The Journal of Physiology

Resistance training lasting a few weeks increases maximal force mainly through neural adaptations that enhance the drive from the nervous system to muscle. While these adaptations have been well documented at the motor unit (MU) level during submaximal force contractions, the mechanisms underlying force increases during maximal voluntary contractions are poorly understood. This is due to a classic technical limitation in tracking MUs longitudinally during maximal force tasks. Here, we solved this technical challenge, enabling the investigation of MU adaptations during MVCs in both the trained and untrained limbs following unilateral resistance training. High-density surface electromyography was recorded from the biceps brachii of both limbs before and after a 4-week unilateral resistance-training intervention, and the same MUs were longitudinally tracked across sessions during MVCs by concatenation of three MVC trials of ~5-s each.Unilateral training increased maximal force in the trained limb (+16%) and induced strength transfer to the untrained limb (+8%). In both limbs, maximal contractions after training were characterized by greater EMG amplitude, faster muscle-fiber conduction velocity, and higher MU discharge rates, indicating enhanced neural drive to the motoneuron pool. These adaptations were strongly associated with improvements in maximal force (R2 > 0.7 for all). Importantly, longitudinal MU tracking revealed a non-uniform adaptation across the MU pool: MUs with higher baseline conduction velocity, indicative of higher recruitment threshold, exhibited the largest pre-post increases in discharge rate, whereas lower-threshold units showed smaller changes. Collectively, these findings demonstrate that gains in maximal force and their transfer to the untrained limb are primarily mediated by enhanced rate coding of higher-threshold MUs during MVCs.

Synthetic opioids like fentanyl are a leading cause of overdose mortality. Although the hallmark of fentanyl overdose is ventilatory depression, fentanyl also induces tonic activation of skeletal musculature, including the diaphragm, which may advance progression of overdose towards death. While tonicity may further restrict diaphragmatic contractility, phase-specific dysregulation may also reflect a larger state of discoordination in respiratory control. Using urethane-anesthetized mice exposed to fentanyl, we test the hypothesis that fentanyl-induced diaphragm tonicity results from a loss of coordinated motor activity. Fentanyl produced two distinct phases: an initial phase of maximal ventilatory depression with preserved phasic activity, and a later phase characterized by unstable ventilation that partially rebounds, tonic diaphragmatic activation with loss of inspiratory phase dominance in EMG activity, and diminished bilateral diaphragmatic coordination. Carotid body denervation eliminated tonic activity and expiratory-phase EMG elevation, but it did not prevent hemi-diaphragm discoordination or ventilatory instability. Rhythmic brainstem slice recordings showed that bilateral preBotzinger complex burst-amplitude coupling was disrupted by u-opioid receptor (MOR) agonism. Furthermore, disordered diaphragm activity was reversed by administration of the MOR antagonist, Naloxone. Our findings reframe fentanyl overdose as a temporally evolving syndrome that involves distinct mechanisms to disrupt respiratory motor coordination.

Persistent inward currents (PICs), which are facilitated by monoaminergic inputs such as serotonin (5-HT), amplify synaptic drive and strongly influence motoneuron excitability. Although rhythmic locomotor activity increases serotonergic drive in animal models, its effects on intrinsic motoneuron properties in humans remain unclear. We examined whether rhythmic arm cycling alters motoneuron excitability of the non-exercising tibialis anterior during submaximal contractions. Twelve healthy adults (8 males, 4 females) performed triangular isometric dorsiflexion contractions at 25% and 50% MVC under four conditions: resting arm (CONTROL), finger tapping (TAP), arm cycling at 50-60 RPM (LOW), and arm cycling at 80-90 RPM (HIGH). Motor unit activity was identified from high-density surface electromyography that was decomposed into spike trains. Recruitment thresholds of identified and tracked motor units were consistent across conditions, but {Delta}F (i.e., an estimate of the PIC-related contributions to motor unit discharge) decreased during high-cadence arm cycling at stronger contraction intensities, which may reflect either reduced neuromodulation and/or increased or altered patterns of inhibition. In contrast, ascending discharge rate modulation deviated from linearity to a greater extent (i.e., brace height was larger) during both low- and high-cadence cycling, indicating greater neuromodulatory influence on the ascending discharge rate pattern. Self-sustained discharge was also elevated during cycling tasks, reflecting prolonged motor unit discharge. Taken together, these findings suggest that rhythmic activity of the arms modulates the discharge characteristics of motoneuron pools in the legs via unique combinations of excitatory, neuromodulatory and inhibitory inputs, which advances our understanding on the mechanisms of interlimb neural coupling.

