Central circuitry and function of the cochlear efferent systems.

The cochlear efferent system comprises multiple populations of brainstem neurons whose axons project to the cochlea, and whose responses to acoustic stimuli lead to regulation of auditory sensitivity. The major groups of efferent neurons are found in the superior olivary complex and are likely activated by neurons of the cochlear nucleus, thus forming a simple reflex pathway back to the cochlea. The peripheral actions of only one of these efferent cell types has been well described. Moreover, the efferent neurons are not well understood at the cellular- and circuit-levels. For example, ample demonstration of descending projections to efferent neurons raises the question of whether these additional inputs constitute a mechanism for modulation of relay function or instead play a more prominent role in driving the efferent response. Related to this is the question of synaptic plasticity at these synapses, which has the potential to differentially scale the degree of efferent activation across time, depending on the input pathway. This review will explore central nervous system aspects of the efferent system, the physiological properties of the neurons, their synaptic inputs, their modulation, and the effects of efferent axon collaterals within the brainstem.

Synaptic plasticity of inhibitory synapses onto medial olivocochlear efferent neurons.

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.

Efferent neurons control hearing sensitivity and protect hearing from noise through the regulation of gap junctions between cochlear supporting cells.

It is critical for hearing that the descending cochlear efferent system provides a negative feedback to hair cells to regulate hearing sensitivity and protect hearing from noise. The medial olivocochlear (MOC) efferent nerves project to outer hair cells (OHCs) to regulate OHC electromotility, which is an active cochlear amplifier and can increase hearing sensitivity. Here, we report that the MOC efferent nerves also could innervate supporting cells (SCs) in the vicinity of OHCs to regulate hearing sensitivity. MOC nerve fibers are cholinergic, and acetylcholine (ACh) is a primary neurotransmitter. Immunofluorescent staining showed that MOC nerve endings, presynaptic vesicular acetylcholine transporters (VAChTs), and postsynaptic ACh receptors were visible at SCs and in the SC area. Application of ACh in SCs could evoke a typical inward current and reduce gap junctions (GJs) between them, which consequently enhanced the direct effect of ACh on OHCs to shift but not eliminate OHC electromotility. This indirect, GJ-mediated inhibition had a long-lasting influence. In vivo experiments further demonstrated that deficiency of this GJ-mediated efferent pathway decreased the regulation of active cochlear amplification and compromised the protection against noise. In particular, distortion product otoacoustic emission (DPOAE) showed a delayed reduction after noise exposure. Our findings reveal a new pathway for the MOC efferent system via innervating SCs to control active cochlear amplification and hearing sensitivity. These data also suggest that this SC GJ-mediated efferent pathway may play a critical role in long-term efferent inhibition and is required for protection of hearing from noise trauma.NEW & NOTEWORTHY The cochlear efferent system provides a negative feedback to control hair cell activity and hearing sensitivity and plays a critical role in noise protection. We reveal a new efferent control pathway in which medial olivocochlear efferent fibers have innervations with cochlear supporting cells to control their gap junctions, therefore regulating outer hair cell electromotility and hearing sensitivity. This supporting cell gap junction-mediated efferent control pathway is required for the protection of hearing from noise.

Axon initial segment geometry in relation to motoneuron excitability.

The axon initial segment (AIS) responsible for action potential initiation is a dynamic structure that varies and changes together with neuronal excitability. Like other neuron types, alpha motoneurons in the mammalian spinal cord express heterogeneity and plasticity in AIS geometry, including length (AISl) and distance from soma (AISd). The present study aimed to establish the relationship of AIS geometry with a measure of intrinsic excitability, rheobase current, that varies by 20-fold or more among normal motoneurons. We began by determining whether AIS length or distance differed for motoneurons in motor pools that exhibit different activity profiles. Motoneurons sampled from the medial gastrocnemius (MG) motor pool exhibited values for average AISd that were significantly greater than that for motoneurons from the soleus (SOL) motor pool, which is more readily recruited in low-level activities. Next, we tested whether AISd covaried with intrinsic excitability of individual motoneurons. In anesthetized rats, we measured rheobase current intracellularly from MG motoneurons in vivo before labeling them for immunohistochemical study of AIS structure. For 16 motoneurons sampled from the MG motor pool, this combinatory approach revealed that AISd, but not AISl, was significantly related to rheobase, as AIS tended to be located further from the soma on motoneurons that were less excitable. Although a causal relation with excitability seems unlikely, AISd falls among a constellation of properties related to the recruitability of motor units and their parent motoneurons.

