms of short-term plasticity, with the VCN input showing depression and the IC input showing marked facilitation. By using a conductance-clamp approach, we found that combinations of facilitating and depressing inputs enabled firing of MOC neurons over a surprisingly wide dynamic range, suggesting an essential role for descending signaling to a brainstem nucleus.

The massive network of descending corticofugal projections has been long-recognized by anatomists, but their functional contributions to sound processing and auditory-guided behaviors remain a mystery. Most efforts to characterize the auditory corticofugal system have been inductive; wherein function is inferred from a few studies employing a wide range of methods to manipulate varying limbs of the descending system in a variety of species and preparations. An alternative approach, which we focus on here, is to first establish auditory-guided behaviors that reflect the contribution of top-down influences on auditory perception. To this end, we postulate that auditory corticofugal systems may contribute to active listening behaviors in which the timing of bottom-up sound cues can be predicted from top-down signals arising from cross-modal cues, temporal integration, or self-initiated movements. Here, we describe a behavioral framework for investigating how auditory perceptual performance is enhanced when subjects can anticipate the timing of upcoming target sounds. Our first paradigm, studied both in human subjects and mice, reports species-specific differences in visually cued expectation of sound onset in a signal-in-noise detection task. A second paradigm performed in mice reveals the benefits of temporal regularity as a perceptual grouping cue when detecting repeating target tones in complex background noise. A final behavioral approach demonstrates significant improvements in frequency discrimination threshold and perceptual sensitivity when auditory targets are presented at a predictable temporal interval following motor self-initiation of the trial. Collectively, these three behavioral approaches identify paradigms to study top-down influences on sound perception that are amenable to head-fixed preparations in genetically tractable animals, where it is possible to monitor and manipulate particular nodes of the descending auditory pathway with unparalleled precision. [ABSTRACT FROM AUTHOR]

White adipose tissue (WAT) stores energy and also plays an important endocrine role in producing adipokines for communication with the peripheral and central nervous system. WAT consists of the major lipogenic unilocular adipocytes and the minor populations of beige and brite multilocular adipocytes. These multilocular adipocytes express thermogenic genes and have phenotypic similarity with thermogenic brown adipose tissue. According to a current paradigm, multilocular adipocytes have a thermogenic function in WAT. In this mini review, we discuss data revealing heterogeneity among multilocular cell subsets in WAT and their functions beyond thermogenesis. We propose a hypothetical neuroendocrine role for multilocular adipocytes subsets in the formation of adaptive sensory-sympathetic circuits between the central nervous system and adipose tissue, which activate lipolysis and thermogenesis in WAT in high energy demand situations.

Traditional cognitive linguistic theories acknowledge that human emotions are embodied, yet they fail to distinguish the dimensions that reflect the direction of neural signaling between the brain and body. Differences exist across languages and cultures in whether embodied emotions are conceptualized as afferent (feelings from the body) or efferent (enacted through the body). This important distinction has been neglected in academic discourse, arguably as a consequence of the ‘lexical approach’, and the dominance within the affective psychology of the cognitive and semantic models that overlook the role of interoception as an essential component of affective experience. Empirical and theoretical advances in human neuroscience are driving a reappraisal of the relationships between the mind, brain and body, with particular relevance to emotions. Allostatic (predictive) control of the internal bodily states is considered fundamental to the experience of emotions enacted through interoceptive sensory feelings and through the evoked physiological and physical actions mediated through efferent neural pathways. Embodied emotion concepts encompass these categorized outcomes of bidirectional brain–body interactions yet can be differentiated further into afferent or interoceptive and efferent or autonomic processes. Between languages, a comparison of emotion words indicates the dominance of afferent or interoceptive processes in how embodied emotions are conceptualized in Chinese, while efferent or autonomic processes feature more commonly in English. Correspondingly, in linguistic expressions of emotion, Chinese-speaking people are biased toward being more receptive, reflective, and adaptive, whereas native English speakers may tend to be more reactive, proactive, and interactive. Arguably, these distinct conceptual models of emotions may shape the perceived divergent values and ‘national character’ of Chinese- and English-speaking cultures.