The distribution of common synaptic inputs across spinal motor neuron pools within and across synergist muscles reveals direct insight in the neural control of movement. We previously documented two dominant common inputs in the human vastus lateralis (VL) and medialis (VM) muscle during isometric leg extensions. Whether these inputs are also shared with rectus femoris (RF), a synergist muscle that contributes substantially to leg extension but is biarticular, remains unknown. We simultaneously recorded motor unit activity from VM, RF, and VL using multiple targeted intramuscular electromyographic sensors during isometric knee extension. Decomposed motor unit spike trains were analyzed using discharge characteristics, pairwise correlation, spectral coherence, explained variance, and factor analysis to characterize the structure of common synaptic input within and across muscles. Despite their shared mechanical output via a common patellar tendon, the three muscles exhibited distinct patterns of neural organization. RF consistently received a strong, low-dimensional common input that was largely independent of the drive to VM and VL, as evidenced by elevated within-muscle correlation and coherence, low between-muscle coupling, and an invariant dedicated latent factor across all participants. VM and VL shared a substantial proportion of common synaptic input, but the degree of coupling and the underlying factor structure varied across individuals, ranging from a single shared factor to largely independent muscle-specific inputs. These findings indicate that the quadriceps are organized in a muscle- and subject-specific manner, with RF receiving a dedicated independent input.

The distribution of slow-and fast-twitch fiber types in a skeletal muscle heavily influences its physiology. Muscle biopsy studies indicate atypical fiber type composition and fiber size variation in children with cerebral palsy (CP), but subjects have variable treatment history and a variety of muscles affected, so uncertainties remain. In this study, we developed a novel machine-learning classification model to perform high-throughput fiber typing of complete transverse muscle sections. Our XGBoost algorithm-based prediction model yielded a balanced accuracy score of 0.89 and a macro F1-score of 0.89, reflecting its ability to robustly predict muscle fiber type from myosin heavy chain (MyHC) isoform immunofluorescence intensities and morphological descriptors. This is the first reported fiber type classifier to consider hybrid fibers, which is a major advance, considering at least 20% of myofibers are hybrid yet they are routinely overlooked due to difficulty in their detection. We used this classification model to define fiber types of more than 7 million myofibers from flexor-extensor muscle pairs in rabbits that experienced hypoxia-ischemia (HI) injury in utero (modeling CP), and typically developing sham rabbits. We observed an oxidative fiber type shift in flexor muscles (biceps brachii and tibialis anterior) of HI rabbits at postnatal day (P)14-20 and P30-32 (weaning age). This altered fiber type composition imparts reduced contractile force and is amenable to sustained muscle activity; it may reflect chronic low-frequency motor unit activation. This work supports prior clinical reports that developmental trajectories of muscle fibers are disrupted in CP.

