Biology subjects

Taylor, J. L.

Publications and source records attributed to Taylor, J. L..

5 recordsLinked to original sources

bioRxiv2023

Excitatory drive to spinal motoneurones is necessary for serotonin to modulate motoneurone excitability via 5-HT2 receptors in humans

Serotonin modulates corticospinal excitability, motoneurone firing rates and contractile strength via 5-HT2 receptors. However, the effects of these receptors on cortical and motoneurone excitability during voluntary contractions have not been explored in humans. Therefore, the purpose of this study was to investigate how 5-HT2 antagonism affects corticospinal and motoneuronal excitability with and without descending drive to motoneurones. Twelve individuals (aged 24 {+/-} 4 years old) participated in a double-blind, placebo-controlled, crossover study, whereby the 5-HT2 antagonist cyproheptadine was administered. Transcranial magnetic stimulation (TMS) was delivered to the motor cortex to produce motor evoked potentials (MEPs) and electrical stimulation at the cervicomedullary junction was used to generate cervicomedullary motor evoked potentials (CMEPs) in the biceps brachii at rest and during a range of submaximal elbow flexions. Evoked potentials were also obtained after a conditioning TMS pulse to produce conditioned MEPs and CMEPs (100 ms inter-stimulus interval). Compared to placebo, 5-HT2 antagonism reduced maximal elbow flexion torque (p = 0.004), unconditioned MEP amplitude at rest (p = 0.003), conditioned MEP amplitude at rest (p = 0.033), and conditioned MEP amplitude during contractions (p = 0.020). 5-HT2 antagonism also increased unconditioned CMEP amplitude during voluntary contractions (p = 0.041) but not at rest. Although 5-HT2 antagonism increased long-interval intracortical inhibition, net corticospinal excitability was unaffected during voluntary contractions. Given that spinal motoneurone excitability was only affected when descending drive to motoneurones was present, the current study indicates that excitatory drive is necessary for 5-HT2 receptors to regulate motoneurone excitability but not intracortical circuits. Significance statementCellular and animal preparations have revealed that somatodendritic 5-HT2 receptors on motoneurones can modulate motoneurone excitability. However, it is mostly unknown how 5-HT2 receptors modulate motor cortical and motoneurone activity to generate muscle contractions in humans. Here we show that antagonism of 5-HT2 receptors reduced muscle responses to motor cortical stimulation only when the muscle was at rest, or when voluntary motor activity was interrupted by a conditioning TMS stimulus. In contrast, antagonism of 5-HT2 receptors increased the muscle response to cervicomedullary electrical stimulation, but only when descending drive to motoneurones was present. These findings not only suggest that 5-HT2 receptors modulate intracortical and motoneurone activity, but sustained synaptic excitation of motoneurones is required for serotonergic mechanisms to modulate motoneurones.

neuroscience↗

bioRxiv2022

A back-translational study of descending interactions with central mechanisms of hyperalgesia induced by high frequency stimulation in rat and human

In humans and animals, high frequency electrocutaneous stimulation (HFS) may produce an early long-term potentiation-like sensitisation. Peripheral and central modulatory processes are proposed to play a role. To explore the impact of descending inhibitory pathway activation on the development of HFS-induced hyperalgesia, we concurrently applied HFS with i) a conditioned pain modulation (CPM) paradigm during psychophysical testing in humans, or ii) a diffuse noxious inhibitory controls (DNIC) paradigm during in vivo electrophysiological recording of spinal neurones in anaesthetised animals in parallel studies that utilised identical stimuli. HFS induced enhanced perceptual responses to pin-prick stimuli in cutaneous areas secondary to the area of stimulation in humans and heightened the excitability of spinal neurones in rats (which exhibited stimulus intensity dependent coded responses to pin-prick stimulation in a manner that tracked with human psychophysics), where we also observed indicators of increased central neuronal hyperexcitability. In humans, a HFS(+CPM) paradigm did not alter primary or secondary hyperalgesia, and the area and pain intensity of secondary hyperalgesia did not correlate with temporal summation of pain or CPM magnitude, while in rats application of a DNIC paradigm concurrent to HFS did not impact the development of neuronal hyperexcitability. Concordance between human and rat data supports their translational validity. Our finding that excitatory signalling exceeds inhibitory controls suggests that dampening facilitatory mechanisms may be a preferable strategy for certain chronic pain states. If facilitatory mechanisms dominate, our data could explain why enhancing activity in descending inhibitory controls is not sufficient to induce pain relief in vulnerable patients.