Functional outcomes of medial olivocochlear reflex (MOCR) activation, such as improved hearing in background noise and protection from noise damage, involve moderate to high sound levels. Previous noninvasive measurements of MOCR in humans focused primarily on otoacoustic emissions (OAEs) evoked at low sound levels. Interpreting MOCR effects on OAEs at higher levels is complicated by the possibility of the middle-ear muscle reflex and by components of OAEs arising from different locations along the length of the cochlear spiral. We overcame these issues by presenting click stimuli at a very slow rate and by time-frequency windowing the resulting click-evoked (CE)OAEs into short-latency (SL) and long-latency (LL) components. We characterized the effects of MOCR on CEOAE components using multiple measures to more comprehensively assess these effects throughout much of the dynamic range of hearing. These measures included CEOAE amplitude attenuation, equivalent input attenuation, phase, and slope of growth functions. Results show that MOCR effects are smaller on SL components than LL components, consistent with SL components being generated slightly basal of the characteristic frequency region. Amplitude attenuation measures showed the largest effects at the lowest stimulus levels, but slope change and equivalent input attenuation measures did not decrease at higher stimulus levels. These latter measures are less commonly reported and may provide insight into the variability in listening performance and noise susceptibility seen across individuals. NEW & NOTEWORTHY The auditory efferent system, operating at moderate to high sound levels, may improve hearing in background noise and provide protection from noise damage. We used otoacoustic emissions to measure these efferent effects across a wide range of sound levels and identified level-dependent and independent effects. Previous reports have focused on level-dependent measures. The level-independent effects identified here may provide new insights into the functional relevance of auditory efferent activity in humans. [ABSTRACT FROM AUTHOR]

Background: A long-standing debate concerns where in the processing hierarchy of the central nervous system (CNS) selective attention takes effect. In the auditory system, cochlear processes can be influenced via direct and mediated (by the inferior colliculus) projections from the auditory cortex to the superior olivary complex (SOC). Studies illustrating attentional modulations of cochlear responses have so far been limited to sound-evoked responses. The aim of the present study is to investigate intermodal (audiovisual) selective attention in humans simultaneously at the cortical and cochlear level during a stimulus-free cue-target interval. Results: We found that cochlear activity in the silent cue-target intervals was modulated by a theta-rhythmic pattern (~ 6 Hz). While this pattern was present independently of attentional focus, cochlear theta activity was clearly enhanced when attending to the upcoming auditory input. On a cortical level, classical posterior alpha and beta power enhancements were found during auditory selective attention. Interestingly, participants with a stronger release of inhibition in auditory brain regions show a stronger attentional modulation of cochlear theta activity. Conclusions: These results hint at a putative theta-rhythmic sampling of auditory input at the cochlear level. Furthermore, our results point to an interindividual variable engagement of efferent pathways in an attentional context that are linked to processes within and beyond processes in auditory cortical regions. [ABSTRACT FROM AUTHOR]

The lateral line (LL) is a sensory system that allows fish and amphibians to detect water currents. LL responsiveness is modulated by efferent neurons that aid in distinguishing between external and self-generated stimuli, maintaining sensitivity to relevant cues. One component of the efferent system is cholinergic, the activation of which inhibits afferent activity. LL hair cells (HCs) share structural, functional, and molecular similarities with those of the cochlea, making them a popular model for studying human hearing and balance disorders. Because of these commonalities, one could propose that the receptor at the LL efferent synapse is a α9α10 nicotinic acetylcholine receptor (nAChR). However, the identities of the molecular players underlying ACh-mediated inhibition in the LL remain unknown. Surprisingly, through the analysis of single-cell expression studies and in situ hybridization, we describe that α9, but not the α10, subunits are enriched in zebrafish HCs. Moreover, the heterologous expression of zebrafish α9 subunits indicates that homomeric receptors are functional and exhibit robust AChgated currents blocked by a-bungarotoxin and strychnine. In addition, in vivo Ca21 imaging on mechanically stimulated zebrafish LL HCs show that ACh elicits a decrease in evoked Ca21 signals, regardless of HC polarity. This effect is blocked by both a-bungarotoxin and apamin, indicating coupling of ACh-mediated effects to small-conductance Ca21-activated potassium (SKs) channels. Our results indicate that an α9-containing (α9p) nAChR operates at the zebrafish LL efferent synapse. Moreover, the activation of α9p nAChRs most likely leads to LL HC hyperpolarization served by SK channels. [ABSTRACT FROM AUTHOR]

