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1.
J Neurosci ; 44(33)2024 Aug 14.
Artículo en Inglés | MEDLINE | ID: mdl-38937103

RESUMEN

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 vivo-like 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.


Asunto(s)
Vías Auditivas , Núcleo Coclear , Inhibición Neural , Neuronas Eferentes , Animales , Ratones , Núcleo Coclear/fisiología , Núcleo Coclear/citología , Inhibición Neural/fisiología , Neuronas Eferentes/fisiología , Neuronas Eferentes/efectos de los fármacos , Vías Auditivas/fisiología , Femenino , Masculino , Nervio Coclear/fisiología , Técnicas de Placa-Clamp
2.
Hear Res ; 447: 109008, 2024 06.
Artículo en Inglés | MEDLINE | ID: mdl-38636186

RESUMEN

The auditory cortex is the source of descending connections providing contextual feedback for auditory signal processing at almost all levels of the lemniscal auditory pathway. Such feedback is essential for cognitive processing. It is likely that corticofugal pathways are degraded with aging, becoming important players in age-related hearing loss and, by extension, in cognitive decline. We are testing the hypothesis that surface, epidural stimulation of the auditory cortex during aging may regulate the activity of corticofugal pathways, resulting in modulation of central and peripheral traits of auditory aging. Increased auditory thresholds during ongoing age-related hearing loss in the rat are attenuated after two weeks of epidural stimulation with direct current applied to the surface of the auditory cortex for two weeks in alternate days (Fernández del Campo et al., 2024). Here we report that the same cortical electrical stimulation protocol induces structural and cytochemical changes in the aging cochlea and auditory brainstem, which may underlie recovery of age-degraded auditory sensitivity. Specifically, we found that in 18 month-old rats after two weeks of cortical electrical stimulation there is, relative to age-matched non-stimulated rats: a) a larger number of choline acetyltransferase immunoreactive neuronal cell body profiles in the ventral nucleus of the trapezoid body, originating the medial olivocochlear system.; b) a reduction of age-related dystrophic changes in the stria vascularis; c) diminished immunoreactivity for the pro-inflammatory cytokine TNFα in the stria vascularis and spiral ligament. d) diminished immunoreactivity for Iba1 and changes in the morphology of Iba1 immunoreactive cells in the lateral wall, suggesting reduced activation of macrophage/microglia; d) Increased immunoreactivity levels for calretinin in spiral ganglion neurons, suggesting excitability modulation by corticofugal stimulation. Altogether, these findings support that non-invasive neuromodulation of the auditory cortex during aging preserves the cochlear efferent system and ameliorates cochlear aging traits, including stria vascularis dystrophy, dysregulated inflammation and altered excitability in primary auditory neurons.


Asunto(s)
Envejecimiento , Corteza Auditiva , Vías Auditivas , Cóclea , Estimulación Eléctrica , Presbiacusia , Animales , Masculino , Factores de Edad , Envejecimiento/patología , Envejecimiento/metabolismo , Corteza Auditiva/metabolismo , Corteza Auditiva/fisiopatología , Vías Auditivas/fisiopatología , Vías Auditivas/metabolismo , Umbral Auditivo , Proteínas de Unión al Calcio , Colina O-Acetiltransferasa/metabolismo , Cóclea/inervación , Cóclea/metabolismo , Cóclea/fisiopatología , Cóclea/patología , Modelos Animales de Enfermedad , Potenciales Evocados Auditivos del Tronco Encefálico , Audición , Proteínas de Microfilamentos , Microglía/metabolismo , Microglía/patología , Neuronas Eferentes/metabolismo , Núcleo Olivar/metabolismo , Presbiacusia/fisiopatología , Presbiacusia/metabolismo , Presbiacusia/patología , Ratas Wistar , Factor de Necrosis Tumoral alfa/metabolismo
3.
Semin Cell Dev Biol ; 156: 210-218, 2024 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-37507330

RESUMEN

The vagus nerve vitally connects the brain and body to coordinate digestive, cardiorespiratory, and immune functions. Its efferent neurons, which project their axons from the brainstem to the viscera, are thought to comprise "functional units" - neuron populations dedicated to the control of specific vagal reflexes or organ functions. Previous research indicates that these functional units differ from one another anatomically, neurochemically, and physiologically but have yet to define their identity in an experimentally tractable way. However, recent work with genetic technology and single-cell genomics suggests that genetically distinct subtypes of neurons may be the functional units of the efferent vagus. Here we review how these approaches are revealing the organizational principles of the efferent vagus in unprecedented detail.


