Journal of Neurophysiology

Sukhanova, Khrystyna Yu; Koirala, Ankeeta; Elmslie, Keith S.

doi: 10.1152/jn.00116.2022pmid: 36043704

Skeletal muscle contraction triggers the exercise pressor reflex (EPR) to regulate the cardiovascular system response to exercise. During muscle contraction, substances are released that generate action potential activity in group III and IV afferents that mediate the EPR. Some of these substances increase afferent activity via G-protein coupled receptor (GPCR) activation, but the mechanisms are incompletely understood. We were interested in determining if tetrodotoxin-resistant (TTX-R) voltage-dependent sodium channels (NaV) were involved and investigated the effect of a mixture of such compounds (bradykinin, prostaglandin, norepinephrine, and ATP, called muscle metabolites). Using whole-cell patch clamp electrophysiology, we show that the muscle metabolites significantly increased TTX-R NaV currents. The rise-time of this enhancement averaged ~2 min, which suggests the involvement of a diffusible second messenger pathway. The effect of muscle metabolites on the current-voltage relationship, channel activation and inactivation kinetics support NaV1.9 channels as the target for this enhancement. When applied individually at the concentration used in the mixture, only prostaglandin and bradykinin significantly enhanced NaV current, but the sum of these enhancements was <1/3 that observed when the muscle metabolites were applied together. This suggests synergism between the activated GPCRs to enhance NaV1.9 current. When applied at a higher concentration, all 4 substances could enhance the current, which demonstrates that the GPCRs activated by each metabolite can enhance channel activity. The enhancement of NaV1.9 channel activity is a likely mechanism by which GPCR activation increases action potential activity in afferents generating the EPR.

Henderson, Tyler T.; Taylor, Janet L.; Thorstensen, Jacob R.; Tucker, Murray G.; Kavanagh, Justin J.

doi: 10.1152/jn.00182.2022pmid: 36001790

Serotonin (5-HT) modulates motoneuron excitability during muscle contractions, where the release of 5-HT in the central nervous system (CNS) is linked to the intensity of physical activity. Although there is evidence that enhanced availability of 5-HT can exacerbate fatigue, these effects on the development of fatigue during different contraction intensities are largely unknown. The purpose of this study was to investigate how enhanced 5-HT availability affects voluntary muscle activation and corticospinal excitability during fatigue-inducing contractions. Two experiments were performed. In the first experiment (n = 11), twelve isometric elbow flexions at 20% maximal voluntary contractions (MVC) were performed for 2-min each with 40-s rest periods. In the second experiment (n = 14), twelve maximal isometric elbow flexions were held for 10-s each with 40-s rest periods. In both experiments, the selective serotonin reuptake inhibitor (20 mg paroxetine), or a placebo, was administered in a two-way crossover-design. Muscle responses to transcranial magnetic stimulation (TMS) of the motor cortex (both experiments 1 and 2), as well as motor point stimulation of the elbow flexors (experiment 2) were assessed. Paroxetine reduced both motor cortical (p = 0.018) and motor point voluntary activation (p = 0.036) during the maximal contraction protocol. Paroxetine also reduced exercise-induced lengthening of the TMS silent period during the submaximal (p = 0.037) and maximal (p = 0.002) contraction protocols. Activation of inhibitory 5-HT1A receptors on motoneurons likely exacerbated exercise-induced reductions in voluntarily drive to the elbow flexors. However, 5-HT modulation of motor activity also appeared at the supraspinal level.

Schwalm, Miriam; Tabuena, Dennis R.; Easton, Curtis; Richner, Thomas J.; Mourad, Pierre; Watari, Hirofumi; Moody, William J.; Stroh, Albrecht

doi: 10.1152/jn.00424.2021pmid: 35975935

The spatiotemporal representation of neural activity during rest and upon sensory stimulation in cortical areas is highly dynamic, and may be predominantly governed by cortical state. On the mesoscale level, intrinsic neuronal activity ranges from a persistent state, generally associated with a sustained depolarization of neurons, to a bimodal, slow-wave like state with bursts of neuronal activation, alternating with silent periods. These different activity states are prevalent under certain types of sedatives, or are associated with specific behavioral or vigilance conditions. Neurophysiological experiments assessing circuit activity, usually assume a constant underlying state, yet reports of variability of neuronal responses under seemingly constant conditions are common in the field. Even when a certain type of neural activity or cortical state can stably be maintained over time, the associated response properties are highly relevant for explaining experimental outcomes. Here we describe the spatiotemporal characteristics of ongoing activity and sensory evoked responses under two predominant functional states in the sensory cortices of mice: persistent activity (PA) and slow wave activity (SWA). Using electrophysiological recordings, and local and wide-field calcium recordings, we examine whether spontaneous and sensory evoked neuronal activity propagate throughout the cortex in a state dependent manner. We find that PA and SWA differ in their spatiotemporal characteristics which determine the cortical network's response to a sensory stimulus. During PA state, sensory stimulation elicits gamma-based short-latency responses which precisely follow each stimulation pulse and are prone to adaptation upon higher stimulation frequencies. Sensory responses during SWA are more variable, dependent on refractory periods following spontaneous slow waves. While spontaneous slow waves propagated in anterior-posterior direction in a majority of observations, the direction of propagation of stimulus-elicited wave depends on the sensory modality. These findings suggest that cortical state explains variance and should be considered when investigating multi-scale correlates of functional neurocircuit activity.

