Biology subjects

Cope, T. C.

Publications and source records attributed to Cope, T. C..

7 recordsLinked to original sources

bioRxiv2026

The mammalian muscle spindle as a tunable feedback controller in locomotion

Although muscle spindle sensory signals have been extensively studied, little is known about how and why muscle spindle firing is modulated by the central nervous system during movement. Specialized motor neurons to the muscle spindle, i.e. gamma motor neurons, can profoundly alter spindle firing during behavior, but technological limitations hinder our ability to record gamma motor and muscle spindle sensory signals during most behaviors. We used a biophysical model of a muscle spindle within a muscle-tendon unit to simulate how gamma drive may modulate muscle spindle Ia firing during locomotion. Based on a few available recordings from decerebrate animals, we demonstrate that our model, tuned to passive stretch conditions, can reproduce profound changes in muscle spindle firing in response to identical joint motions in locomotor vs. relaxed stretch conditions. Our model can discover phasic patterns of two types of gamma motor neuron drive based on recorded muscle spindle Ia firing and joint motion. By simulating perturbations, we conclude that: 1) sinusoidal activation of static gamma motor neurons during locomotion, encoding intended movement, modulates muscle spindle signals such that they act as sensorimotor feedback signals based on errors from the intended muscle fascicle length; 2) phasic on/off activation of dynamic gamma motor neurons during locomotion acts as an event detector, heightening muscle spindle Ia responses to discrete perturbations. As such, their muscle-within-muscle structure allows the muscle spindle to act as a highly tunable physical internal model of muscle state to guide movement. Our model supports proposed but as-yet-untested theories of muscle spindle function and offers a framework for extending the testing of muscle spindle function to active, behavioral conditions.

neuroscience↗

bioRxiv2026

Oxaliplatin Induces Spontaneous Firing at Sensory Endings Across Touch and Proprioceptive Afferents

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. HighlightsO_LIOxaliplatin rapidly induces spontaneous firing across touch and proprioceptors. C_LIO_LIThe earliest spontaneous firing localizes to sensory endings, not the DRG. C_LIO_LISensory endings are a shared site of spontaneous and evoked hyperexcitability. C_LIO_LISpontaneous firing engages some sensory pathways while sparing others. C_LI

neuroscience↗

bioRxiv2025

Influence of exoskeleton stiffness on primary afferent feedback during stretch perturbations of isolated muscle-tendon unit

Exoskeletons assist and augment movement, but their effects on proprioceptive feedback remain poorly understood due to challenges in making direct measures of sensory signals in humans. Here, we leveraged a benchtop animal model to begin to explore how mechanical context akin to an elastic exoskeleton operating on a human lower limb joint may influence primary muscle spindle firing. In an anesthetized rat preparation, we applied controlled stretches to the medial gastrocnemius with engineered springs (0-0.5 N/mm) attached in parallel to the muscle-tendon unit (MTU) while modulating muscle activation to maintain overall system stiffness. Fascicle length was measured with sonomicrometry, force and MTU length with a servo motor, and spindle instantaneous firing rate (IFR) using dorsal root recordings. Trading off increases in parallel exoskeleton stiffness with reductions in muscle activation decreased biological muscle force (3.1 {+/-} 0.6 N to 1.6 {+/-} 0.6 N, p < 0.001) and stiffness (4.4 {+/-} 1.5 N/mm to 2.3 {+/-} 1.3 N/mm, p < 0.01), and increased fascicle length (7.9 {+/-} 1.3 mm to 8.3 {+/-} 1.5 mm, p < 0.005). We found significant correlations between spindle firing and each independent muscle fascicle kinematic and kinetic factor we investigated (p < 0.005). Thus, parallel stiffness emulating a passive elastic exoskeleton modifies muscle fascicle dynamics but does not alter spindle firing, possibly due to internal trade-offs in the salient muscle fascicle kinetic and kinematic features that drive spindle behavior. Leveraging in situ experimental frameworks that enable monitoring of primary afferent feedback during active contractions in complex mechanical contexts such as added parallel stiffness can provide a window into the effects of wearable devices on underlying sensory systems.

neuroscience↗

bioRxiv2023

Attenuation of muscle spindle firing with artificially increased series compliance during stretch of relaxed muscle

