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Cholestenoic acids are formed as intermediates in metabolism of cholesterol to bile acids, and the biosynthetic enzymes that generate cholestenoic acids are expressed in the mammalian CNS. Here, we evaluated the cholestenoic acid profile of mammalian cerebrospinal fluid (CSF) and determined that specific cholestenoic acids activate the liver X receptors (LXRs), enhance islet-1 expression in zebrafish, and increase the number of oculomotor neurons in the developing mouse in vitro and in vivo. While 3β,7α-dihydroxycholest-5-en-26-oic acid (3β,7α-diHCA) promoted motor neuron survival in an LXR-dependent manner, 3β-hydroxy-7-oxocholest-5-en-26-oic acid (3βH,7O-CA) promoted maturation of precursors into islet-1+ cells. Unlike 3β,7α-diHCA and 3βH,7O-CA, 3β-hydroxycholest-5-en-26-oic acid (3β-HCA) caused motor neuron cell loss in mice. Mutations in CYP7B1 or CYP27A1, which encode enzymes involved in cholestenoic acid metabolism, result in different neurological diseases, hereditary spastic paresis type 5 (SPG5) and cerebrotendinous xanthomatosis (CTX), respectively. SPG5 is characterized by spastic paresis, and similar symptoms may occur in CTX. Analysis of CSF and plasma from patients with SPG5 revealed an excess of the toxic LXR ligand, 3β-HCA, while patients with CTX and SPG5 exhibited low levels of the survival-promoting LXR ligand 3β,7α-diHCA. Moreover, 3β,7α-diHCA prevented the loss of motor neurons induced by 3β-HCA in the developing mouse midbrain in vivo.Our results indicate that specific cholestenoic acids selectively work on motor neurons, via LXR, to regulate the balance between survival and death.

Motor learning relies on experience-dependent plasticity in relevant neural circuits. In four experiments, we provide initial evidence and a double-blinded, sham-controlled replication (Experiment I-II) demonstrating that motor learning involving ballistic index finger movements is improved by preceding paired corticospinal-motoneuronal stimulation (PCMS), a human model for exogenous induction of spike-timing-dependent plasticity. Behavioral effects of PCMS targeting corticomotoneuronal (CM) synapses are order- and timing-specific and partially bidirectional (Experiment III). PCMS with a 2 ms inter-arrival interval at CM-synapses enhances learning and increases corticospinal excitability compared to control protocols. Unpaired stimulations did not increase corticospinal excitability (Experiment IV). Our findings demonstrate that non-invasively induced plasticity interacts positively with experience-dependent plasticity to promote motor learning. The effects of PCMS on motor learning approximate Hebbian learning rules, while the effects on corticospinal excitability demonstrate timing-specificity but not bidirectionality. These findings offer a mechanistic rationale to enhance motor practice effects by priming sensorimotor training with individualized PCMS. Whether paired corticospinal-motoneuronal stimulation (PCMS)-protocols can promote motor learning and how PCMS protocols interact with mechanisms of experience-dependent plasticity is not fully understood. Here authors show that non-invasively induced plasticity targeting corticomotoneuronal synapses promotes motor learning by interacting positively with experience-dependent plasticity.

Neuromodulation plays a central role in human movement control. An imbalance of neurotransmitters, especially dopamine and serotonin, can be associated with various neurological disorders causing tremors or spasms. Specifically, serotonin was shown to scale motoneuron excitability following intense muscle contractions, affecting short-latency reflexes. Likely, it may also influence motoneuron modulation in prolonged contractions, although this lacks experimental evidence. An intriguing test case for this hypothesis is presented by the Kohnstamm phenomenon, where sustained muscle contractions lead to prolonged amplified EMG activity and involuntary motions, aligning with the timescale of serotonergic amplification. The suspected serotonin influence on this effect was tested in a placebo-controlled human user study with 14 participants, where half were administered the serotonin antagonist Cyproheptadine and the other half a placebo. Comparing EMG and force responses after inducing the Kohnstamm phenomenon in the deltoid muscles revealed statistically significant faster EMG decay with the serotonin antagonist, while decay remained consistent in the placebo group compared to the response of the same participant group without medication. The force measurements showed the same trend, although no significance. This provides new data-based evidence that serotonin contributes to long-term motoneuron modulation, extending previous findings about the dedicated role and influence of this neurotransmitter. Additionally, the work suggests the phenomenon as an interesting test case to investigate the dedicated involvement of different neurocontrol mechanisms such as Persistent Inward Currents.

