Search

Motoneuron properties and their firing patterns undergo significant changes throughout development and in response to neuromodulators such as serotonin. Here, we examined the age‐related development of self‐sustained firing and general excitability of tibialis anterior motoneurons in a young development (7–17 years), young adult (18–28 years) and adult (32–53 years) group, as well as in a separate group of participants taking selective serotonin reuptake inhibitors (SSRIs, aged 11–28 years). Self‐sustained firing, as measured by ΔF, was larger in the young development (∼5.8 Hz, n = 20) compared to the young adult (∼4.9 Hz, n = 13) and adult (∼4.8 Hz, n = 8) groups, consistent with a developmental decrease in self‐sustained firing mediated by persistent inward currents (PIC). ΔF was also larger in participants taking SSRIs (∼6.5 Hz, n = 9) compared to their age‐matched controls (∼5.3 Hz, n = 26), consistent with increased levels of spinal serotonin facilitating the motoneuron PIC. Participants in the young development and SSRI groups also had higher firing rates and a steeper acceleration in initial firing rates (secondary ranges), consistent with the PIC producing a steeper acceleration in membrane depolarization at the onset of motoneuron firing. In summary, both the young development and SSRI groups exhibited increased intrinsic motoneuron excitability compared to the adults, which, in the young development group, was also associated with a larger unsteadiness in the dorsiflexion torque profiles. We propose several intrinsic and extrinsic factors that affect both motoneuron PICs and cell discharge which vary during development, with a time course similar to the changes in motoneuron firing behaviour observed in the present study. Key points: Neurons in the spinal cord that activate muscles in the limbs (motoneurons) undergo increases in excitability shortly after birth to help animals stand and walk.We examined whether the excitability of human ankle flexor motoneurons also continues to change from child to adulthood by recording the activity of the muscle fibres they innervate.Motoneurons in children and adolescents aged 7–17 years (young development group) had higher signatures of excitability that included faster firing rates and more self‐sustained activity compared to adults aged ≥18 years.Participants aged 11–28 years of age taking serotonin reuptake inhibitors had the highest measures of motoneuron excitability compared to their age‐matched controls.The young development group also had more unstable contractions, which might partly be related to the high excitability of the motoneurons. [ABSTRACT FROM AUTHOR]

Suppression of the extensor H‐reflex by flexor afferent conditioning is thought to be produced by a long‐lasting inhibition of extensor Ia afferent terminals via GABAA receptor‐activated primary afferent depolarization (PAD). Given the recent finding that PAD does not produce presynaptic inhibition of Ia afferent terminals, we examined in 28 participants if H‐reflex suppression is instead mediated by post‐activation depression of the extensor Ia afferents triggered by PAD‐evoked spikes and/or by a long‐lasting inhibition of the extensor motoneurons. A brief conditioning vibration of the flexor tendon suppressed both the extensor soleus H‐reflex and the tonic discharge of soleus motor units out to 150 ms following the vibration, suggesting that part of the H‐reflex suppression during this period was mediated by postsynaptic inhibition of the extensor motoneurons. When activating the flexor afferents electrically to produce conditioning, the soleus H‐reflex was also suppressed but only when a short‐latency reflex was evoked in the soleus muscle by the conditioning input itself. In mice, a similar short‐latency reflex was evoked when optogenetic or afferent activation of GABAergic (GAD2+) neurons produced a large enough PAD to evoke orthodromic spikes in the test Ia afferents, causing post‐activation depression of subsequent monosynaptic EPSPs. The long duration of this post‐activation depression and related H‐reflex suppression (seconds) was similar to rate‐dependent depression that is also due to post‐activation depression. We conclude that extensor H‐reflex inhibition by brief flexor afferent conditioning is produced by both post‐activation depression of extensor Ia afferents and long‐lasting inhibition of extensor motoneurons, rather than from PAD inhibiting Ia afferent terminals. Key points: Suppression of extensor H‐reflexes by flexor afferent conditioning was thought to be mediated by GABAA receptor‐mediated primary afferent depolarization (PAD) shunting action potentials in the Ia afferent terminal.In line with recent findings that PAD has a facilitatory role in Ia afferent conduction, we show here that when large enough, PAD can evoke orthodromic spikes that travel to the Ia afferent terminal to evoke EPSPs in the motoneuron.These PAD‐evoked spikes also produce post‐activation depression of Ia afferent terminals and may mediate the short‐ and long‐lasting suppression of extensor H‐reflexes in response to flexor afferent conditioning.Our findings highlight that we must re‐examine how changes in the activation of GABAergic interneurons and PAD following nervous system injury or disease affects the regulation of Ia afferent transmission to spinal neurons and ultimately motor dysfunction in these disorders. [ABSTRACT FROM AUTHOR]