Different contributions of efferent and reafferent feedback to sensorimotor temporal recalibration.

Adaptation to delays between actions and sensory feedback is important for efficiently interacting with our environment. Adaptation may rely on predictions of action-feedback pairing (motor-sensory component), or predictions of tactile-proprioceptive sensation from the action and sensory feedback of the action (inter-sensory component). Reliability of temporal information might differ across sensory feedback modalities (e.g. auditory or visual), which in turn influences adaptation. Here, we investigated the role of motor-sensory and inter-sensory components on sensorimotor temporal recalibration for motor-auditory (button press-tone) and motor-visual (button press-Gabor patch) events. In the adaptation phase of the experiment, action-feedback pairs were presented with systematic temporal delays (0 ms or 150 ms). In the subsequent test phase, audio/visual feedback of the action were presented with variable delays. The participants were then asked whether they detected a delay. To disentangle motor-sensory from inter-sensory component, we varied movements (active button press or passive depression of button) at adaptation and test. Our results suggest that motor-auditory recalibration is mainly driven by the motor-sensory component, whereas motor-visual recalibration is mainly driven by the inter-sensory component. Recalibration transferred from vision to audition, but not from audition to vision. These results indicate that motor-sensory and inter-sensory components contribute to recalibration in a modality-dependent manner.

The early development and physiology of Xenopus laevis tadpole lateral line system.

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.

Impact of anesthesia and sex on sympathetic efferent and hemodynamic responses to renal chemo- and mechanosensitive stimuli.

Activation of renal sensory nerves by chemo- and mechanosensitive stimuli produces changes in efferent sympathetic nerve activity (SNA) and arterial blood pressure (ABP). Anesthesia and sex influence autonomic function and cardiovascular hemodynamics, but it is unclear to what extent anesthesia and sex impact SNA and ABP responses to renal sensory stimuli. We measured renal, splanchnic, and lumbar SNA and ABP in male and female Sprague-Dawley rats during contralateral renal infusion of capsaicin and bradykinin or during elevation in renal pelvic pressure. Responses were evaluated with a decerebrate preparation or Inactin, urethane, or isoflurane anesthesia. Intrarenal arterial infusion of capsaicin (0.1-30.0 µM) increased renal SNA, splanchnic SNA, or ABP but decreased lumbar SNA in the Inactin group. Intrarenal arterial infusion of bradykinin (0.1-30.0 µM) increased renal SNA, splanchnic SNA, and ABP but decreased lumbar SNA in the Inactin group. Elevated renal pelvic pressure (0-20 mmHg, 30 s) significantly increased renal SNA and splanchnic SNA but not lumbar SNA in the Inactin group. In marked contrast, SNA and ABP responses to every renal stimulus were severely blunted in the urethane and decerebrate groups and absent in the isoflurane group. In the Inactin group, the magnitude of SNA responses to chemo- and mechanosensory stimuli were not different between male and female rats. Thus, chemo- and mechanosensitive stimuli produce differential changes in renal, splanchnic, and lumbar SNA. Experimentally, future investigations should consider Inactin anesthesia to examine sympathetic and hemodynamic responses to renal sensory stimuli.NEW & NOTEWORTHY The findings highlight the impact of anesthesia, and to a lesser extent sex, on sympathetic efferent and hemodynamic responses to chemosensory and mechanosensory renal stimuli. Sympathetic nerve activity (SNA) and arterial blood pressure (ABP) responses were present in Inactin-anesthetized rats but largely absent in decerebrate, isoflurane, or urethane preparations. Renal chemosensory stimuli differentially changed SNA: renal and splanchnic SNA increased, but lumbar SNA decreased. Future investigations should consider Inactin anesthesia to study SNA and hemodynamic responses to renal sensory nerve activation.