The aim of the present study was to investigate the acute effect of caffeine or quercetin ingestion on motor unit firing patterns and muscle contractile properties before and after resistance exercise. High-density surface electromyography (HDs-EMG) during submaximal contractions and electrically elicited torque in knee extensor muscles were measured before (PRE) and 60 min after (POST1) ingestion of caffeine, quercetin glycosides, or placebo, and after resistance exercise (POST2) in ten young males. The Convolution Kernel Compensation technique was used to identify individual motor units of the vastus lateralis muscle for the recorded HDs-EMG. Ingestion of caffeine or quercetin induced significantly greater decreases in recruitment thresholds (RTs) from PRE to POST1 compared with placebo (placebo: 94.8 ± 9.7%, caffeine: 84.5 ± 16.2%, quercetin: 91.9 ± 36.7%), and there were significant negative correlations between the change in RTs (POST1-PRE) and RT at PRE for caffeine (rs = − 0.448, p < 0.001) and quercetin (rs =  − 0.415, p = 0.003), but not placebo (rs =  − 0.109, p = 0.440). Significant positive correlations between the change in firing rates (POST2-POST1) and RT at PRE were noted with placebo (rs = 0.380, p = 0.005) and quercetin (rs = 0.382, p = 0.007), but not caffeine (rs = 0.069, p = 0.606). No significant differences were observed in electrically elicited torque among the three conditions. These results suggest that caffeine or quercetin ingestion alters motor unit firing patterns after resistance exercise in different threshold-dependent manners in males.

BackgroundMotor unit (MU) activation during maximal contractions is lower in children compared with adults. Among adults, discrete MU activation differs, depending on the rate of contraction. We investigated the effect of contraction rate on discrete MU activation in boys and men.MethodsFollowing a habituation session, 14 boys and 20 men completed two experimental sessions for knee extension and wrist flexion, in random order. Maximal voluntary isometric torque (MVIC) was determined before completing trapezoidal isometric contractions (70%MVIC) at low (10%MVIC/s) and high (35%MVIC/s) contraction rates. Surface electromyography was captured from the vastus lateralis (VL) and flexor carpi radialis (FCR) and decomposed into individual MU action potential (MUAP) trains.ResultsIn both groups and muscles, the initial MU firing rate (MUFR) was greater (p < 0.05) at high compared with low contraction rates. The increase in initial MUFR at the fast contraction in the VL was greater in men than boys (p < 0.05). Mean MUFR was significantly lower during fast contractions only in the FCR (p < 0.05). In both groups and muscles, the rate of decay of MUFR with increasing MUAP amplitude was less steep (p < 0.05) during fast compared with slow contractions.ConclusionIn both groups and muscles, initial MUFRs, as well as MUFRs of large MUs were higher during fast compared with slow contractions. However, in the VL, the increase in initial MUFR was greater in men compared with boys. This suggests that in large muscles, men may rely more on increasing MUFR to generate torque at faster rates compared with boys.

IntroductionWe tested two strategies that hypothetically increase serotonin availability (α-lactalbumin consumption and a remote submaximal handgrip contraction) on estimates of persistent inward currents (PICs) amplitude of soleus muscle in healthy participants.MethodsWith a randomised, double-blind, and cross-over design, 13 healthy participants performed triangular-shaped ramp contractions with their plantar flexors (20% of maximal torque), followed by a 30-s handgrip sustained contraction (40% of maximal force) and consecutive repeated triangular-shaped contractions. This was performed before and after the consumption of either 40 g of α-lactalbumin, an isonitrogenous beverage (Zein) or an isocaloric beverage (Corn-starch). Soleus motor units discharge rates were analysed from high-density surface electromyography signals. PICs were estimated by calculating the delta frequency (ΔF) of motor unit train spikes using the paired motor unit technique.ResultsΔF (0.19 pps; p = 0.001; d = 0.30) and peak discharge rate (0.20 pps; p < 0.001; d = 0.37) increased after the handgrip contraction, irrespective of the consumed supplement. No effects of α-lactalbumin were observed.ConclusionsOur results indicate that 40 g of α-lactalbumin was unable to modify intrinsic motoneuron excitability. However, performing a submaximal handgrip contraction before the plantar flexion triangular contraction was capable of increasing ΔF and discharge rates on soleus motor units. These findings highlight the diffused effects of serotonergic input, its effects on motoneuron discharge behaviour, and suggest a cross-effector effect within human motoneurons.