The present paper considers recent progress in our understanding of the afferent/ascending neural pathways and neural circuits of interoception. Of particular note is the extensive role of rostral neural systems, including cortical systems, in the recognition of internal body states, and the reciprocal role of efferent/descending systems in the regulation of those states. Together these reciprocal interacting networks entail interoceptive circuits that play an important role in a broad range of functions beyond the homeostatic maintenance of physiological steady-states. These include the regulation of behavioral, cognitive, and affective processes across conscious and nonconscious levels of processing. We highlight recent advances and knowledge gaps that are important for accelerating progress in the study of interoception. The nervous system receives ascending communication of interoceptive signals originating from the periphery via chemoreceptor, mechanoreceptor, and osmoreceptor pathways, several of which were discovered only recently. Visceral systems and associated interoceptive signals are regulated in part by descending central nervous system (CNS) control of the autonomic nervous system, yielding a reciprocal circuit that regulates bodily organs and a wide array of motor, cognitive, and affective processes. A gap in our understanding of how interoceptive signals are relayed through the CNS from the body centers on inputs to the nucleus tractus solitarius and higher relay pathways. The neural circuits of interoception are important for behavioral, cognitive, and emotional regulation across conscious and nonconscious levels of processing. [ABSTRACT FROM AUTHOR]

Olivocochlear neurons make temporary cholinergic synapses on inner hair cells of the rodent cochlea in the first 2 to 3 wk after birth. Repetitive stimulation of these efferent neurons causes facilitation of evoked release and increased spontaneous release that continues for seconds to minutes. Presynaptic nicotinic acetylcholine receptors (nAChRs) are known to modulate neurotransmitter release from brain neurons. The present study explores the hypothesis that presynaptic nAChRs help to increase spontaneous release from efferent terminals on cochlear hair cells. Direct application of nicotine (which does not activate the hair cells’ α9α10-containing nAChRs) produces sustained efferent transmitter release, implicating presynaptic nAChRs in this response. The effect of nicotine was reduced by application of ryanodine that reduces release of calcium from intraterminal stores. NEW & NOTEWORTHY Sensory organs exhibit spontaneous activity before the onset of response to external stimuli. Such activity in the cochlea is subject to modulation by cholinergic efferent neurons that directly inhibit sensory hair cells (inner hair cells). Those efferent neurons are themselves subject to various modulatory mechanisms. One such mechanism is positive feedback by released acetylcholine onto presynaptic nicotinic acetylcholine receptors causing further release of acetylcholine. [ABSTRACT FROM AUTHOR]

Activation of GABAB receptors results in excitatory modulation of calyx terminals in rat semicircular canal cristae. J Neurophysiol 124: 962-972, 2020. First published August 20, 2020; doi:10.1152/jn.00243.2020.--Previous studies have found GABA in vestibular end organs. However, existence of GABA receptors or possible GABAergic effects on vestibular nerve afferents has not been investigated. The current study was conducted to determine whether activation of GABAB receptors affects calyx afferent terminals in the central region of the cristae of semicircular canals. We used patch-clamp recording in postnatal day 13-18 (P13-P18) Sprague-Dawley rats of either sex. Application of GABAB receptor agonist baclofen inhibited voltage-sensitive potassium currents. This effect was blocked by selective GABAB receptor antagonist CGP 35348. Application of antagonists of small (SK)- and large-conductance potassium (BK) channels almost completely blocked the effects of baclofen. The remaining baclofen effect was blocked by cadmium chloride, suggesting that it could be due to inhibition of voltage-gated calcium channels. Furthermore, baclofen had no effect in the absence of calcium in the extracellular fluid. Inhibition of potassium currents by GABAB activation resulted in an excitatory effect on calyx terminal action potential firing. While in the control condition calyces could only fire a single action potential during step depolarizations, in the presence of baclofen they fired continuously during steps and a few even showed repetitive discharge. We also found a decrease in threshold for action potential generation and a decrease in first-spike latency during step depolarization. These results provide the first evidence for the presence of GABAB receptors on calyx terminals, showing that their activation results in an excitatory effect and that GABA inputs could be used to modulate calyx response properties. [ABSTRACT FROM AUTHOR]