Maillet, Jean; Avrillon, Simon; Nordez, Antoine; Rossi, Jeremy; Hug, François

doi: 10.1152/jn.00237.2022pmid: 36001792

Whether the neural control of manual behaviours differs between the dominant and non-dominant hand is poorly understood. This study aimed to determine whether the level of common synaptic input to motor neurons innervating the same or different muscles differs between the dominant and the non-dominant hand. Seventeen participants performed two motor tasks with distinct mechanical requirements: an isometric pinch and an isometric rotation of a pinched dial. Each task was performed at 30% of maximum effort and was repeated with the dominant and non-dominant hand. Motor units were identified from two intrinsic (flexor digitorum interosseous and thenar) and one extrinsic muscle (flexor digitorum superficialis) from high-density surface electromyography recordings. Two complementary approaches were used to estimate common synaptic inputs. First, we calculated the coherence between groups of motor neurons from the same and from different muscles. Then, we estimated the common input for all pairs of motor neurons by correlating the low-frequency oscillations of their discharge rate. Both analyses led to the same conclusion, indicating less common synaptic input between motor neurons innervating different muscles in the dominant hand than in the non-dominant hand, which was only observed during the isometric rotation task. No between-side differences in common input were observed between motor neurons of the same muscle. This lower level of common input could confer higher flexibility in the recruitment of motor units, and therefore, in mechanical outputs. Whether this difference between the dominant and non-dominant arm is the cause or the consequence of handedness remains to be determined.

Harris, Christian M.; Szczecinski, Nicholas S.; Büschges, Ansgar; Zill, Sasha N.

doi: 10.1152/jn.00285.2022pmid: 36043841

In control of walking, sensory signals of decreasing forces are used to regulate leg lifting in swing and to detect loss of substrate grip (leg slipping). We used extracellular recordings in two insect species to characterize and model responses to force decrements of tibial campaniform sensilla, receptors that detect forces as cuticular strains. Discharges to decreasing forces did not occur upon direct stimulation of the sites of mechanotransduction (cuticular caps) but were readily elicited by bending forces applied to the leg. Responses to bending force decreases were phasic but had rate sensitivities similar to discharges elicited by force increases in the opposite direction. Application of stimuli of equivalent amplitude at different offset levels showed that discharges were strongly dependent upon the tonic level of loading: firing was maximal to complete unloading of the leg but substantially decreased or eliminated by sustained loads. The contribution of cuticle properties to sensory responses was also evaluated: discharges to force increases showed decreased adaptation when mechanical stress relaxation was minimized; firing to force decreases could be related to viscoelastic 'creep' in the cuticle. Discharges to force decrements apparently occur due to cuticle viscoelasticity which generates transient strains similar to bending in the opposite direction. Tuning of sensory responses through cuticular and membrane properties effectively distinguishes loss of substrate grip/complete unloading from force variations due to gait in walking. We have successfully reproduced these properties in a mathematical model of the receptors. Sensors with similar tuning could fulfill these functions in legs of walking machines.

Park, Sungwoo; Finley, James M.

doi: 10.1152/jn.00377.2021pmid: 35946807

A fundamental feature of human locomotor control is the need to adapt walking patterns in response to changes in the environment. For example, when people walk on a split-belt treadmill, which has belts that move at different speeds, they adapt to the asymmetric speed constraints by reducing spatiotemporal asymmetry. Here, we aim to understand the role of balance control as a potential factor driving this adaptation process. We recruited 24 healthy, young adults to adapt to walking on a split-belt treadmill while either holding on to a handrail or walking with free arm swing. We measured whole-body angular momentum and step length asymmetry as measures of dynamic balance and spatiotemporal asymmetry, respectively. To understand how changes in intersegmental coordination influenced whole-body angular momentum, we also measured segmental angular momenta and the coefficient of cancellation. When participants were initially exposed to the asymmetry in belt speeds, we observed an increase in whole-body angular momentum that was due to both an increase in the momentum of individual segments and a reduction in the coefficient of cancellation. Holding on to a handrail reduced the perturbation to asymmetry during the early phase of adaptation and resulted in a smaller after-effect during early post-adaptation. In addition, the stabilization provided by holding on to a handrail led to reductions in the coupling between angular momentum and asymmetry. These results suggest that regulation of dynamic balance is most important during the initial, transient phase of adaptation to walking on a split-belt treadmill.