BackgroundDynamic power declines earlier across the lifespan and shows a more pronounced and complex pattern than isometric strength, particularly in ageing females. However, the functional, skeletal muscle and molecular mechanisms underpinning power loss across the female lifespan remain to be collectively examined. MethodsEighty-six females aged 18-80 years and stratified per decade of age completed a series of maximal voluntary knee extensions to construct torque-velocity and power-velocity relationships of the quadriceps. Data points corresponding to >95% maximal power were selected for the evaluation of rate of torque development (RTD) and quadriceps surface electromyography (EMG). Outcomes were quantified within discrete 50ms time bins from torque onset to +200ms and included absolute RTD, RTD normalised to peak force, and EMG amplitude and rate of rise normalised to the maximal compound action potential. Quadriceps morphology was assessed via computed tomography, and a vastus lateralis muscle biopsy was collected to assess markers of denervation and expression of genes associated with the neuromuscular junction and calcium-handling transcriptome. ResultsAgeing led to linear reductions in maximal power (-1.39 {+/-} 0.01% p/year), torque (-0.98 {+/-} 0.13% p/year) and velocity (-0.38 {+/-} 0.01% p/year) (all p < 0.05). Quadriceps skeletal muscle CSA attenuated power loss by [~]40% (p < 0.001), largely through reduction of the decline in torque ([~]50%), with no effect on the decline in velocity. During early time bins, older females generated higher relative RTD accompanied by higher EMG amplitude, whereas during later time bins, older females generated less absolute and relative RTD accompanied by lower EMG amplitude and rate of rise (all p < 0.05). Ageing increased neural cell adhesion molecule (NCAM) positive fibres and fibrosis (both p < 0.05). The presence of NCAM{square} fibres was associated with attenuation of the age-related decline in maximal power ([~]15%), torque ([~]35%) and velocity ([~]60%), suggesting that NCAM{square} fibre prevalence may partially explain the observed age associations. Within the neuromuscular junction transcriptome, ageing reduced acetylcholinesterase and increased laminin alpha-2 and muscle-specific kinase (all FDR < 0.05), whereas lesser changes were observed within the calcium-handling transcriptome. ConclusionsSkeletal muscle CSA explains [~]40% of the age-related decline in quadriceps dynamic maximal power across the female lifespan, whereas a neurodegenerative profile mainly evidenced by age-related changes in voluntary neural drive, denervation and markers of neuromuscular junction instability further contribute to the decline.

It is well documented that both motoneuron output and the effectiveness of activated Ia afferents to discharge soleus -motoneurons decrease during eccentric (muscle lengthening) contractions. Evidence suggests that these modulations can be explained by recurrent inhibition and greater presynaptic inhibition of Ia afferents. However, the influence of angular velocity on the modulation of the effectiveness of activated Ia afferents to discharge -motoneurons observed during eccentric contractions remains unclear. We investigated the influence of angular velocity on spinal mechanisms involved in the effectiveness of activated Ia afferents to discharge -motoneurons during eccentric plantar flexor contractions using 16 healthy adults. We used both simple and conditioned Hoffmann reflex with different conditioning techniques to assess presynaptic inhibition, heteronymous Ia facilitation and heteronymous recurrent inhibition coupled with electromyography during eccentric contractions of the plantar flexors at three angular velocities. Our results showed that during eccentric contractions, the effectiveness of Ia afferents to discharge -motoneurons was lower at 90{degrees}{middle dot}s-{superscript 1} than 60{degrees}{middle dot}s-{superscript 1} and 20{degrees}{middle dot}s-{superscript 1} angular velocities. A similar velocity-dependent pattern was observed for heteronymous recurrent inhibition, decreasing at 90{degrees}{middle dot}s-{superscript 1} when compared with 60{degrees}{middle dot}s-{superscript 1} and 20{degrees}{middle dot}s-{superscript 1}. In contrast, presynaptic inhibition of Ia afferents was not different between the velocities. These demonstrate a differential influence of angular velocity on spinal recurrent inhibitory mechanisms during eccentric contractions and support distinct functional roles of recurrent and presynaptic inhibition in modulating -motoneurons discharge with increasing movement velocity. The findings provide new insights into the velocity-dependent and mechanism-specific modulation of spinal inhibitory circuits during eccentric contractions. KEY POINTSO_LIDuring eccentric contractions in soleus muscle, the effectiveness of activated Ia afferents to discharge -motoneurones decreases with increasing angular velocity, indicating a velocity-dependent modulation. C_LIO_LIPresynaptic inhibition of Ia afferents does not differ between angular velocities, suggesting that it does not contribute to the observed changes. C_LIO_LIHeteronymous recurrent inhibition from the quadriceps to the soleus increases with angular velocity, indicating that increasing movement velocity promotes a functional reorganization of intermuscular recurrent inhibition. C_LIO_LIThese findings suggest a differential functional role of the two spinal inhibitory mechanisms, indicating that increasing angular velocity primarily influences recurrent postsynaptic inhibition rather than presynaptic inhibition. C_LI