Sensory and corticospinal tract (CST) pathways activate spinal GABAergic interneurons that have axoaxonic connections onto proprioceptive (Ia) afferents that cause long‐lasting depolarizations (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 spike propagation to motoneurons by preventing branch‐point failures, rather than causing presynaptic inhibition. We examined in 40 human participants whether putative activation of Ia‐PAD by sensory or CST pathways can also facilitate Ia afferent activation of motoneurons via the H‐reflex. H‐reflexes in several leg muscles were facilitated by prior conditioning from low‐threshold proprioceptive, cutaneous or CST pathways, with a similar long‐lasting time course (∼200 ms) to phasic PAD measured in rodent Ia afferents. Long trains of cutaneous or proprioceptive afferent conditioning produced longer‐lasting facilitation of the H‐reflex for up to 2 min, consistent with tonic PAD in rodent Ia afferents mediated by nodal α5‐GABAA receptors for similar stimulation trains. Facilitation of H‐reflexes by this conditioning was likely not mediated by direct facilitation of the motoneurons because isolated stimulation of sensory or CST pathways did not alone facilitate the tonic firing rate of motor units. Furthermore, cutaneous conditioning increased the firing probability of single motor units (motoneurons) during the H‐reflex without increasing their firing rate at this time, indicating that the underlying excitatory postsynaptic potential 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: Controlled execution of posture and movement requires continually adjusted feedback from peripheral sensory pathways, especially those that carry proprioceptive information about body position, movement and effort.It was previously thought that the flow of proprioceptive feedback from Ia afferents was only reduced by GABAergic neurons in the spinal cord that sent axoaxonic projections to the terminal endings of sensory axons (termed GABAaxo neurons).Based on new findings in rodents, we provide complementary evidence in humans to suggest that sensory and corticospinal pathways known to activate GABAaxo neurons that project to dorsal parts of the Ia afferent also increase the flow of proprioceptive feedback to motoneurons in the spinal cord.These findings support a new role for spinal GABAaxo neurons in facilitating afferent feedback to the spinal cord during voluntary or reflexive movements. [ABSTRACT FROM AUTHOR]

Peripheral sensory afferents in the hand activate both excitatory and inhibitory intracortical circuits to potentially facilitate and prune descending motor commands. In this study, we characterized how afferent inputs modulate the excitability of cortical circuits in the leg area of the primary motor cortex by examining how stimulation of the tibial nerve (TN) at the ankle alters motor evoked potentials (MEPs) activated by transcranial magnetic stimulation (TMS). Resting MEPs in the tibialis anterior (TA) muscle were facilitated in response to heteronymous activation of the TN 45–50 ms earlier, whereas MEPs were inhibited at interstimulus intervals of 32.5–37.5 ms. Similar time-dependent modulation occurred in the soleus (SOL) muscle with stimulation of the homonymous posterior tibial nerve (PTN) at the knee. To determine the site of this afferent-evoked facilitation and inhibition (spinal or cortical), we compared the effects of afferent stimulation to responses evoked at subcortical sites. At interstimulus intervals where MEP facilitation was observed (near 50 ms), spinal H-reflexes and responses evoked from corticospinal tract stimulation at the brainstem were predominantly depressed by the sensory stimulus suggesting that the observed MEP facilitation was cortical in origin. At interstimulus intervals where MEP depression was observed (near 35 ms), brainstem evoked responses were depressed to a similar degree and, in contrast to the hand, this suggests that spinal rather than cortical circuits mediate short-latency afferent inhibition (SAI) of leg MEPs. When the MEP was facilitated by afferent inputs, short-interval intracortical inhibition (SICI) was reduced and intracortical facilitation (ICF) was increased, but long-interval intracortical inhibition (LICI) at a 100 ms interval was unchanged. In addition, sensory excitation increased the recruitment of early, middle and late descending corticospinal volleys as evidenced from increases in MEP facilitation at the corresponding I-wave periodicity. We propose that sensory activation from the leg has a diffuse and predominantly facilitatory effect on the leg primary motor cortex. [ABSTRACT FROM AUTHOR]