Kuebler, Isabel R. K.; Jolton, Joshua A.; Hermreck, Chase; Hubbard, Nicholas A.; Wakabayashi, Ken T.

doi: 10.1152/jn.00257.2022pmid: 36043803

Glucose is the brain's primary energetic resource. The brain's use of glucose is dynamic, balancing delivery from the neurovasculature with local metabolism. While glucose metabolism is known to differ in humans with and without Methamphetamine Use Disorder (MUD), it is unknown how central glucose regulation changes with acute methamphetamine experience. Here, we determined how intravenous methamphetamine regulates extracellular glucose levels in a brain region implicated in MUD-like behavior, the lateral hypothalamus (LH). We measured extracellular LH glucose in awake adult male and female drug-naive Wistar rats using enzyme-linked amperometric glucose biosensors. Changes in LH glucose were monitored during a single session after: (1) natural non-drug stimuli (novel object presentation and a tail-touch), (2) increasing cumulative doses of intravenous methamphetamine (0.025, 0.05, 0.1 and 0.2 mg/kg), and (3) an injection of 60 mg of glucose. We found second-scale fluctuations in LH glucose in response to natural stimuli which differed by both stimulus type and sex. While rapid, second-scale changes in LH glucose during methamphetamine injections were variable, slow, minute-scale changes following most injections were robust and resulted in a reduction in LH glucose levels. Dose and sex differences at this timescale indicated that female rats may be more sensitive to the impact of methamphetamine on central glucose regulation. These findings suggest that the effects of MUD on healthy brain function may be linked to how methamphetamine alters extracellular glucose regulation in the LH and point to possible mechanisms by which methamphetamine influences central glucose metabolism more broadly.

Wang, Siyan; Kfoury, Cristen; Marion, Alexis; Lévesque, Maxime; Avoli, Massimo

doi: 10.1152/jn.00192.2022pmid: 36043700

GABAA signaling is surprisingly involved in the initiation of epileptiform activity since increased interneuron firing, presumably leading to excessive GABA release, often precedes ictal discharges. Field potential theta (4-12 Hz) oscillations, which are thought to mirror the synchronization of interneuron networks, also lead to ictogenesis. However, the exact role of parvalbumin-positive (PV) interneurons in generating theta oscillations linked to epileptiform discharges remains unexplored. We analyzed here the field responses recorded in the CA3, entorhinal cortex (EC) and dentate gyrus (DG) during 8 Hz optogenetic stimulation of PV-positive interneurons in brain slices obtained from PV-ChR2 mice during 4-aminopyridine (4AP) application. This optogenetic protocol triggered similar field oscillations in both control conditions and during 4AP application. However, in the presence of 4AP, optogenetic stimuli also induced: (i) interictal discharges that were associated in all regions with 8 Hz field oscillations; and (ii) low-voltage fast onset ictal discharges. Interictal and ictal events occurred more frequently during optogenetic activation than during periods of no stimulation. 4AP also increased synchronicity during PV-interneuron activation in all three regions. In opsin-negative mice, optogenetic stimulation did not change the rate of both types of epileptiform activity. Our findings suggest that PV-interneuron recruitment at theta (8 Hz) frequency contributes to epileptiform synchronization in limbic structures in the in vitro 4AP model.

Berger, Michael J.; Adewuyi, Adenike A.; Fox, Ida K.; Franz, Colin K.

doi: 10.1152/jn.00289.2022pmid: 36043801

In this review, we highlight the important role of the clinical electrodiagnostic (EDX) evaluation after cervical spinal cord injury (SCI). Our discussion focuses on the need for timely, frequent and accurate EDX evaluations in the context of nerve transfer surgery to restore critical upper limb functions, including elbow extension, hand opening and hand closing. The EDX evaluation is crucial to define the extent of lower motor neuron lesions and determine candidacy for surgery. We also discuss the important role of the post-operative EDX evaluation in determining prognosis and supporting rehabilitation. We propose a practical framework for EDX evaluation in this clinical setting.

Zhou, Weiwei; Kruse, Elizabeth A.; Brower, Rylee; North, Ryan; Joiner, Wilsaan M.

doi: 10.1152/jn.00520.2021pmid: 36043804

Recent studies have shown that adaptation to visual feedback perturbations during arm reaching movements involves implicit and explicit learning components. Evidence also suggests that explicit, intentional learning mechanisms are largely responsible for savings - a faster recalibration compared to initial training. However, the extent explicit learning mechanisms facilitate learning and early savings (i.e., the rapid recall of previous performance) for motion state-dependent learning is generally unknown. To address this question we compared the early savings/recall achieved by two groups of human subjects. One experienced physical perturbations (a velocity-dependent force-field, vFF) to promote adaptation that is thought to be a largely implicit process. The second was only given visual feedback of the required force-velocity relationship; subjects moved in force channels and we provided visual feedback of the lateral force exerted during the movement, as well as the required force pattern based on the movement velocity. Thus, subjects were shown explicit information on the extent the applied temporal pattern of force matched the required velocity-dependent force profile if the force-field perturbation had been applied. After training, both groups experienced a decay and washout period, which was followed by a re-exposure block to assess early savings/recall. Although decay was faster for the explicit visual feedback group, the single-trial recall was similar to the physical perturbation group. Thus, comparable to visual feedback perturbations, conscious modification of motor output based on motion state-dependent feedback demonstrates rapid recall, but this adjustment is less stable than adaptation based on experiencing the multisensory errors that accompany physical perturbations.