Motor planning and control is executed by different motor areas within the neocortex. Despite their distinct functions these areas are built by the same archetypes of neurons as the rest of the cortex, with the pyramidal neurons (PNs) as their principal building blocks. Recent results suggest that the synapses of the PNs are modeled and adapted to their required functions in an area specific manner. PN synapses in a cortical area engaged in higher order functions, the prefrontal cortex (PFC), were found to operate with loose microdomain calcium-influx-to-release coupling and showed short-term facilitation, whereas synapses processing sensory information in a lower order cortical area, the primary somatosensory cortex (S1), featured tight nanodomain coupling and showed short-term depression. In the present study, we asked for the functional coupling configuration of an intermediate processing area. We focused on PN synapses in the premotor cortex M2 and compared their properties to those of PN synapses in the primary motor cortex M1. In both areas we found tight nanodomain coupling and high release probability, but a significant difference in short-term plasticity. Synapses in M1 showed paired-pulse depression similar to S1. In contrast, synapses in M2 exhibited paired-pulse facilitation. Our data suggest that this facilitation results from an accelerated recruitment of synaptic vesicles to the readily releasable pool from an enlarged replenishment pool. Thus, PN synapses in M2 appear to have properties intermediate between those in PFC and M1.

Intrinsic lateral olivocochlear (iLOC) neurons provide vital brainstem efferent feedback to the cochlea in order to modulate hearing sensitivity through synapses onto type-I spiral ganglion neurons. During ageing or mutations affecting hair cell transduction in mice, efferent neurons rewire to form direct axo-somatic synapses onto inner hair cells (IHCs), recapitulating a synaptic configuration typically only restricted to the immature cochlea. Whether this rewiring reflects a compensatory mechanism or some form of attempted repair, or how iLOC biophysics change throughout ageing and this rewiring process, is not known. We utilised whole-cell patch-clamp electrophysiology to investigate iLOC activity and their underlying biophysics across the wild-type mouse lifespan. We show that iLOC neurons undergo a progressive increase in excitability with post-natal development and ageing, producing more spikes for a given stimulus. This intrinsic excitability shift was driven by the developmental decline in the A-type Kv4 mediated potassium current and increase in Kv2 mediated current. In ageing animals, and distinct from post-natal development, further increased firing rates were supported by an increased size of the fast-activating Kv3 current. Spontaneous bursting activity remained present in ageing iLOC neurons, and no reversion to an immature biophysics profile was evident. Interestingly, despite robustly eliciting efferent rewiring of IHCs, an accelerated ageing-like re-innervation genetic model did not recreate the biophysical changes in the iLOC neurons that reflected the ageing system. This work reveals distinct processes occurring within the iLOC feedback system, and shows that age-related enhancements of SGN resting activity are not triggered by deficits in IHC transduction.

Fascicle operating length during dynamic tasks is often compared to the isometric torque-length relationship, but there is a lack of evidence regarding the influence of joint velocity on optimal fascicle length. Moreover, there is no consensus in the literature regarding the influence of contraction initiation (pre-activation or passive start), although it could alter the interaction between fascicles and the tendon. This study aimed to investigate the effect of joint velocity and pre-activation on the torque-angle and torque-length relationships of the vastus lateralis during mono-articular isokinetic knee extensions. Twenty-one participants performed isometric, isokinetic (50{degrees}.s-1 to 450{degrees}.s-1), and isokinetic knee extensions with maximal isometric or eccentric pre-activation at 100{degrees}.s-1 and 300{degrees}.s-1. Torque, joint angle, fascicle length, and electromyographic activity of the quadriceps femoris muscles were recorded during contractions and then used to model the torque-angle and torque-length relationships. We were able to successfully fit the torque-angle and torque-length relationships (R{superscript 2}=0.93 and R{superscript 2}=0.92, respectively). A main effect of velocity was detected regarding the optimal angle (p<0.05), but no significant change was observed for the optimal fascicle length. Isometric pre-activation induced a reduction in maximal torque production compared with eccentric pre-activation and passive conditions at both isokinetic velocities (p<0.001), with no change in muscle activity. Our results suggest that muscle-tendon interactions may permit a dissimilar behavior between the torque-angle and the torque-fascicle length relationships. The reduction in torque following isometric pre-activation may be related to a contraction history-dependent phenomenon. NEW & NOTEWORTHYWe demonstrated that, at a given joint angle, increasing velocity altered fascicle operating length without shifting optimal fascicle length, likely because of muscle-tendon interactions. We also showed that maximal isometric pre-activation before a concentric contraction reduced mean and maximal torque during the isokinetic phase compared with eccentric pre-activation or no pre-activation. This effect may be linked to contraction history, since muscle activity did not differ between conditions.