Distinct forms of synaptic plasticity during ascending vs descending control of medial olivocochlear efferent neurons.

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.

Projections from the ventral nucleus of the lateral lemniscus to the cochlea in the mouse.

Auditory efferents originate in the central auditory system and project to the cochlea. Although the specific anatomy of the olivocochlear (OC) efferents can vary between species, two types of auditory efferents have been identified based upon the general location of their cell bodies and their distinctly different axon terminations in the organ of Corti. In the mouse, the relatively small somata of the lateral (LOC) efferents reside in the lateral superior olive (LSO), have unmyelinated axons, and terminate around ipsilateral inner hair cells (IHCs), primarily against the afferent processes of type I auditory nerve fibers. In contrast, the larger somata of the medial (MOC) efferents are distributed in the ventral nucleus of the trapezoid body (VNTB), have myelinated axons, and terminate bilaterally against the base of multiple outer hair cells (OHCs). Using in vivo retrograde cell body marking, anterograde axon tracing, immunohistochemistry, and electron microscopy, we have identified a group of efferent neurons in mouse, whose cell bodies reside in the ventral nucleus of the lateral lemniscus (VNLL). By virtue of their location, we call them dorsal efferent (DE) neurons. Labeled DE cells were immuno-negative for tyrosine hydroxylase, glycine, and GABA, but immuno-positive for choline acetyltransferase. Morphologically, DEs resembled LOC efferents by their small somata, unmyelinated axons, and ipsilateral projection to IHCs. These three classes of efferent neurons all project axons directly to the cochlea and exhibit cholinergic staining characteristics. The challenge is to discover the contributions of this new population of neurons to auditory efferent function.

Mechanism behind the neuronal ephaptic coupling during synchronizing by specific brain-triggered wave as neuronal motor toolkit.

Probable mechanism behind the neuronal ephaptic coupling is investigated based on the introduction of "Brain"-triggered potential excitation signal smartly with a specific very low frequency (VLF) waves as a neuronal motor toolkit. Detection of this electric motor toolkit is attributed to in-vitro precise analyses of a neural network of snail, along to the disconnected snail's neuronal network as a control. This is achieved via rapid (real-time) electrical signals acquisition by blind patch-clamp method during micro-electrode implanting in the neurons at the gigaseal conditions by the surgery operations. This process is based on its waveform (potential excitation signal) detection by mathematical curve fitting process. The characterized waveform of this electrical signal is "Saw Tooth" that is smartly stimulated, alternatively, by the brain during triggering the action potential's (AP's) hyperpolarization zone at a certain time interval at the several µs levels. Triggering the neuron cells results in (1) observing a positive shift (10.0%, depending on the intensity of the triggering wave), and (2) major promotion in the electrical current from sub nano (n) to micro (µ) amper (nA, µA) levels. Direct tracing the time domain (i.e., electrical signal vs. time) and estimation of the frequency domain (diagram of electrical response vs. the applied electrical frequencies) by the "Discrete Fast Fourier Transform" algorithm approve the presence of bilateral and reversible electrical currents between axon and dendrite. This mechanism therefore opens a novel view about the neuronal motor toolkit mechanism, versus the general knowledge about the unilateral electrical current flow from axon to dendrite operations in as neural network. The reliability of this mechanism is evaluated via (1) sequential modulation and demodulation of the snail's neuron network by a simulation electrical functions and sequentially evaluation of the neuronal current sensitivity between pA and nA (during the promotion of the signal-to-noise ratio, via averaging of 30 ± 1 (n = 15) and recycling the electrical cycles before any neuronal response); and (2) operation of the process on the differentiated stem cells. The interstice behavior is attributed to the effective role of Ca2+ channels (besides Na+ and K+ ionic pumping), during hyper/hypo calcium processes, evidenced by inductively coupled plasma as the selected analytical method. This phenomenon is also modeled during proposing quadrupole well potential levels in the neuron systems. This mechanism therefore points to the microprocessor behavior of neuron networks. Stimulation of the neuronal system based on this mechanism, not only controls the sensitivity of neuron electrical stimulation, but also would open a light window for more efficient operating the neuronal connectivity during providing interruptions by phenomena such as neurolysis as well as an efficient treatment of neuron-based disorders.

