Biology subjects

Thompson, C. K.

Publications and source records attributed to Thompson, C. K..

12 recordsLinked to original sources

bioRxiv2026

The variability of reflex amplitude estimates in motor unit pools depends on the phenotype distribution and discharge statistics

Motor unit (MU) activity during electrically or mechanically evoked reflexes is used to examine the relationship between neural inputs and MU properties. However, variations in single-MU reflex amplitudes are not fully understood and limit their reliability in determining the input-output relation of motor neurons (MNs). Using experiments and computer simulations, we investigated (i) whether MN discharge statistics and muscle activation explain the variability of reflex amplitude estimates and (ii) whether these variations are reflected differently across distinct reflex amplitude estimation methods. We analyzed MU spike trains extracted from isometric contractions of the tibialis anterior muscle at 10 % and 20 % MVC (maximum voluntary contraction). Estimating reflex amplitudes based on the peristimulus frequencygram (PSF) at 10 % MVC, the linear regression between discharge rate (DR) and reflex amplitude was always positive, with p < 0.05 in 3 out of 6 subjects; however, the linear correlation was inconsistent at 20 % MVC. We thereby observed that inter-subject variability was associated with the coefficient of variation of the interspike intervals. Furthermore, the linear correlation between DR and peristimulus time histogram (PSTH) based reflex amplitudes was inconsistent for both contraction forces. To obtain further insights into the influence of MN properties, we simulated reflexes in a heterogeneous MN population using electrical circuit models and varied MN inputs. The simulations indicate that, besides mean input current and membrane noise, MN properties also contribute to the variability of reflex amplitude estimates. The MN heterogeneity is well captured by PSF-based reflex estimates but not by PSTH-based ones. These results show that variations in amplitude estimates of individual MU reflexes are due to complex interactions between intrinsic and extrinsic factors. As PSF-based reflex amplitude estimates reflect the MN size distribution, tracking PSF-based reflex amplitudes at fixed MVC levels across individual subjects could serve as a marker for investigating spinal adaptations under (patho)physiological conditions. Author summaryMotor neurons are specialized nerve cells that control human movement. Each motor neuron activates a specific set of muscle fibers, and the functional unit consisting of a motor neuron and muscle fibers is called a motor unit. We can observe the activity of motor neurons in humans by decomposing the electrical activity of muscles (the electromyogram) into contributions from individual motor units. Reflex responses of motor units are often used to study the input-output relation of motor neurons in humans. We used a combination of experiments and computer simulations to study the factors that influence the reflex amplitude of motor units during an excitatory reflex. We found that the reflex amplitude is non-linearly influenced by a number of intrinsic and extrinsic factors, e. g., motor neuron size, but also the muscle force. Additionally, we found that these factors have different effects on the results of the two common methods used to calculate the reflex amplitude. These results provide guidance on choosing a suitable evaluation method and on interpreting reflex experiments.

neuroscience↗

bioRxiv2026

Subcellular partitioning of Nhlh2 mRNA reveals how SNORD116 loss contributes to Prader-Willi Syndrome.

Deletion of the SNORD116 non-coding RNA is associated with the development of Prader-Willi Syndrome (PWS). We and others have identified NHLH2/Nhlh2 as a putative SNORD116/Snord116 target and in this study report that Nhlh2 and Snord116 are co-expressed in forebrain neurons. Nhlh2 mRNA is found predominantly in the nucleus of Snord116+ hypothalamic neurons but is evenly distributed between the nuclear and cytoplasmic compartments in Snord116- neurons. A hypothalamic cell line co-expressing Nhlh2 and Snord116 recapitulates this nuclear partitioning pattern for Nhlh2 only when the putative Snord116 binding site is present in the 3 untranslated region of the Nhlh2 mRNA. In a PWS mouse model (Snord116del), Nhlh2 mRNA levels are unchanged in Pomc neurons but are reduced and primarily cytoplasmic in lateral hypothalamic neurons. These findings demonstrate that Snord116 regulates mRNA levels via mRNA partitioning, fundamentally altering our understanding of gene expression networks in PWS. HighlightsO_LISnord116 snoRNA and its mRNA target Nhlh2 are co-expressed in forebrain neurons. C_LIO_LINhlh2 mRNA is predominantly nuclear co-localized in hypothalamic Snord116+ neurons. C_LIO_LIA putative Snord116 binding site is within the region required for cellular partitioning. C_LIO_LINhlh2 partitioning is lost in Snord116del mice, a model of Prader-Willi Syndrome. C_LI

neuroscience↗

bioRxiv2025

Independent directional tuning of the human triceps surae muscles during standing postural control