Asunto(s)
Neuronas Eferentes , Nervio Vago , Nervio Vago/metabolismo , Neuronas/fisiología
4.
Adv Anat Embryol Cell Biol ; 236: 111-129, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37955773

RESUMEN

The relationships between motor neurons and the skeletal muscle during development and in pathologic contexts are addressed in this Chapter.We discuss the developmental interplay of muscle and nervous tissue, through neurotrophins and the activation of differentiation and survival pathways. After a brief overview on muscular regulatory factors, we focus on the contribution of muscle to early and late neurodevelopment. Such a role seems especially intriguing in relation to the epigenetic shaping of developing motor neuron fate choices. In this context, emphasis is attributed to factors regulating energy metabolism, which may concomitantly act in muscle and neural cells, being involved in common pathways.We then review the main features of motor neuron diseases, addressing the cellular processes underlying clinical symptoms. The involvement of different muscle-associated neurotrophic factors for survival of lateral motor column neurons, innervating MyoD-dependent limb muscles, and of medial motor column neurons, innervating Myf5-dependent back musculature is discussed. Among the pathogenic mechanisms, we focus on oxidative stress, that represents a common and early trait in several neurodegenerative disorders. The role of organelles primarily involved in reactive oxygen species scavenging and, more generally, in energy metabolism-namely mitochondria and peroxisomes-is discussed in the frame of motor neuron degeneration.We finally address muscular involvement in amyotrophic lateral sclerosis (ALS), a multifactorial degenerative disorder, hallmarked by severe weight loss, caused by imbalanced lipid metabolism. Even though multiple mechanisms have been recognized to play a role in the disease, current literature generally assumes that the primum movens is neuronal degeneration and that muscle atrophy is only a consequence of such pathogenic event. However, several lines of evidence point to the muscle as primarily involved in the disease, mainly through its role in energy homeostasis. Data from different ALS mouse models strongly argue for an early mitochondrial dysfunction in muscle tissue, possibly leading to motor neuron disturbances. Detailed understanding of skeletal muscle contribution to ALS pathogenesis will likely lead to the identification of novel therapeutic strategies.


Asunto(s)
Esclerosis Amiotrófica Lateral , Tejido Nervioso , Animales , Ratones , Neuronas Motoras , Músculo Esquelético , Neuronas Eferentes
5.
Sci Rep ; 13(1): 13905, 2023 08 25.
Artículo en Inglés | MEDLINE | ID: mdl-37626145

RESUMEN

After an individual experiences a cervical cord injury, the cell body's adaptation to the smaller size of phrenic motoneurons occurs within several weeks. It is not known whether a routine hypercapnic load can alter this adaptation of phrenic motoneurons. We investigated this question by using rats with high cervical cord hemisection. The rats were divided into four groups: control, hypercapnia, sham, and sham hypercapnia. Within 72 h post-hemisection, the hypercapnia groups began a hypercapnic challenge (20 min/day, 4 times/week for 3 weeks) with 7% CO2 under awake conditions. After the 3-week challenge, the phrenic motoneurons in all of the rats were retrogradely labeled with horseradish peroxidase, and the motoneuron sizes in each group were compared. The average diameter, cross-sectional area, and somal surface area of stained phrenic motoneurons as analyzed by software were significantly smaller in only the control group compared to the other groups. The histogram distribution was unimodal, with larger between-group size differences for motoneurons in the horizontal plane than in the transverse plane. Our findings indicate that a routine hypercapnic challenge may increase the input to phrenic motoneurons and alter the propensity for motoneuron adaptations.


Asunto(s)
Hipercapnia , Neuronas Motoras , Animales , Ratas , Cuello , Neuronas Eferentes , Aclimatación
6.
J Neurophysiol ; 130(4): 883-894, 2023 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-37646076

