Chronic defects in intraspinal mechanisms of spike encoding by spinal motoneurons following chemotherapy

Housley, Stephen N.; Nardelli, Paul; Powers, Randal K.; Rich, Mark M.; Cope, Timothy C.

doi:10.1016/j.expneurol.2020.113354

Cited by 16 publications

(18 citation statements)

References 85 publications

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“…The few available recordings of muscle spindle receptor potentials during muscle stretch exhibit fast initial transients similar to muscle fiber yank, as well as a sustained potential that resembles muscle force and its decay following a stretch (Hunt & Ottoson, 1975a). We show that sweeping a range of sensitivities to intrafusal force and yank predicts a continuum of firing phenotypes resembling those seen previously in both healthy and perturbed conditions (Housley et al, 2020; Vincent et al, 2016). Further, each set of sensitivities can predict muscle spindle firing across different stretch velocities and displacements.…”

Section: Discussionsupporting

confidence: 69%

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Diverse and complex muscle spindle afferent firing properties emerge from multiscale muscle mechanics

Blum

Campbell

Horslen

et al. 2019

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1 Sensory information about the body's mechanical interactions with the environment are critical for neural 2 control of movement. Muscle spindle sensory neurons richly innervate muscles in vertebrates; their firing 3 patterns as muscles stretch have been well-characterized experimentally, but have not been fully explained 4 mechanistically. Here, we show that a diverse range of muscle spindle firing characteristics are emergent 5 from first principles of muscle contractile mechanics. We develop a mechanistic muscle spindle model that 6 predicts well-known phenomena such as variations in muscle spindle sensitivity due to prior movement 7 history and nonlinear scaling with muscle stretch velocity. The model further predicts how central 8 commands to muscle spindles-fusimotor drive-alters their firing responses, and shows how seemingly 9 paradoxical muscle spindle firing during voluntary force production in humans can arise. Our multiscale 10 muscle spindle model provides a unifying biophysical framework that may broadly explain and predict 11 movement-related sensory signals in health and disease. 13Precise movements depend on sensory information from throughout the body. Vertebrates have specialized 14 sensors called muscle spindles that are widely distributed throughout skeletal muscles, providing critical 15 information for all movements-from basic knee-jerk reflexes to playing musical instruments. Muscle 16 spindles are all the more remarkable because they are not simply passive sensors: muscle spindles contain 17 specialized muscle fibers that, when activated by central motor commands, alter the sensory information 18 received by the nervous system. Despite decades of research, we still lack a mechanistic framework capable 19 of explaining and predicting how movement-related biomechanical signals are transformed into the broad 20 diversity of muscle spindle firing patterns observed experimentally, particularly in naturalistic behaviors. 21Developing a mechanistic framework for understanding how muscle spindle organs generate the complex 22 sensory signals observed during movement will be critical for understanding not only the functional role of 23 muscle spindles as proprioceptive sensors, but also neural control of movement and how it is affected by 24 neurological disorders. 25We recently demonstrated that a combination of muscle fiber force and yank, i.e. the first time 26 derivative of force 1 , matches the profile of muscle spindle firing throughout the stretch of a relaxed 27 muscle 2,3 . The role of muscle mechanics and force in muscle spindle function has long been discussed 4,5 , 28 but not integrated into a mechanistic framework. We first used a phenomenological approach to 29 demonstrate the parallel dependence of muscle spindle firing and muscle mechanics on prior movement of 30 the muscle. Muscle spindle firing rates, together with muscle force and yank are high when the muscle is 31 stretched after being held at a constant length, and lower if the muscle was moving prior to stretch 6 . In both ...

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Section: Discussionsupporting

confidence: 69%

“…muscle. (Bullinger et al, 2011a; Cope et al, 2014; Housley et al, 2020). Accordingly, the characteristics of the estimated intrafusal muscle fiber force and yank were qualitatively similar in intact and OX rats, suggesting there was no change in muscle fiber force in the OX animals.…”

Section: Resultsmentioning

confidence: 99%

Diverse and complex muscle spindle afferent firing properties emerge from multiscale muscle mechanics

Blum

Campbell

Horslen

et al. 2019

Preprint

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“…Finally, the left-hand side is the posterior -the joint probability distribution of all parameters θ after we observed data y 56 Marginally informative priors were applied to model parameters and variance components such that inferences were driven predominantly by the experimental data to explicitly answer our central questions. Prior specifications were based on results from previous preliminary data and published studies by our group 52 and others 17,19 .…”

Section: Collecting and Processing Both In Vivo Electrophysiology Andmentioning

confidence: 99%

“…to explicitly answer our central questions. Prior specifications were based on results from previous preliminary data and published studies by our group 52 and others 17,19 .…”

Section: Statistical Analysis and Bayesian Modelingmentioning

confidence: 99%

“…Each model was run with four independent chains for 400 warm-up and 4,000 sampling steps. Steps to perform model evaluation and validation have been extensively described in our previous work [53][54][55] . Briefly, for all parameters, the number of effective samples was >2000, convergence was assessed and assumed to have Models were conditioned on previous reports 22,43 and datasets from this study.…”

Section: Statistical Analysis and Bayesian Modelingmentioning

confidence: 99%

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Somatic Proximity of the Axon Initial Segment Predicts Motoneuron Excitability

Rotterman

Carrasco

Housley

et al. 2021

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As the neuronal site where voltage gated channel density is highest, the axon initial segment (AIS) plays a key role in establishing a neuron’s action potential threshold, i.e. excitability. Among the properties of AIS that gain attention are length (AISl) and distance from the soma (AISd), which are variously found to change together with neuronal excitability following experimentally-induced perturbations in neural activity. The present study was designed to test the possibility that variation in AIS structural parameters regulates the native range in intrinsic excitability for one class of mature neurons. Spinal motoneurons were selected for their naturally large range in excitability and for their experimental accessibility to in vivo study. 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 more than for motoneurons from the soleus (SOL) motor pool, which is more readily activated in low-level movements. Next, we tested whether AISd covaried with intrinsic excitability of individual motoneurons. Using anesthetized rats, we measured rheobase current intracellularly from MG motoneurons before labeling them for later immunohistochemical study of AIS. This combinatory approach revealed a significant correlation between AISd and rheobase, for 16 motoneurons sampled within the MG motor pool. Among multiple electrophysiological and morphological parameters measured here, AISd stood out as the dominant predictor of motoneuron excitability. These findings suggest an important role for AISd in setting the intrinsic excitability of spinal motoneurons.

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Effects of route of administration on neural exposure to platinum-based chemotherapy treatment: a pharmacokinetic study in rat

et al. 2021

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Chronic defects in intraspinal mechanisms of spike encoding by spinal motoneurons following chemotherapy

Cited by 16 publications

References 85 publications

Diverse and complex muscle spindle afferent firing properties emerge from multiscale muscle mechanics

Diverse and complex muscle spindle afferent firing properties emerge from multiscale muscle mechanics

Somatic Proximity of the Axon Initial Segment Predicts Motoneuron Excitability

Effects of route of administration on neural exposure to platinum-based chemotherapy treatment: a pharmacokinetic study in rat

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