The triceps surae, composed of the soleus (SOL) and medial (MG) and lateral (LG) gastrocnemii, are anatomically-derived synergists which act as a functional unit to plantarflex the ankle. However, anatomical differences suggest that each muscle is capable of generating distinct torques at the ankle, raising the possibility that each can be independently controlled to suit the needs of a given task. This possibility was explored by investigating the activation patterns of the triceps surae during two balance tasks that use different neuromechanical control strategies to maintain equilibrium. High-density surface EMG was recorded from the triceps surae of 14 healthy young adults during multiple trials of dual-and single-legged standing. Newly developed analyses examined how each muscle tuned its activity with center of pressure (COP) movement throughout 2-D space. During dual-legged standing, only the SOL and MG were active and both tuned their activity uniformly with anteroposterior COP movement. By contrast, during single-legged standing, each muscle showed robust activation and significantly different directional tuning, with the LG most active before medial COP movement, while SOL and MG were most active before lateral COP movement. Further analyses demonstrated the LG could be activated entirely independent of the SOL and MG, and vice versa, with independent activation of each muscle causing different angular deflections of the COP during single-, but not dual-legged standing. These observations reveal a sophisticated level of neural control, whereby the nervous system exploits subtle differences between highly similar muscles to tune balance corrective adjustments in a task-dependent manner. SignificanceThe triceps surae, composed of the soleus and medial and lateral gastrocnemii, are anatomical synergists with shared roles in plantarflexion. By applying new analytical techniques to high-density surface EMG and kinetic data, we show that each triceps surae muscle can produce directionally tuned torques at the ankle joint and the nervous system exploits this functional heterogeneity to regulate balance corrective adjustments in a task-dependent manner. Analyses of regionally-defined motor unit subpopulations revealed negligible intramuscular functional differences, suggesting that each triceps surae muscle are treated as homogenous, but independent, actuators. This fractionated control of closely related lower limb postural muscles is likely critical to the maintenance of equilibrium and may be impaired by musculoskeletal and neurological impairments.

neuroscience↗

bioRxiv2024

Acute Triclosan Exposure Alters Mitochondrial Form and Function in Xenopus laevis Tadpoles, Including the Developing Brain

Mitochondrial health is critical for normal brain development, and mitochondrial toxicants impair energy production and induce mitophagy, resulting in network fission. This can substantially impact cellular and molecular pathways essential for brain development. Recent studies have shown that triclosan, a once widely used antibacterial and antifungal agent, acts as a mitochondrial uncoupler. However, the impact of triclosan on mitochondrial function in the developing brain has yet to be thoroughly investigated. We performed a series of experiments designed to assess the effects of triclosan on mitochondrial form and function in the developing Xenopus laevis tadpole brain. We injected tadpole brains with TMRM, a fluorescent reporter of mitochondrial membrane potential. After two hours, we imaged the brain using high-resolution confocal microscopy to obtain a baseline level of TMRM fluorescence, then immediately treated tadpoles with either triclosan (10uM, 5uM, 1uM, 0.5uM 0.1uM), FCCP (0.5uM), or control, and then continued imaging the brain once every five min for 30 min. We found that 10uM triclosan significantly decreased TMRM fluorescence in mitochondria in the end feet of radial glial cells in [~] 15-20 min; lower concentrations operated over a longer time course. We also observed that mitochondrial networking was disrupted as they underwent fission. We also measured metabolic function in vivo in whole tadpoles using an XF Seahorse Flux Analyzer, acutely exposing tadpoles to either triclosan (30uM, 10uM, 1uM) or control. Triclosan immediately increased oxygen consumption rates dose-dependently, suggesting mitochondrial uncoupling. These results show that triclosan has the capacity to impair mitochondrial form and function in developing neural tissue.

developmental biology↗

bioRxiv2024

Dose-Dependent Effects of PFOS on Thyroid Hormone-Driven Neurodevelopment and Metamorphic-like change in Xenopus laevis larvae