Mimicking efferent nerves using a graphdiyne-based artificial synapse with multiple ion diffusion dynamics.

A graphdiyne-based artificial synapse (GAS), exhibiting intrinsic short-term plasticity, has been proposed to mimic biological signal transmission behavior. The impulse response of the GAS has been reduced to several millivolts with competitive femtowatt-level consumption, exceeding the biological level by orders of magnitude. Most importantly, the GAS is capable of parallelly processing signals transmitted from multiple pre-neurons and therefore realizing dynamic logic and spatiotemporal rules. It is also found that the GAS is thermally stable (at 353 K) and environmentally stable (in a relative humidity up to 35%). Our artificial efferent nerve, connecting the GAS with artificial muscles, has been demonstrated to complete the information integration of pre-neurons and the information output of motor neurons, which is advantageous for coalescing multiple sensory feedbacks and reacting to events. Our synaptic element has potential applications in bioinspired peripheral nervous systems of soft electronics, neurorobotics, and biohybrid systems of brain-computer interfaces.

The mammalian efferent vestibular system utilizes cholinergic mechanisms to excite primary vestibular afferents.

Electrical stimulation of the mammalian efferent vestibular system (EVS) predominantly excites primary vestibular afferents along two distinct time scales. Although roles for acetylcholine (ACh) have been demonstrated in other vertebrates, synaptic mechanisms underlying mammalian EVS actions are not well-characterized. To determine if activation of ACh receptors account for efferent-mediated afferent excitation in mammals, we recorded afferent activity from the superior vestibular nerve of anesthetized C57BL/6 mice while stimulating EVS neurons in the brainstem, before and after administration of cholinergic antagonists. Using a normalized coefficient of variation (CV*), we broadly classified vestibular afferents as regularly- (CV* < 0.1) or irregularly-discharging (CV* > 0.1) and characterized their responses to midline or ipsilateral EVS stimulation. Afferent responses to efferent stimulation were predominantly excitatory, grew in amplitude with increasing CV*, and consisted of fast and slow components that could be identified by differences in rise time and post-stimulus duration. Both efferent-mediated excitatory components were larger in irregular afferents with ipsilateral EVS stimulation. Our pharmacological data show, for the first time in mammals, that muscarinic AChR antagonists block efferent-mediated slow excitation whereas the nicotinic AChR antagonist DHßE selectively blocks efferent-mediated fast excitation, while leaving the efferent-mediated slow component intact. These data confirm that mammalian EVS actions are predominantly cholinergic.

Development and migration of the zebrafish rhombencephalic octavolateral efferent neurons.

In vertebrate animals, motor and sensory efferent neurons carry information from the central nervous system (CNS) to peripheral targets. These two types of efferent systems sometimes bear a close resemblance, sharing common segmental organization, axon pathways, and chemical messengers. Here, we focus on the development of the octavolateral efferent neurons (OENs) and their interactions with the closely-related facial branchiomotor neurons (FBMNs) in zebrafish. Using live-imaging approaches, we investigate the birth, migration, and projection patterns of OENs. We find that OENs are born in two distinct groups: a group of rostral efferent neurons (RENs) that arises in the fourth segment, or rhombomere (r4), of the hindbrain and a group of caudal efferent neurons (CENs) that arises in r5. Both RENs and CENs then migrate posteriorly through the hindbrain between 18 and 48 hrs postfertilization, alongside the r4-derived FBMNs. Like the FBMNs, migration of the r4-derived RENs depends on function of the segmental identity gene hoxb1a; unlike the FBMNs, however, both OEN populations move independently of prickle1b. Further, we investigate whether the previously described "pioneer" neuron that leads FBMN migration through the hindbrain is an r4-derived FBMN/REN or an r5-derived CEN. Our experiments verify that the pioneer is an r4-derived neuron and reaffirm its role in leading FBMN migration across the r4/5 border. In contrast, the r5-derived CENs migrate independently of the pioneer. Together, these results indicate that the mechanisms OENs use to navigate the hindbrain differ significantly from those employed by FBMNs.