neuroscience↗

bioRxiv2020

Passive muscle stretching reduces estimates of persistent inward current strength in soleus motor units

Prolonged ([≥]60 s) passive muscle stretching acutely reduces maximal force production at least partly through a suppression of efferent neural drive. The origin of this neural suppression has not been determined, however some evidence suggests that reductions in the amplitude of persistent inward currents (PICs) in the motoneurons may be important. The aim of the present study was to determine whether acute passive (static) muscle stretching affects PIC strength in gastrocnemius medialis (GM) and soleus (SOL) motor units. We calculated the difference in instantaneous discharge rates at recruitment and derecruitment ({Delta}F) for pairs of motor units in GM and SOL during triangular isometric plantar flexor contractions (20% maximum) both before and immediately after a 5-min control period and immediately after five 1-min passive plantar flexor stretches. After stretching there was a significant reduction in SOL {Delta}F (-25.6%; 95%CI = -45.1 to -9.1 %, p=0.002) but not GM {Delta}F. These data suggest passive muscle stretching can reduce the intrinsic excitability, via PICs, of SOL motor units. These findings (1) suggest that PIC strength might be reduced after passive stretching, (2) are consistent with previously-established post-stretch decreases in SOL but not GM EMG amplitudes during contraction, and (3) indicate that reductions in PIC strength could underpin the stretch-induced force loss. SUMMARY STATEMENTMotoneurons require an amplification mechanism to operate within the firing frequencies observed during normal motor behaviour. Here we present evidence that this amplification mechanism is reduced after passive muscle stretching.

physiology↗

bioRxiv2019

Scrambling the skin: Simulated skin re-arrangement using apparent motion

I.AO_SCPCAPBSTRACTC_SCPCAPAn age-old hypothesis proposes that object motion across the receptor surface organizes sensory maps (Lotze, 19th century). Skin patches learn their relative positions from the order in which they are stimulated during motion events. We test this idea by reversing the local motion within a 6-point apparent motion sequence along the forearm. In the Scrambled sequence, two middle locations were touched in reversed order (1-2-4-3-5-6, followed by 6-5-3-4-2-1, in a continuous loop). This created a local acceleration, a double U-turn, within an otherwise constant-velocity motion, as if the physical location of skin patches 3 and 4 was surgically swapped. The control condition, Orderly, proceeded at constant velocity at inter-stimulus onset interval (ISOI) of 120 ms. In the test, our twenty participants reported motion direction between the two middle tactors, presented on their own at 75, 120 or 190-ms ISOI. Results show degraded motion discrimination following exposure to Scrambled pattern: for the 120-ms test stimulus, it was 0.31 d weaker than following Orderly conditioning (p = .007). This is the aftereffect we expected; its maximal expression would be a complete reversal in perceived motion direction between locations 3 and 4 for either motion direction. We propose that the somatosensory system was beginning to correct reversed local motion to uncurl and remove the U-turns that always occurred on the same part of the receptor surface. Such de-correlation between accelerations and their location on the sensory surface is one possible mechanism for organization of sensory maps.

neuroscience↗

bioRxiv2019

Selective Affimers Recognize BCL-2 Family Proteins Through Non-Canonical Structural Motifs

The BCL-2 family is a challenging set of proteins to target selectively due to sequence and structural homologies across the family. Selective ligands for the BCL-2 family regulators of apoptosis are desirable as probes to understand cell biology and apoptotic signalling pathways, and as starting points for inhibitor design. We have used phage display to isolate Affimer reagents (non-antibody binding proteins based on a conserved scaffold) to identify ligands for MCL-1, BCL-xL, BCL-2, BAK and BAX, then used multiple biophysical characterisation methods to probe the interactions. We established that purified Affimers elicit selective and potent recognition of their target BCL-2 protein. For anti-apoptotic targets, competitive inhibition of their canonical protein-protein interactions is demonstrated. Co-crystal structures reveal an unprecedented mode of molecular recognition; where a BH3 helix is normally bound, flexible loops from the Affimer dock into the BH3 binding cleft. Moreover, the Affimers induce a change in the target proteins towards a desirable drug bound like conformation. These results indicate Affimers can be used as alternative templates to inspire design of selective BCL-2 family modulators, and provide proof-of-concept for the elaboration of selective non-antibody binding reagents for use in cell-biology applications.

biochemistry↗