PFOS is a banned stain repellent that is a type of PFAS, a category of chemicals commonly referred to as "forever chemicals." These substances are known for their bioaccumulative nature and their resistance to degradation in the environment. Emerging data indicates that PFOS may disrupt thyroid hormone (TH) signaling, which plays a pivotal role in healthy vertebrate development, particularly neural development. Our study investigates whether PFOS interferes with TH-dependent developmental changes, with focus on the developing brain, in Xenopus laevis larvae. To assess this, we exposed five-day old larvae to varying concentrations of PFOS (25 g/L, 2.5 g/L, and 250 ng/L). Additionally, some larvae were exposed to either 15 g/L or 1.5 g/L of thyroxine to evaluate PFOSs potential interference with TH-dependent developmental mechanisms. After four days, we euthanized larvae and examined body length and hind limb size, dissected out brains and performed immunostaining for markers of neuronal proliferation and apoptosis. We found that PFOS significantly impeded overall body growth in a dose-dependent manner, irrespective of TH status. Moreover, PFOS impaired TH-stimulated hind limb development. In the brain, PFOS had no effect on proliferation but hindered TH-stimulated growth of the optic tectum. Last, PFOS increased apoptosis in the optic tectum, indicative of cytotoxicity. These findings suggest that PFOS may have the capacity to disrupt TH-dependent mechanisms involved in brain development. The observed pattern of change also suggests that its impact is cytotoxic and may not stem solely from a canonical endocrine disruption mechanism.

neuroscience↗

bioRxiv2023

Myomatrix arrays for high-definition muscle recording

Neurons coordinate their activity to produce an astonishing variety of motor behaviors. Our present understanding of motor control has grown rapidly thanks to new methods for recording and analyzing populations of many individual neurons over time. In contrast, current methods for recording the nervous systems actual motor output - the activation of muscle fibers by motor neurons - typically cannot detect the individual electrical events produced by muscle fibers during natural behaviors and scale poorly across species and muscle groups. Here we present a novel class of electrode devices ("Myomatrix arrays") that record muscle activity at unprecedented resolution across muscles and behaviors. High-density, flexible electrode arrays allow for stable recordings from the muscle fibers activated by a single motor neuron, called a "motor unit", during natural behaviors in many species, including mice, rats, primates, songbirds, frogs, and insects. This technology therefore allows the nervous systems motor output to be monitored in unprecedented detail during complex behaviors across species and muscle morphologies. We anticipate that this technology will allow rapid advances in understanding the neural control of behavior and in identifying pathologies of the motor system.

neuroscience↗

bioRxiv2022

Lead (Pb) impairs thyroid hormone mediated changes in brain development and body length in Xenopus laevis tadpoles

Lead (Pb) poisoning during early development is associated with behavioral and cognitive deficits, but the specific mechanisms by which Pb impairs brain development are not fully understood. One potential mechanism is that Pb poisoning may impair thyroid hormone (TH)- mediated changes in brain development To address this issue, we performed experiments to assess the effects of Pb poisoning on (TH) -dependent changes in cellular and molecular mechanisms in the developing Xenopus laevis tadpole brain. We treated stage 48 tadpoles to combinations of 1000 ppb Pb bath for seven days and added one of three different concentrations of thyroxine (T4) for the final two days of treatment. We found that lead exposure decreased body length, including in T4-treated tadpoles. We also performed immuno-staining for proliferative marker pH3 and found that Pb disrupts T4-induced increases in neuronal proliferation. Finally, we used syGlass VR data visualization software to measure volume of the forebrain, midbrain, and hindbrain in 3D and found that Pb exposure impaired T4-mediated changes in brain volume. Last, we found that Pb poisoning reduced the T4-mediated increase in proliferating cell nuclear antigen (PCNA), a TH-sensitive gene. These results illustrate that Pb poisoning impairs some TH-dependent changes in the developing brain.

pharmacology and toxicology↗

bioRxiv2022

SARS-CoV-2 Infects Peripheral and Central Neurons of Mice Before Viremia, Facilitated by Neuropilin-1

Neurological symptoms associated with COVID-19, acute and long-term, suggest SARS-CoV-2 affects both central and peripheral nervous systems. Although studies have shown olfactory and hematogenous entry into the brain and neuroinflammation, little attention has been paid to the susceptibility of the peripheral nervous system to infection or to alternative routes of CNS invasion. We show that neurons in the central and peripheral nervous system are susceptible to productive infection with SARS-CoV-2. Infection of K18-hACE2 mice, wild-type mice, golden Syrian hamsters, and primary neuronal cultures demonstrate viral RNA, protein, and infectious virus in peripheral nervous system neurons and satellite glial cells, spinal cord, and specific brain regions. Moreover, neuropilin-1 facilitates SARS-CoV-2 neuronal infection. Our data show that SARS-CoV-2 rapidly invades and establishes a productive infection in the peripheral and central nervous system via direct invasion of neurons prior to viremia, which may underlie some cognitive and sensory symptoms associated with COVID-19.