Operant conditioning of motor cortex neurons reveals neuron-subtype-specific responses in a brain-machine interface task.

Operant conditioning is implemented in brain-machine interfaces (BMI) to induce rapid volitional modulation of single neuron activity to control arbitrary mappings with an external actuator. However, intrinsic factors of the volitional controller (i.e. the brain) or the output stage (i.e. individual neurons) might hinder performance of BMIs with more complex mappings between hundreds of neurons and actuators with multiple degrees of freedom. Improved performance might be achieved by studying these intrinsic factors in the context of BMI control. In this study, we investigated how neuron subtypes respond and adapt to a given BMI task. We conditioned single cortical neurons in a BMI task. Recorded neurons were classified into bursting and non-bursting subtypes based on their spike-train autocorrelation. Both neuron subtypes had similar improvement in performance and change in average firing rate. However, in bursting neurons, the activity leading up to a reward increased progressively throughout conditioning, while the response of non-bursting neurons did not change during conditioning. These results highlight the need to characterize neuron-subtype-specific responses in a variety of tasks, which might ultimately inform the design and implementation of BMIs.

Nicotine evoked efferent transmitter release onto immature cochlear inner hair cells.

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.

Efferent synaptic transmission at the vestibular type II hair cell synapse.

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 calcium-activated 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.NEW & NOTEWORTHY Type II vestibular hair cells (HCs) receive inputs from efferent neurons in the brain stem. We used in vitro optogenetic and electrical stimulation of vestibular efferent fibers to study their synaptic inputs to type II HCs. Stimulation of efferents inhibited type II HCs, similar to efferent effects on cochlear HCs. We propose that efferent inputs adjust the contribution of signals from type I and II HCs to vestibular nerve fibers.

Functional Postnatal Maturation of the Medial Olivocochlear Efferent-Outer Hair Cell Synapse.

The organ of Corti, the auditory mammalian sensory epithelium, contains two types of mechanotransducer cells, inner hair cells (IHCs) and outer hair cells (OHCs). IHCs are involved in conveying acoustic stimuli to the CNS, while OHCs are implicated in the fine tuning and amplification of sounds. OHCs are innervated by medial olivocochlear (MOC) cholinergic efferent fibers. The functional characteristics of the MOC-OHC synapse during maturation were assessed by electrophysiological and pharmacological methods in mouse organs of Corti at postnatal day 11 (P11)-P13, hearing onset in altricial rodents, and at P20-P22 when the OHCs are morphologically and functionally mature. Synaptic currents were recorded in whole-cell voltage-clamped OHCs while electrically stimulating the MOC fibers. A progressive increase in the number of functional MOC-OHC synapses, as well as in their strength and efficacy, was observed between P11-13 and P20-22. At hearing onset, the MOC-OHC synapse presented facilitation during MOC fibers high-frequency stimulation that disappeared at mature stages. In addition, important changes were found in the VGCC that are coupled to transmitter release. Ca2+ flowing in through L-type VGCCs contribute to trigger ACh release together with P/Q- and R-type VGCCs at P11-P13, but not at P20-P22. Interestingly, N-type VGCCs were found to be involved in this process at P20-P22, but not at hearing onset. Moreover, the degree of compartmentalization of calcium channels with respect to BK channels and presynaptic release components significantly increased from P11-P13 to P20-P22. These results suggest that the MOC-OHC synapse is immature at the onset of hearing.SIGNIFICANCE STATEMENT The functional expression of both VGCCs and BK channels, as well as their localization with respect to the presynaptic components involved in transmitter release, are key elements in determining synaptic efficacy. In this work, we show dynamic changes in the expression of VGCCs and Ca2+-dependent BK K+ channels coupled to ACh release at the MOC-OHC synapse and their shift in compartmentalization during postnatal maturation. These processes most likely set the short-term plasticity pattern and reliability of the MOC-OHC synapse on high-frequency activity.