Consumption of high fat diet (HFD) is linked to reduced cardiac vagal motor output, a main contributor to progression of cardiovascular disease. HFD for 15 days increases extrasynaptic or tonic gamma aminobutyric acid (GABA) current in cardiac projecting neurons in the dorsal motor nucleus of the vagus (CVNDMV), which contributes to dampening cardiac parasympathetic output. However, the mechanism underlying this increased inhibition is unknown. Here, we hypothesize that increased activity of protein kinase C {delta} isoform (PKC{delta}) enhances tonic GABA current in CVNDMV after HFD. Whole-cell patch-clamp recording of retrogradely labeled CVNDMV demonstrated that pan inhibition of PKC activity with GFX, and isoform specific inhibition of PKC{delta} with rottlerin normalize 15-day HFD-induced increases in tonic GABA current, suggesting that PKC{delta} mediates enhanced tonic inhibition. This effect persisted in the presence of dynasore, a clathrin-mediated endocytosis blocker, indicating that the normalization effect of PKC{delta} inhibition on tonic current in HFD is likely independent of clathrin-mediated endocytosis. Furthermore, no differences in PKC{delta} mRNA or protein expression were observed between NFD and HFD, suggesting a post-translational mechanism underpinning increased tonic GABA current after 15 days of HFD. Altogether, this study provides evidence that HFD-induces increased PKC{delta} activity, but not expression, leading to increased tonic GABAergic inhibition in CVNDMV. This increase PKC{delta} activity could explain the cardiac vagal motor output dampening in CVD and be developed into treatments targeting PKC{delta} for CVD.

Predictions of skeletal muscle energy consumption under a diverse range of muscle contractile conditions are critical for improving our understanding of locomotion. Existing mathematical models, while capturing the mechanical dependence of energy consuming processes, neglect the time-dependent behaviour and recovery costs associated with regenerating ATP. This time-dependence is important for predicting the energetic response of muscles during repetitive or cyclical tasks like locomotion, where muscle undergoes many contraction cycles. This study presents a novel model to predict energetic rates based on physiological processes: Ca2+ transport costs, cross-bridge cycling costs, and ATP regeneration. Previous mathematical models include the dependence on Ca2+ transport and cross-bridge cycling, but neglect the time-dependent response and the subsequent recovery of ATP following the contraction. Model parameters were obtained from existing data on isolated muscle preparations, and predicted energetic rates were validated on separate datasets across a range of contractile conditions including dynamic, sub-maximal, and twitch contractions. The time-dependent model was able to capture the influence of contraction frequency on peak energetic rates and the time-course of energetic recovery observed experimentally. The model captures key physiological processes while maintaining a minimal number of free parameters and low computational cost. This enables generalisability across muscles and species, and implementation into larger scale musculoskeletal models.

Body size and limb posture vary widely across mammals and are expected to shape locomotor stability, yet direct comparative evidence remains limited. Here, we tested whether smaller, crouched mammals exhibit greater lateral dynamic stability than larger, more upright species by comparing treadmill walking in mice and cats at dynamically similar speeds. Using kinematic analyses and size normalized measures of stability, we show that mice are substantially more laterally stable than cats. This increased stability is associated with relatively wider step widths and more crouched limb posture, indicating that support geometry and posture play dominant roles in stabilizing locomotion. Despite these differences, both species regulate lateral balance on a step-by-step basis, as revealed by relationships between center of mass motion and subsequent adjustments of the border of support. Our findings demonstrate that locomotor stability does not scale simply with body size but depends critically on posture dependent strategies that differ across species. These results identify lateral stability as a key factor of locomotor adaptation and suggest that crouched postures in small mammals may reduce reliance on active neural control while enhancing robustness in complex environments. SUMMARY STATEMENTLateral dynamic stability during quadrupedal locomotion depends primarily on limb posture and support geometry rather than body size. Smaller mammals achieve greater stability through crouched postures and wider step widths, whereas larger mammals operate closer to stability limits and rely more heavily on active control.