neuroscience↗

bioRxiv2021

Facilitation of sensory axon conduction to motoneurons during cortical or sensory evoked primary afferent depolarization (PAD) in humans

Sensory and corticospinal (CST) pathways activate spinal GABAergic interneurons with axo-axonic connections onto proprioceptive (Ia) afferents that depolarize these afferents (termed primary afferent depolarization, PAD). In rodents sensory-evoked PAD is produced by GABAA receptors at nodes of Ranvier in Ia-afferents, rather than at presynaptic terminals, and facilitates action potential propagation to motoneurons by preventing branch point failures, rather than causing presynaptic inhibition. Here we examined if PAD likewise facilitates the Ia-afferent mediated H-reflex in humans by evoking PAD with both sensory and CST stimulation. H-reflexes in several lower limb muscles were facilitated by prior conditioning from low-threshold proprioceptive, cutaneous or CST pathways, with a similar time course ([~]200 ms) to the PAD measured in rodent Ia-afferents. Long trains of repeated cutaneous or proprioceptive afferent stimulation produced long-lasting facilitation of the H-reflex for up to 2 minutes, consistent with the tonic depolarization of rodent Ia-afferents mediated by nodal 5-GABA receptors for similar stimulation trains. Facilitation of the conditioned H-reflexes was not mediated by direct facilitation of the motoneurons because isolated stimulation of sensory or CST pathways did not modulate the firing rate of tonically activated motor units in tested muscles. Furthermore, cutaneous conditioning increased the firing probability of a single motor unit during the H-reflex without increasing its firing rate at this time, indicating that the underlying excitatory postsynaptic potential (EPSP) was more probable, but not larger. These results are consistent with sensory and CST pathways activating nodal GABAA receptors that reduce intermittent failure of action potentials propagating into Ia-afferent branches. Key Points SummaryO_LIThe control of posture and movement requires peripheral sensory feedback, which was previously thought to be inhibited by specialized GABAergic neurons in the spinal cord. C_LIO_LIBased on new findings in rodents, we provide evidence in humans that sensory and corticospinal pathways that likely activate these GABAergic pathways facilitate, rather than inhibit, the flow of sensory feedback in afferents that carry information about body position, movement and effort. C_LIO_LIThese new findings of how sensory and descending pathways facilitate this sensory feedback to spinal motor neurons can now be applied to people with injury to the brain or spinal cord where these GABA neurons are affected, allowing us to understand how altered sensory control may affect residual motor function and the production of involuntary muscle spasticity. C_LI

neuroscience↗

bioRxiv2020

Reconstituted Mining Effluent Reduces Neuronal Proliferation in the Developing Brain and Slows Growth of Body and Facial Features in Wild-Caught Wood Frog Tadpoles.

Mining, whether current or inactive, generally increases salt concentrations in catchment watersheds due to precipitation on and through exposed rock surfaces. Practices like mountaintop removal mining have exacerbated this issue, with measurements of salt concentrations in nearby catchment systems well above normal levels. Nevertheless, the impact of the ionic composition of mining effluent on aquatic animal health is not well understood. This is a particularly important issue in Appalachia because it is home to an enormous diversity of organisms, including a huge array of amphibians that live in streams that receive mining effluent from operating and abandoned mines. To investigate this issue, we examined the effects of reconstituted mining effluent on the development of wild-caught wood frog (Lithobates sylvaticus) tadpoles. We collected day-old fertilized eggs from a creek near Blacksburg, VA in early March, 2018 and raised them to hatch. Tadpoles were then assigned to either sulfate or chloride-based reconstituted mining effluent diluted to six different conductivities (100 S/cm - 2,400 S/cm). After 7 or 14 days of treatment, tadpoles were euthanized and fixed in paraformaldehyde. We imaged the heads and bodies of tadpoles for morphometric analysis before dissecting out brains and immunostaining them for phospho-histone H3, which labels dividing progenitor cells in the brain. We found that sulfate-based reconstituted mining effluent significantly lowered progenitor cell division at 1200 S/cm at Day 7 and at 600 S/cm at Day 14 relative to control. Chloride-based reconstituted mining effluent was less impactful, with no significant differences observed at Day 7 and significantly lowered progenitor cell division at 2400 S/cm at Day 14. In addition, both treatments slowed growth of some head morphological features, including head size and interocular distance. Chloride treatment slowed growth of body length at Day 14 at 600 S/cm, whereas sulfate-based reconstituted mining effluent had no effect on body length. These data show that sulfate-based mining effluent has a substantial impact on aspects of neural development, whereas chloride-based reconstituted mining effluent had less effect. In contrast, chloride-based reconstituted mining effluent had a much greater impact than sulfate on body morphology and growth. These experiments demonstrate that the chemical composition of salts in mining effluent can have divergent effects on the development of amphibians.