It is challenging to stimulate gamma motor neurons, which are important regulators of muscle spindle afferent function, without also recruiting alpha motor neurons. Here, we test the feasibility of stimulating gamma motor neuron axons using optogenetics in two transgenic mouse lines. We used an ex vivo muscle–nerve preparation in adult mice to monitor muscle spindle afferent firing, which should increase in response to gamma motor neuron‐induced lengthening of the sensory region of the muscle spindle. A force transducer measured alpha motor neuron‐mediated twitch contractions. Blue LED light (470 nm; 1–5 mW) was delivered via a light guide to the sciatic nerve. We confirmed that the more slowly conducting gamma motor neurons were recruited first in mice expressing channelrhodopsin 2 in choline acetyltransferase‐positive motor neurons, whereas alpha motor neurons required higher optical intensities, enabling co‐activation of alpha and gamma motor neurons depending on light intensity. However, this approach cannot isolate gamma motor neuron activity completely. Cre‐dependent channelrhodopsin 2 optoactivation using the putative gamma motor neuron marker neuronal PAS domain protein 1 (Npas1) also increased muscle spindle afferent firing rates and caused only small twitch contractions. This provides functional validation that Npas1 is present primarily in gamma motor neurons and can be used to manipulate gamma motor neurons independently. We propose optogenetic stimulation as a promising tool to manipulate gamma motor neuron activity. What is the central question of this study? Additional tools are needed to modulate gamma motor neuron function independently to gain a better understanding of the function of the fusimotor system. What is the main finding and its importance? Optogenetics tools can be used to stimulate gamma motor neurons independently of alpha motor neurons by expressing channelrhodopsin 2 in neuronal PAS domain protein 1‐expressing cells or using lower light intensities with channelrhodopsin 2 expressed in all choline acetyltransferase‐positive motor neurons. This technique could be used to study the role of gamma motor neurons in motor control and proprioception during normal behaviour and disease.

The output from a motor nucleus is determined by the synaptic input to the motor neurons and their intrinsic properties. Here, we explore whether the source of synaptic inputs to the motor neurons (cats) and the age or post-stroke conditions (humans) may change the recruitment gain of the motor neuron pool. In cats, the size of Ia EPSPs in triceps surae motor neurons (input) and monosynaptic reflexes (MSRs; output) was recorded in the soleus and medial gastrocnemius motor nerves following graded stimulation of dorsal roots. The MSR was plotted against the EPSP thereby obtaining a measure of the recruitment gain. Conditioning stimulation of sural and peroneal cutaneous afferents caused significant increase in the recruitment gain of the medial gastrocnemius, but not the soleus motor neuron pool. In humans, the discharge probability of individual soleus motor units (input) and soleus H-reflexes (output) was performed. With graded stimulation of the tibial nerve, the gain of the motor neuron pool was assessed as the slope of the relation between probability of firing and the reflex size. The gain in young subjects was higher than in elderly subjects. The gain in post-stroke survivors was higher than in age-matched neurologically intact subjects. These findings provide experimental evidence that recruitment gain of a motor neuron pool contributes to the regulation of movement at the final output stage from the spinal cord and should be considered when interpreting changes in reflex excitability in relation to movement or injuries of the nervous system.

To investigate an alternative approach to family participatory nursing in neonatal intensive care units (NICUs) during the COVID-19 pandemic, focusing on auditory interventions to mitigate the effects of maternal separation (MS) on neonatal neurological development. This study was a randomized, double-blind, prospective trial involving 100 newborns younger than 6 months old, born between January 2022 and October 2022, who experienced MS for more than 2 weeks. Newborns were randomly allocated into control and study groups using a computer-generated list to ensure unbiased selection. Inclusion criteria were gestational age ≥37 weeks and admission to NICU due to various medical conditions; exclusion criteria included severe hearing impairment and congenital neurological disorders. The intervention group received maternal voice exposure at 40-50 dB for eight 30-minute sessions daily, while the control group was exposed to children's songs at the same volume and duration. Key metrics such as oxygen saturation, heart rate, Neonatal Infant Pain Scale (NIPS) scores, and Neonatal Behavioral Neurological Assessment (NBNA) scores were measured before and after the intervention period, which lasted one week. Post-intervention, the NIPS scores in the intervention group were significantly lower (3.45±0.99) compared to the control group (5.36±0.49, P < .01), indicating reduced pain sensitivity. Additionally, NBNA scores were higher in the intervention group (39.90±1.56) than in the control group (35.86±1.05, P < .01), suggesting enhanced neurological development. No significant difference in pre-intervention blood oxygen saturation levels was observed between the groups. However, the intervention group showed less reduction in oxygen saturation during and post-blood collection, with significantly higher levels at 2, 4, and 6 minutes post-procedure (P < .01). The findings underscore the significance of maternal voice as a non-pharmacological intervention to alleviate pain and foster neurological development in neonates facing MS, especially in situations where traditional family participatory nursing is hindered by the COVID-19 pandemic. Integrating maternal voice stimulation into neonatal care strategies offers a viable method to improve outcomes for newborns undergoing MS. Maternal voice intervention presents a promising strategy to diminish pain sensitivity and bolster neurological development in neonates separated from their mothers, particularly when family participatory nursing practices are constrained by pandemic-related restrictions. These findings advocate for the broader implementation of maternal voice stimulation in NICU settings.