Age-related reductions in muscle fiber size and contractile function, particularly in fibers expressing fast myosin heavy chains, contribute to declines in whole-muscle power. However, methodological limitations in estimating fiber size during contractile experiments have likely contributed to conflicting findings regarding whether reduced single-fiber force and power in older adults reflects their smaller size and/or impaired intrinsic contractile function. To address this, we coupled single-fiber contractile experiments with 3D-imaging in 7 young (19-40yrs) and 6 older (69-84yrs) males to assess intrinsic contractile function and compare agreement between 3D-derived cross-sectional area (CSA) and CSA estimates obtained either in air or solution. Fast fiber CSA from older males were [~]28-45% smaller across measurement conditions compared with young, whereas slow fiber CSA did not differ. Accordingly, absolute force and power of fast fibers were 41% and 37% lower. When normalized to CSA from measurements in air or 3D-imaging, size-specific force and power either did not differ or were greater in older adults, indicating preserved intrinsic contractile function in both fiber types. This was supported by no age-related differences in the rate of tension redevelopment (ktr), a size-independent measure of intrinsic contractile function. In contrast, size-specific force and power calculated using solution-based CSA estimates were lower in older compared with young adults, and Bland-Altman analyses demonstrated the poorest agreement between solution-based and 3D CSA measurements. These findings indicate that intrinsic contractile function is preserved with aging and suggest that methodological differences in CSA measurement contributes to the disparate findings in the literature.

Individuals with cervical spinal cord injury (SCI) often exhibit asymmetric recovery of upper-limb function, with greater weakness in elbow extensors than flexors. To determine whether muscle-specific changes in motor unit (MU) behavior contribute to this disparity, we identified MU firing instants from high-density surface electromyography to characterize MU firing characteristics in the biceps brachii (BIC) and triceps brachii (TRI) of individuals with cervical SCI (n = 20) and non-injured controls (n = 18). We quantified rate-coding behavior and metrics related to persistent inward currents (PICs), including onset-offset hysteresis ({Delta}F), ascending firing rate nonlinearity, and self-sustained firing. At the group level, BIC MUs in SCI participants showed reduced rate coding and altered ascending firing rate nonlinearity relative to controls. In contrast, TRI MUs showed no clear group-level differences. However, subgroup analysis revealed that SCI participants with low-strength during extension (n = 9) exhibited lower {Delta}F and longer self-sustained firing durations in TRI MUs than those with high-strength (n = 6). In BIC, SCI participants with low-strength during flexion (n = 8) showed reduced rate-coding behavior relative to high-strength SCI participants (n = 9), with no differences in PIC-related metrics. Together, these results demonstrate muscle-specific alterations in MU firing after cervical SCI that may relate to strength recovery or preservation and underscore the need for nuanced analyses in heterogeneous SCI populations. Key pointsO_LIRate coding and nonlinear firing behaviors are significantly altered in the biceps brachii, but not triceps brachii, of participants with cervical spinal cord injury. C_LIO_LIStrength based subgroup analyses revealed muscle-specific differences in motor unit behaviors that may be associated with strength preservation or recovery following spinal cord injury. C_LIO_LIFunctional heterogeneity following spinal cord injury may mask group differences in motor unit behaviors and warrants careful interpretation of results of future studies. C_LI