In the vestibular peripheral organs, type I and type II hair cells (HCs) transmit incoming signals via glutamatergic quantal transmission onto afferent nerve fibers. Additionally, type I HCs transmit via “non-quantal” transmission to calyx afferent fibers, by accumulation of glutamate and potassium in the synaptic cleft. Vestibular efferent inputs originating in the brainstem contact type II HCs and vestibular afferents. Here, synaptic inputs to type II HCs were characterized by using electrical and optogenetic stimulation of efferent fibers combined with in vitro whole cell patch-clamp recording from type II HCs in the rodent vestibular crista. Properties of efferent synaptic currents in type II HCs were similar to those found in cochlear HCs and mediated by activation of α9-containing nicotinic acetylcholine receptors (nAChRs) and small-conductance calciumactivated potassium (SK) channels. While efferents showed a low probability of release at low frequencies of stimulation, repetitive stimulation resulted in facilitation and increased probability of release. Notably, the membrane potential of type II HCs during optogenetic stimulation of efferents showed a strong hyperpolarization in response to single pulses and was further enhanced by repetitive stimulation. Such efferent-mediated inhibition of type II HCs can provide a mechanism to adjust the contribution of signals from type I and type II HCs to vestibular nerve fibers, with a shift of the response to be more like that of calyx-only afferents with faster non-quantal responses. [ABSTRACT FROM AUTHOR]

Medial olivocochlear (MOC) efferent neurons in the brainstem comprise the final stage of descending control of the mammalian peripheral auditory system through axon projections to the cochlea. MOC activity adjusts cochlear gain and frequency tuning, and protects the ear from acoustic trauma. The neuronal pathways that activate and modulate the MOC somata in the brainstem to drive these cochlear effects are poorly understood. Evidence suggests that MOC neurons are primarily excited by sound stimuli in a three-neuron activation loop from the auditory nerve via an intermediate neuron in the cochlear nucleus. Anatomical studies suggest that MOC neurons receive diverse synaptic inputs, but the functional effect of additional synaptic influences on MOC neuron responses is unknown. Here we use patch-clamp electrophysiological recordings from identified MOC neurons in brainstem slices from mice of either sex to demonstrate that in addition to excitatory glutamatergic synapses, MOC neurons receive inhibitory GABAergic and glycinergic synaptic inputs. These synapses are activated by electrical stimulation of axons near the medial nucleus of the trapezoid body (MNTB). Focal glutamate uncaging confirms MNTB neurons as a source of inhibitory synapses onto MOC neurons. MNTB neurons inhibit MOC action potentials, but this effect depresses with repeat activation. This work identifies a new pathway of connectivity between brainstem auditory neurons and indicates that MOC neurons are both excited and inhibited by sound stimuli received at the same ear. The pathway depression suggests that the effect of MNTB inhibition of MOC neurons diminishes over the course of a sustained sound. [ABSTRACT FROM AUTHOR]

After a yeast two-hybrid screen identified prosaposin as a potential interacting protein with the nicotinic acetylcholine receptor (nAChR) subunit alpha 10, studies were performed to characterize prosaposin in the normal rodent inner ear. Prosaposin demonstrates diffuse organ of Corti expression at birth, with gradual localization to the inner hair cells (IHCs) and its supporting cells, inner pillar cells, and synaptic region of the outer hair cells (OHCs) and Deiters' cells (DCs) by postnatal day 21 (P21). Microdissected OHC and DC quantitative reverse transcriptase-PCR and immunohistology localizes prosaposin mRNA to DCs and OHCs, and protein predominantly to the apex of the DCs. Subsequent studies in a prosaposin knock-out (KO) (-/-) mouse showed intact but slightly reduced hearing through P19, but deafness by P25 and reduced distortion product otoacoustic emissions from P15 onward. Beginning at P12, the prosaposin KO mice showed histologic organ of Corti changes including cellular hypertrophy in the region of the IHC and greater epithelial ridge, a loss of OHCs from cochlear apex, and vacuolization of OHCs. Immunofluorescence revealed exuberant overgrowth of auditory afferent neurites in the region of the IHCs and proliferation of auditory efferent neurites in the region of the tunnel of Corti. IHC recordings from these KO mice showed normal I-V curves and responses to applied acetylcholine. Together, these results suggest that prosaposin helps maintain normal innervation patterns to the organ of Corti. Furthermore, prosaposin's overlapping developmental expression pattern and binding capacity toward the nAChR alpha 10 suggest that alpha 10 may also play a role in this function.

Keywords: afferent; efferent; auditory; descending control; memory; sound; BEAMS EN afferent efferent auditory descending control memory sound BEAMS 1 3 3 10/25/21 20211018 NES 211018 Once upon a time, I spent hours threading microelectrodes into auditory cortex neurons and counting spikes as the rabbits learned a tone-signaled task. A one-sentence theme of this special issue and of our knowledge of descending control in the auditory system could be "the hearing brain is vast." There is a range of plasticity across the auditory system - a continuum between stability and mutability. [Extracted from the article]