RESUMEN

Estimating the state of tract-specific inputs to spinal motoneurons is critical to understanding movement deficits induced by neurological injury and potential pathways to recovery but remains challenging in humans. In this study, we explored the capability of trans-spinal magnetic stimulation (TSMS) to modulate distal reflex circuits in young adults. TSMS was applied over the thoracic spine to condition soleus H-reflexes involving sacral-level motoneurons. Three TSMS intensities below the motor threshold were applied at interstimulus intervals (ISIs) between 2 and 20 ms relative to peripheral nerve stimulation (PNS). Although low-intensity TSMS yielded no changes in H-reflexes across ISIs, the two higher stimulus intensities yielded two phases of H-reflex inhibition: a relatively long-lasting period at 2- to 9-ms ISIs, and a short phase at 11- to 12-ms ISIs. H-reflex inhibition at 2-ms ISI was uniquely dependent on TSMS intensity. To identify the candidate neural pathways contributing to H-reflex suppression, we constructed a tract-specific conduction time estimation model. Based upon our model, H-reflex inhibition at 11- to 12-ms ISIs is likely a manifestation of orthodromic transmission along the lateral reticulospinal tract. In contrast, the inhibition at 2-ms ISI likely reflects orthodromic transmission along sensory fibers with activation reaching the brain, before descending along motor tracts. Multiple pathways may contribute to H-reflex modulation between 4- and 9-ms ISIs, orthodromic transmission along sensorimotor tracts, and antidromic transmission of multiple motor tracts. Our findings suggest that noninvasive TSMS can influence motoneuron excitability at distal segments and that the contribution of specific tracts to motoneuron excitability may be distinguishable based on conduction velocities.NEW & NOTEWORTHY This study explored the capability of trans-spinal magnetic stimulation (TSMS) over the thoracic spine to modulate distal reflex circuits, H-reflexes involving sacral-level motoneurons, in young adults. TSMS induced two inhibition phases of H-reflex across interstimulus intervals (ISIs): a relatively long-lasting period at 2- to 9-ms ISIs, and a short phase at 11- to 12-ms ISIs. An estimated probability model constructed from tract-specific conduction velocities allowed the identification of potential spinal tracts contributing to the changes in motoneuron excitability.


Asunto(s)
Encéfalo , Sacro , Humanos , Adulto Joven , Neuronas Motoras , Neuronas Eferentes , Luz
7.
Brain Behav ; 13(8): e3064, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37401009

RESUMEN

INTRODUCTION: The efferent vestibular system (EVS) is a feedback circuit thought to modulate vestibular afferent activity by inhibiting type II hair cells and exciting calyx-bearing afferents in the peripheral vestibular organs. In a previous study, we suggested EVS activity may contribute to the effects of motion sickness. To determine an association between motion sickness and EVS activity, we examined the effects of provocative motion (PM) on c-Fos expression in brainstem efferent vestibular nucleus (EVN) neurons that are the source of efferent innervation in the peripheral vestibular organs. METHODS: c-Fos is an immediate early gene product expressed in stimulated neurons and is a well-established marker of neuronal activation. To study the effects of PM, young adult C57/BL6 wild-type (WT), aged WT, and young adult transgenic Chat-gCaMP6f mice were exposed to PM, and tail temperature (Ttail ) was monitored using infrared imaging. After PM, we used immunohistochemistry to label EVN neurons to determine any changes in c-Fos expression. All tissue was imaged using laser scanning confocal microscopy. RESULTS: Infrared recording of Ttail during PM indicated that young adult WT and transgenic mice displayed a typical motion sickness response (tail warming), but not in aged WT mice. Similarly, brainstem EVN neurons showed increased expression of c-Fos protein after PM in young adult WT and transgenic mice but not in aged cohorts. CONCLUSION: We present evidence that motion sickness symptoms and increased activation of EVN neurons occur in young adult WT and transgenic mice in response to PM. In contrast, aged WT mice showed no signs of motion sickness and no change in c-Fos expression when exposed to the same provocative stimulus.


Asunto(s)
Mareo por Movimiento , Ratones , Animales , Mareo por Movimiento/metabolismo , Neuronas/metabolismo , Núcleos Vestibulares/metabolismo , Neuronas Eferentes/metabolismo , Ratones Transgénicos
8.
Nat Commun ; 14(1): 4452, 2023 07 24.
Artículo en Inglés | MEDLINE | ID: mdl-37488133

RESUMEN

Neuronal cell death and subsequent brain dysfunction are hallmarks of aging and neurodegeneration, but how the nearby healthy neurons (bystanders) respond to the death of their neighbors is not fully understood. In the Drosophila larval neuromuscular system, bystander motor neurons can structurally and functionally compensate for the loss of their neighbors by increasing their terminal bouton number and activity. We term this compensation as cross-neuron plasticity, and in this study, we demonstrate that the Drosophila engulfment receptor, Draper, and the associated kinase, Shark, are required for cross-neuron plasticity. Overexpression of the Draper-I isoform boosts cross-neuron plasticity, implying that the strength of plasticity correlates with Draper signaling. In addition, we find that functional cross-neuron plasticity can be induced at different developmental stages. Our work uncovers a role for Draper signaling in cross-neuron plasticity and provides insights into how healthy bystander neurons respond to the loss of their neighboring neurons.