The early-onset, high-frequency hearing loss phenotype of CD-1 mice is rescued by the A88V mutation of the connexin 30 gap-junctional protein, despite a reduced endocochlear potential (EP), which drives cochlear hair cell receptor potentials. The mutation enables organ of Corti (OoC) extracellular receptor potentials to be similar in size to those of sensitive-hearing CBA/J mice, presumably through increased OoC resistance, despite smaller intracellular outer hair cell (OHC) receptor potentials. Low-frequency hearing in CD-1Cx30A88V/A88V mice is impaired, compared with those of CBA/J and wild-type CD-1 mice. To investigate the cellular basis of OoC resistance increase and EP decrease, we made in situ electrophysiological measurements from Deiters cells (DCs) in the OoC of homozygous CD-1Cx30A88V/A88V mice. DCs contribute to the OHC cytoskeletal scaffold and cochlear K+ recycling, and are interconnected by syncytial junctions comprising connexins 30 and 26. Measurements from CD-1Cx30A88V/A88V mice were compared with those from wild-type CD-1 mice, with sensitive hearing below 12 kHz, and from the CBA/J strain. Syncytial junctional-coupling between DCs of CD-1Cx30A88V/A88V mice was weaker, input resistance greater, potassium current expression was modified, and voltage-sensitive activation was shifted to more negative values compared to those of CD-1 and CBA/J mice. Inactivating potassium currents dominate in DCs of CBA/J and CD-1Cx30A88V/A88V mice with excellent high-frequency hearing, and sustained currents dominate in DCs of CD-1 mice with early-onset hearing loss. These findings are discussed in relation to maintenance of OoC electrochemistry, rescue of early-onset hearing loss, impaired low-frequency hearing in CD-1Cx30A88V/A88V mice, and the basis of high-frequency hearing.

Sympathetic preganglionic neurons (SPNs) provide the sole spinal output to the peripheral sympathetic nervous system. Although sympathetic control is traditionally attributed to synaptic integration within the spinal cord and ganglia, the reliability of spike propagation along SPN axons themselves has received little attention. Here, and in companion papers, we show that axonal conduction in adult mouse thoracic SPNs is highly modifiable and constitutes a critical site of sympathetic gain control. Using an ex vivo preparation preserving intact paravertebral and splanchnic pathways while blocking synaptic transmission, we recorded compound action potentials evoked across multiple ganglia. Slower-conducting, unmyelinated SPN axons, particularly those with branching axons traversing the interganglionic nerve (IGN), exhibited pronounced, temperature-dependent conduction failures. Elevation of temperature produced membrane hyperpolarization and loss of conduction, consistent with activation of temperature-sensitive K2P leak channels, as supported by pharmacological evidence. Pharmacological activation of TREK-family channels with riluzole or arachidonic acid preferentially suppressed conduction in these axons. In contrast, blockade of voltage-gated K+ channels with 4-aminopyridine (4-AP) robustly facilitated conduction, recruited previously silent axons, and restored propagation under conditions of temperature-induced failure. Surprisingly, tetraethylammonium (TEA) block of K+ channels were without effect or depressant. Transmitter systems further shaped axonal reliability: agonists and antagonists of GABAA receptors, as well as cholinergic manipulations, selectively depressed conduction in slow, branching axons. Together, these findings establish SPN axons, particularly slow-conducting branching fibers, as an active and dynamically regulated substrate for sympathetic output control, revealing a presynaptic mechanism with implications for autonomic physiology and disease. SIGNIFICANCESympathetic output is commonly viewed as being regulated primarily through synaptic integration within spinal and autonomic circuits, while axons are often treated as passive transmission elements. Emerging evidence suggests this assumption is incomplete, particularly in slowly conducting and highly branched sympathetic preganglionic neuron (SPN) axons that may operate near the limits of conduction reliability. This study identifies branch point conduction as a dynamic and pharmacologically modifiable control mechanism governing sympathetic signal transmission. By demonstrating selective vulnerability of distinct SPN populations and revealing strong modulation by potassium channel mechanisms, these findings establish axonal conduction security as an underappreciated site of autonomic gain control. These mechanisms may represent novel therapeutic targets for restoring autonomic function after spinal cord injury and related disorders.

Postural control depends on the ability to adapt motor responses to changing environmental and physiological conditions. Neuromuscular fatigue (NMF) is known to alter balance and muscle activation patterns, yet its effects on motor adaptation during whole-body postural tasks and on the persistence of learned strategies remain unclear. This study investigated whether localized NMF of the ankle dorsiflexors influences adaptation to a novel postural perturbation task and whether learning under fatigue induces persistent changes during subsequent re-exposure. Twenty-five healthy young adults were assigned to either a fatigue (FAT) or no-fatigue (NoFAT) group and completed two experimental sessions separated by 48-72 h allowing recovery from acute fatigue for fatigued group. Participants adapted to repeated mechanical perturbations while standing upright, while ground reaction forces and electromyographic activity of lower-limb muscles were recorded. NMF did not impair overall adaptation performance, as both groups exhibited similar reductions in performance error across practice. However, participants exposed to fatigue exhibited altered postural recovery dynamics, characterized by a reduced return toward the initial posture following perturbation release. These differences persisted during re-exposure on the subsequent day, despite the absence of acute fatigue. In parallel, NMF modified muscle activation and coactivation patterns involving both fatigued and non-fatigued muscles, several of which were retained during re-exposure. These findings indicate that the central nervous system preserves successful adaptation to postural perturbations under fatigue by reorganizing neuromuscular coordination and stabilization strategies. Learning under fatigue therefore influences not only immediate motor execution, but also shapes the longer-term representation of postural control strategies.