pharmacology and toxicology↗

bioRxiv2019

Sensitivity of the paired motor unit analysis for estimation of motoneuron excitability to commonly used constraints and filters

The nervous system has a tremendous ability to modify motoneuron excitability according to task demands through neuromodulatory synaptic input to motoneurons. Neuromodulatory inputs adjust the response of the motoneuron to excitatory and inhibitory ionotropic input and can facilitate the induction of persistent inward currents (PICs). PICs amplify and prolong the motoneuron response to synaptic inputs, and PIC impairment may play a major role in motor deficits observed in pathological conditions. Noninvasive estimation of the magnitude of neuromodulatory input and persistent inward currents in human motoneurons is achieved through a paired motor unit analysis ({Delta}F) that quantifies hysteresis in the firing rates at motor unit recruitment and derecruitment. While the {Delta}F technique is commonly used for estimating motoneuron excitability, computational parameters used for the technique vary across studies. In the present study, we assessed the sensitivity of the {Delta}F technique to several criteria commonly used in selecting motor unit pairs for analysis, as well as to methods used for smoothing the instantaneous motor unit firing rates. Using HD-sEMG and motor unit decomposition we obtained 5,409 motor unit pairs from the triceps brachii of ten healthy individuals during submaximal triangle contractions. The mean (SD) {Delta}F was 4.9 (1.08) pps, consistent with previous work using intramuscular recordings. There was an exponential plateau relationship between {Delta}F and the recruitment time difference between the motor unit pairs, with the plateau occurring at approximately 1 s. There was an exponential decay relationship between {Delta}F and the derecruitment time difference between the motor unit pairs, with the decay stabilizing at approximately 1.5 s. We found that reducing or removing the minimum threshold for the correlation of the rate-rate slope for the two units did not affect {Delta}F values or variance. Additionally, we found that removing motor unit pairs in which the control unit was saturated had no significant effect on {Delta}F. Smoothing filter selection had no substantial effect on {Delta}F values and {Delta}F variance; however, the length and type of smoothing filter affected the minimum recruitment and derecruitment time differences. Our results facilitate interpretation of findings from studies that implement the {Delta}F approach but use different computational parameters.

neuroscience↗

bioRxiv2019

The flavor enhancer maltol increases pigment aggregation in dermal and neural melanophores in Xenopus laevis tadpoles

Melanophores are pigmented cells that change the distribution of pigmented melanosomes, enabling animals to appear lighter or darker for camouflage, thermoregulation, and UV-protection. A complex series of hormonal and neural mechanisms regulates melanophore pigment distribution, making these cells a valuable tool to screen toxicants as a dynamic cell type that responds rapidly to the environment. We found that maltol, a naturally occurring flavor enhancer and fragrance agent, induces melanophore pigment aggregation in a dose-dependent manner in Xenopus laevis tadpoles. To determine if maltol affects camouflage adaptation, we placed tadpoles into maltol baths situated over either white or black background. Maltol induced pigment aggregation in a similar dose-dependent pattern regardless of background color. We also tested how maltol treatment compares to melatonin treatment and found that the degree of pigment aggregation induced by maltol is similar to treatment with melatonin, but the time course differs significantly. Last, maltol had no effect on mRNA expression of pro-opiomelanocortin or melanin concentrating hormone receptor in the brain, both of which regulate camouflage-related pigment aggregation. Our results suggest that maltol does not exert its effects via the camouflage adaptation mechanism nor via melatonin-based mechanisms. These results are the first to identify a specific toxicological effect of maltol exposure and rules out several mechanisms by which maltol may exert its effects on pigment aggregation.

pharmacology and toxicology↗