Asunto(s)
Drosophila , Neuroglía , Animales , Neuronas Motoras , Muerte Celular , Neuronas Eferentes
9.
Nat Genet ; 55(7): 1149-1163, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-37386251

RESUMEN

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.


Asunto(s)
Parálisis Facial , Animales , Ratones , Parálisis Facial/genética , Parálisis Facial/congénito , Parálisis Facial/metabolismo , Factor de Transcripción GATA2/genética , Factor de Transcripción GATA2/metabolismo , Neuronas Motoras/metabolismo , Neurogénesis , Neuronas Eferentes
10.
Am J Physiol Renal Physiol ; 325(1): F61-F72, 2023 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-37167271

RESUMEN

Diabetic bladder dysfunction (DBD) is a prevalent diabetic complication that is recalcitrant to glucose control. Using the Akita mouse model (type 1) bred to be NLR family pyrin domain containing 3 (NLRP3)+/+ or NLRP3-/-, we have previously found that females (mild hyperglycemia) progress from an overactive to underactive bladder phenotype and that this progression was dependent on NLRP3-induced inflammation. Here, we examined DBD in the male Akita mouse (severe hyperglycemia) and found by urodynamics only a compensated underactive-like phenotype (increased void volume and decreased frequency but unchanged efficiency). Surprisingly, this phenotype was still present in the NLRP3-/- strain and so was not dependent on NLRP3 inflammasome-induced inflammation. To examine the cause of the compensated underactive-like phenotype, we assessed overall nerve bundle density and afferent nerve bundles (Aδ-fibers). Both were decreased in density during diabetes, but denervation was absent in the diabetic NLRP3-/- strain so it was deemed unlikely to cause the underactive-like symptoms. Changes in bladder smooth muscle contractility to cell depolarization and receptor activation were also not responsible as KCl (depolarizing agent), carbachol (muscarinic agonist), and α,ß-methylene-ATP (purinergic agonist) elicited equivalent contractions in denuded bladder strips in all groups. However, electrical field stimulation revealed a diabetes-induced decrease in contractility that was not blocked in the NLRP3-/- strain, suggesting that the bladder compensated underactive-like phenotype in the male Akita mouse is likely through a decrease in efferent neurotransmitter release.NEW & NOTEWORTHY In this study, we show that diabetic bladder dysfunction (the most common diabetic complication) manifests through different mechanisms that may be related to severity of hyperglycemia and/or sex. Male Akita mice, which have severe hyperglycemia, develop bladder underactivity as a result of a decrease in efferent neurotransmitter release that is independent of inflammation. This contrasts with females, who have milder hyperglycemia, where diabetic bladder dysfunction progresses from overactivity to underactivity in an inflammation-dependent manner.


Asunto(s)
Hiperglucemia , Enfermedades Urológicas , Femenino , Ratones , Masculino , Animales , Vejiga Urinaria/inervación , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Inflamación , Neuronas Eferentes
11.
J Neurophysiol ; 129(3): 635-650, 2023 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-36752407

RESUMEN

This study investigated the effects of high-intensity resistance training on estimates of the motor neuron persistent inward current (PIC) in older adults. Seventeen participants (68.5 ± 2.8 yr) completed a 2-wk nonexercise control period followed by 6 wk of resistance training. Surface electromyographic signals were collected with two 32-channel electrodes placed over soleus to investigate motor unit discharge rates. Paired motor unit analysis was used to calculate delta frequency (ΔF) as an estimate of PIC amplitudes during 1) triangular-shaped contractions to 20% of maximum torque capacity and 2) trapezoidal- and triangular-shaped contractions to 20% and 40% of maximum torque capacity, respectively, to understand their ability to modulate PICs as contraction intensity increases. Maximal strength and functional capacity tests were also assessed. For the 20% triangular-shaped contractions, ΔF [0.58-0.87 peaks per second (pps); P ≤ 0.015] and peak discharge rates (0.78-0.99 pps; P ≤ 0.005) increased after training, indicating increased PIC amplitude. PIC modulation also improved after training. During the control period, mean ΔF differences between 20% trapezoidal-shaped and 40% triangular-shaped contractions were 0.09-0.18 pps (P = 0.448 and 0.109, respectively), which increased to 0.44 pps (P < 0.001) after training. Also, changes in ΔF showed moderate to very large correlations (r = 0.39-0.82) with changes in peak discharge rates and broad measures of motor function. Our findings indicate that increased motor neuron excitability is a potential mechanism underpinning training-induced improvements in motor neuron discharge rate, strength, and motor function in older adults. This increased excitability is likely mediated by enhanced PIC amplitudes, which are larger at higher contraction intensities.NEW & NOTEWORTHY Resistance training elicited important alterations in soleus intrinsic motor neuronal excitability, likely mediated by enhanced persistent inward current (PIC) amplitude, in older adults. Estimates of PICs increased after the training period, accompanied by an enhanced ability to increase PIC amplitudes at higher contraction intensities. Our data also suggest that changes in PIC contribution to self-sustained discharging may contribute to increases in motor neuron discharge rates, maximal strength, and functional capacity in older adults after resistance training.