Muscle spindles relay vital mechanosensory information for movement and posture, but muscle spindle feedback is coupled to skeletal motion by a compliant tendon. Little is known about the effects of tendon compliance on muscle spindle feedback during movement, and the complex firing of muscle spindles make these effects difficult to predict. Our goal was to investigate changes in muscle spindle firing using added series elastic elements (SEEs) to mimic a more compliant tendon, and to characterize the accompanying changes in firing with respect to muscle-tendon unit (MTU) and muscle fascicle displacements (recorded via sonomicrometry). Sinusoidal, ramp-hold-release, and triangular stretches were analyzed to examine potential changes in muscle spindle instantaneous firing rates (IFRs) in locomotor-and perturbation-like stretches as well as history dependence. Added SEEs effectively reduced overall MTU stiffness and generally reduced muscle spindle firing rates, but the effect differed across stretch types. During sinusoidal stretches, peak firing rates were reduced and IFR was strongly correlated with fascicle velocity. During ramp stretches, SEEs reduced the dynamic and static responses of the spindle during lengthening but had no effect on initial bursts at the onset of stretch. Notably, IFR was negatively related to fascicle displacement during the hold phase. During triangular stretches, SEEs reduced the mean IFR during the first and second stretches, affecting the history dependence of mean IFR. Overall, these results demonstrate that tendon compliance may attenuate muscle spindle feedback during movement, but these changes cannot be fully explained by reduced muscle fascicle length and velocity. New FindingsO_ST_ABSWhat is the central question of the study?C_ST_ABSLittle is known about the effects of tendon compliance on muscle spindle function. We asked whether increasing the series compliance the muscle-tendon unit muscle spindle Ia responses to stretch. We also test the relationship between muscle spindle firing rates and muscle fascicle biomechanics. What is the main finding and its importance?Muscle spindle firing was generally attenuated with added series compliance, with the exception of the initial burst at the onset of stretch. Overall, the changes depended upon stretch profiles, and could not be fully explained by muscle fascicle length and velocity.

physiology↗

bioRxiv2019

Diverse muscle spindle firing properties emerge from multiscale muscle mechanics

AO_SCPLOWBSTRACTC_SCPLOWDespite decades of research, we lack a mechanistic framework capable of predicting how movement-related signals are transformed into the diversity of muscle spindle afferent firing patterns observed experimentally, particularly in naturalistic behaviors. Here, a biophysical model demonstrates that well-known firing characteristics of muscle spindle Ia afferents - including dependence on movement history, and nonlinear scaling with muscle stretch velocity - emerge from first principles of muscle contractile mechanics. Further, mechanical interactions of the muscle spindle with muscle-tendon dynamics reveal how motor commands to the muscle (alpha drive) versus muscle spindle (gamma drive) can cause highly variable and complex activity during active muscle contraction and muscle stretch that defy simple explanation. Depending on the neuromechanical conditions, the muscle spindle model output appears to "encode" aspects of muscle force, yank, length, stiffness, velocity, and/or acceleration, providing an extendable, multiscale, biophysical framework for understanding and predicting proprioceptive sensory signals in health and disease.

neuroscience↗

bioRxiv2019

Cancer Exacerbates Chemotherapy Induced Sensory Neuropathy

For the constellation of neurological disorders known as chemotherapy induced peripheral neuropathy, mechanistic understanding, and treatment remain deficient. Here we present the first evidence in preclinical investigation of rats that chronic sensory neuropathy depends on non-linear interactions between cancer and chemotherapy. Global transcriptional profiling of dorsal root ganglia revealed differential expression, notably in regulators of neuronal excitability, metabolism and inflammatory responses, all of which were unpredictable from effects observed with either chemotherapy or cancer alone. Systemic interactions between cancer and chemotherapy also determined the extent of deficits in sensory encoding and ion channel protein expression by single mechanosensory neurons, with the potassium ion channel Kv3.3 emerging as a potential contributor to sensory neuron dysfunction. These original findings identify novel contributors to peripheral neuropathy, and emphasize the fundamental dependence of neuropathy on the systemic interaction between chemotherapy and cancer.

neuroscience↗

bioRxiv2018

Noncontractile tissue forces mask muscle fiber forces underlying muscle spindle Ia afferent firing rates in stretch of relaxed rat muscle

Stretches of relaxed cat and rat muscle elicit similar history-dependent muscle spindle Ia firing rates that resemble history-dependent forces seen in single activated muscle fibers (Nichols and Cope, 2004). During stretch of relaxed cat muscle, whole musculotendon forces exhibit history-dependence that mirror history-dependent muscle spindle firing rates, where both muscle force and muscle spindle firing rates are elevated in the first stretch in a series of stretch-shorten cycles (Blum et al., 2017). By contrast, rat musculotendon are only mildly history-dependent and do not mirror history-dependent muscle spindle firing rates in the same way (Haftel et al., 2004). We hypothesized that history-dependent muscle spindle firing rates elicited in stretch of relaxed rat muscle would mirror history-dependent muscle fiber forces, which are masked by noncontractile tissue at the level of whole musculotendon force. We removed noncontractile tissue force contributions from the recorded musculotendon force using an exponentially-elastic tissue model. We then show that the remaining estimated muscle fiber force resembles history-dependent muscle spindle firing rates recorded simultaneously. These forces also resemble history-dependent forces recorded in stretch of single activated fibers and attributed to muscle cross-bridge mechanisms (Campbell and Moss, 2000). Our results suggest that history-dependent muscle spindle firing in both rats and cats arise from stretch of cross-bridges in muscle fibers.

neuroscience↗