The pelvic floor muscles (PFM) are critical for maintaining continence and are a primary target of physiotherapy training to manage urinary incontinence. PFM training relies on voluntarily activating this muscle group, limiting its translation to neurological populations where recovery of bladder function is a priority. Indirect evidence suggests that sensory feedback from the lower limb can modulate PFM activity, which may provide alternative strategies for PFM training. Cutaneous reflexes have been used as a proxy to study how sensory inputs from the skin influence motoneuron excitability. To explore the feasibility of eliciting cutaneous reflexes in the PFM and their role in controlling PFM activity, this study examined: 1) the input-output relationship and 2) the nerve-specificity of PFM cutaneous reflex responses from tibial and superficial peroneal nerve stimulation. Twenty-one neurologically intact adults participated in this study. We recorded PFM and lower leg muscle electromyography while participants received cutaneous stimulation to the right distal tibial nerve, bilateral distal tibial nerve, or right superficial peroneal nerve in a standing position. We delivered stimulation at the intensity below motor threshold (MT), 1.2 x MT and 1.5 x MT and quantified tibial-PFM reflex amplitude over a 50-150 ms window after stimulation. PFM reflex responses were evoked from both nerves stimulation. Reflex amplitude increased with stimulus intensity with tibial nerve stimulation but not with superficial peroneal nerve stimulation. Bilateral tibial nerve stimulation evoked larger responses compared to unilateral stimulation. These findings support the existence of neural connections between lower limb afferents and the PFM, and open up possibilities for designing rehabilitation strategies to manage pelvic health conditions in people with neurological disorders. New & NoteworthyO_LICutaneous sensory feedback from the foot, specifically that related to limb loading, can evoke reflex responses in the pelvic floor muscles C_LIO_LINerve-specific modulation was observed. Reflex amplitudes in the pelvic floor muscles increased with tibial nerve stimulation intensity but not with superficial peroneal nerve stimulation. C_LI

Spontaneous activity in primary sensory neurons has been implicated in neuropathic symptoms, yet its earliest origins and immediate functional consequences remain incompletely understood. This gap is especially consequential in chemotherapy-induced peripheral neuropathy (CIPN), where sensory toxicities commonly limit effective cancer treatment. Using in vivo recordings in rats, we show that a single dose of oxaliplatin (OX) induces spontaneous firing within 24 h across touch and proprioceptive low-threshold mechanoreceptor (LTMR) afferents. Spontaneous firing consistently originated distally in peripheral axons and was accompanied by enhanced responses to mechanical stimulation, identifying LTMR sensory endings as the earliest source of spontaneous firing and a common site for spontaneous and stimulus-evoked hyperexcitability. OX also induced early structural abnormalities at sensory endings; however, SF+ LTMRs retained mechanosensory response profiles, indicating that spontaneous firing can emerge within otherwise functional sensory endings. Although coincident spontaneous and stimulus-evoked activity distorted encoding in individual LTMRs, these effects had little impact on population LTMR responses or motor behavior relying on mechanosensory feedback. Together, these findings identify sensory endings as an early target of OX neurotoxicity and demonstrate that spontaneous firing spanning multiple tactile and proprioceptive LTMR submodalities can coexist with largely preserved sensory function, indicating that even broad engagement across mechanosensory pathways is insufficient to disrupt all LTMR-dependent functions. These observations indicate that abnormal afferent activity initiated at sensory endings may be sufficient to engage sensory pathways underlying some paresthetic symptoms while leaving others largely unaffected, whereas progression to chronic neuropathic symptoms may require subsequent recruitment of the dorsal root ganglion.