Asunto(s)
Entrenamiento de Fuerza , Humanos , Anciano , Músculo Esquelético/fisiología , Electromiografía , Neuronas Motoras/fisiología , Neuronas Eferentes
12.
Elife ; 122023 02 21.
Artículo en Inglés | MEDLINE | ID: mdl-36805807

RESUMEN

Cerebrospinal fluid-contacting neurons (CSF-cNs) are enigmatic mechano- or chemosensory cells lying along the central canal of the spinal cord. Recent studies in zebrafish larvae and lampreys have shown that CSF-cNs control postures and movements via spinal connections. However, the structures, connectivity, and functions in mammals remain largely unknown. Here we developed a method to genetically target mouse CSF-cNs that highlighted structural connections and functions. We first found that intracerebroventricular injection of adeno-associated virus with a neuron-specific promoter and Pkd2l1-Cre mice specifically labeled CSF-cNs. Single-cell labeling of 71 CSF-cNs revealed rostral axon extensions of over 1800 µm in unmyelinated bundles in the ventral funiculus and terminated on CSF-cNs to form a recurrent circuitry, which was further determined by serial electron microscopy and electrophysiology. CSF-cNs were also found to connect with axial motor neurons and premotor interneurons around the central canal and within the axon bundles. Chemogenetic CSF-cNs inactivation reduced speed and step frequency during treadmill locomotion. Our data revealed the basic structures and connections of mouse CSF-cNs to control spinal motor circuits for proper locomotion. The versatile methods developed in this study will contribute to further understanding of CSF-cN functions in mammals.


Asunto(s)
Locomoción , Pez Cebra , Animales , Ratones , Interneuronas , Neuronas Motoras , Neuronas Eferentes , Mamíferos , Receptores de Superficie Celular , Canales de Calcio
13.
Compr Physiol ; 12(4): 3989-4037, 2022 08 11.
Artículo en Inglés | MEDLINE | ID: mdl-35950655

RESUMEN

We review the structure and function of the vagus nerve, drawing on information obtained in humans and experimental animals. The vagus nerve is the largest and longest cranial nerve, supplying structures in the neck, thorax, and abdomen. It is also the only cranial nerve in which the vast majority of its innervation territory resides outside the head. While belonging to the parasympathetic division of the autonomic nervous system, the nerve is primarily sensory-it is dominated by sensory axons. We discuss the macroscopic and microscopic features of the nerve, including a detailed description of its extensive territory. Histochemical and genetic profiles of afferent and efferent axons are also detailed, as are the central nuclei involved in the processing of sensory information conveyed by the vagus nerve and the generation of motor (including parasympathetic) outflow via the vagus nerve. We provide a comprehensive review of the physiological roles of vagal sensory and motor neurons in control of the cardiovascular, respiratory, and gastrointestinal systems, and finish with a discussion on the interactions between the vagus nerve and the immune system. © 2022 American Physiological Society. Compr Physiol 12: 1-49, 2022.


Asunto(s)
Neuronas Eferentes , Nervio Vago , Animales , Sistema Nervioso Autónomo , Humanos , Mamíferos , Neuronas Motoras/fisiología , Nervio Vago/fisiología
14.
Hear Res ; 425: 108516, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-35606211

RESUMEN

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.