Divergent Neural Pathways Emanating from the Lateral Parabrachial Nucleus Mediate Distinct Components of the Pain Response.

The lateral parabrachial nucleus (lPBN) is a major target of spinal projection neurons conveying nociceptive input into supraspinal structures. However, the functional role of distinct lPBN efferents in diverse nocifensive responses have remained largely uncharacterized. Here we show that that the lPBN is required for escape behaviors and aversive learning to noxious stimulation. In addition, we find that two populations of efferent neurons from different regions of the lPBN collateralize to distinct targets. Activation of efferent projections to the ventromedial hypothalamus (VMH) or lateral periaqueductal gray (lPAG) drives escape behaviors, whereas activation of lPBN efferents to the bed nucleus stria terminalis (BNST) or central amygdala (CEA) generates an aversive memory. Finally, we provide evidence that dynorphin-expressing neurons, which span cytoarchitecturally distinct domains of the lPBN, are required for aversive learning.

Exploring the role of nerves in asthma; insights from the study of cough.

Cough in asthma predicts disease severity, prognosis, and is a common and troublesome symptom. Cough is the archetypal airway neuronal reflex, yet little is understood about the underlying neuronal mechanisms. It is generally assumed that symptoms arise because of airway hyper-responsiveness and/or airway inflammation, but despite using inhaled corticosteroids and bronchodilators targeting these pathologies, a large proportion of patients have persistent coughing. This review focuses on the prevalence and impact of cough in asthma and explores data from pre-clinical and clinical studies which have explored neuronal mechanisms of cough and asthma. We present evidence to suggest patients with asthma have evidence of neuronal dysfunction, which is further heightened and exaggerated by both bronchoconstriction and airway eosinophilia. Identifying patients with excessive coughing with asthma may represent a neuro-phenotype and hence developing treatment for this symptom is important for reducing the burden of disease on patients' lives and currently represents a major unmet clinical need.

Contralateral suppression of otoacoustic emissions in pre-school children.

BACKGROUND: Contralateral suppression of otoacoustic emissions (OAEs) may serve as an index of the medial olivocochlear (MOC) reflex. To date, this index has been studied in various populations but never in pre-school children. The purpose of this study was to fill this gap and describe how the MOC reflex affects the properties of transiently evoked OAEs (TEOAEs) in this age group. In addition, the influence of the presence of spontaneous OAEs (SOAEs) in the studied ear on the suppression of TEOAEs was also investigated. METHODS: TEOAEs with and without contralateral acoustic stimulation (CAS) by white noise were measured in 126 normally hearing pre-school children aged 3-6 years. The values of response levels, suppression by CAS, and signal-to-noise ratios (SNRs) of TEOAEs were investigated for the whole signal (global) and for half-octave frequency bands from 1 to 4 kHz. Only ears with SNR >6 dB were used in the analyses. SOAEs were acquired using the so-called synchronized SOAEs (SSOAEs) technique. RESULTS: Ears with SSOAEs had higher response levels and SNRs than ears without SSOAEs, and suppression was lower (0.58 dB compared to 0.85 dB). Only 22% of all studied ears had an SNR >20 dB, a level recommended in some studies for measuring suppression. There were no significant effects of age or gender on TEOAE suppression. CONCLUSIONS: Suppression levels for pre-school children did not differ appreciably from those of adults measured under similar conditions in other studies. Taken together with no effect of age in the data studied here, it seems that there is no effect of age on TEOAE suppression. However, we did find that the presence of SSOAEs had an effect on TEOAE suppression, a finding which has not been reported in earlier studies on different populations. We suggest that the presence of SSOAEs might be a crucial factor related to MOC function.