Asunto(s)
Cóclea , Núcleo Coclear , Estimulación Acústica , Vías Auditivas , Tronco Encefálico/fisiología , Cóclea/fisiología , Núcleo Coclear/fisiología , Vías Eferentes/fisiología , Neuronas Eferentes/fisiología , Núcleo Olivar/fisiología
16.
J Physiol ; 600(11): 2747-2763, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35443073

RESUMEN

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.


Asunto(s)
Calcio , Cuerpo Trapezoide , Animales , Cóclea/fisiología , Ratones , Plasticidad Neuronal/fisiología , Neuronas Eferentes/fisiología , Núcleo Olivar/fisiología , Sinapsis/fisiología , Cuerpo Trapezoide/fisiología
17.
J Neurophysiol ; 127(1): 313-327, 2022 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-34907797

RESUMEN

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.


Asunto(s)
Nervio Coclear/fisiopatología , Células Ciliadas Auditivas Externas/fisiología , Pérdida Auditiva Provocada por Ruido/fisiopatología , Neuronas Eferentes/fisiología , Animales , Vías Eferentes/fisiopatología , Femenino , Cobayas , Masculino
18.
Nat Commun ; 12(1): 6914, 2021 11 25.
Artículo en Inglés | MEDLINE | ID: mdl-34824257

RESUMEN

Mislocalization of the predominantly nuclear RNA/DNA binding protein, TDP-43, occurs in motor neurons of ~95% of amyotrophic lateral sclerosis (ALS) patients, but the contribution of axonal TDP-43 to this neurodegenerative disease is unclear. Here, we show TDP-43 accumulation in intra-muscular nerves from ALS patients and in axons of human iPSC-derived motor neurons of ALS patient, as well as in motor neurons and neuromuscular junctions (NMJs) of a TDP-43 mislocalization mouse model. In axons, TDP-43 is hyper-phosphorylated and promotes G3BP1-positive ribonucleoprotein (RNP) condensate assembly, consequently inhibiting local protein synthesis in distal axons and NMJs. Specifically, the axonal and synaptic levels of nuclear-encoded mitochondrial proteins are reduced. Clearance of axonal TDP-43 or dissociation of G3BP1 condensates restored local translation and resolved TDP-43-derived toxicity in both axons and NMJs. These findings support an axonal gain of function of TDP-43 in ALS, which can be targeted for therapeutic development.


Asunto(s)
Axones/metabolismo , Proteínas de Unión al ADN/química , Proteínas de Unión al ADN/metabolismo , Inhibición Psicológica , Proteínas Mitocondriales/metabolismo , Unión Neuromuscular/metabolismo , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Animales , Proteína C9orf72/genética , ADN Helicasas , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/farmacología , Modelos Animales de Enfermedad , Femenino , Humanos , Células Madre Pluripotentes Inducidas , Ratones , Ratones Endogámicos C57BL , Mitocondrias/efectos de los fármacos , Proteínas Mitocondriales/química , Proteínas Mitocondriales/genética , Neuronas Motoras , Enfermedades Neurodegenerativas/tratamiento farmacológico , Unión Neuromuscular/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas Eferentes , Fosforilación , Proteínas de Unión a Poli-ADP-Ribosa , ARN Helicasas , Proteínas con Motivos de Reconocimiento de ARN
19.
PLoS One ; 16(11): e0259918, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34797870

RESUMEN

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.


Asunto(s)
Segmento Inicial del Axón/metabolismo , Segmento Inicial del Axón/fisiología , Neuronas Motoras/fisiología , Potenciales de Acción/fisiología , Animales , Segmento Inicial del Axón/patología , Axones/metabolismo , Axones/patología , Electrofisiología , Masculino , Neuronas Motoras/metabolismo , Neuronas Motoras/patología , Músculos/fisiología , Conducción Nerviosa , Neuronas Eferentes/fisiología , Ratas , Ratas Wistar , Médula Espinal/fisiología
20.
Sci Rep ; 11(1): 22631, 2021 11 19.
Artículo en Inglés | MEDLINE | ID: mdl-34799622

RESUMEN

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.


Asunto(s)
Adaptación Fisiológica , Retroalimentación Sensorial , Neuronas Eferentes/fisiología , Desempeño Psicomotor , Estimulación Acústica , Adulto , Percepción Auditiva , Calibración , Retroalimentación , Femenino , Humanos , Masculino , Modelos Estadísticos , Destreza Motora , Movimiento , Distribución Normal , Percepción , Reproducibilidad de los Resultados , Visión Ocular , Percepción Visual , Adulto Joven
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