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A series of recent studies identified key structures in the mesencephalic locomotor region and the caudal brainstem of mice involved in the initiation and control of slow (exploratory) and fast (escape-type) locomotion and gait. However, the interactions of these brainstem centers with each other and with the spinal locomotor circuits are poorly understood. Previously we suggested that commissural and long propriospinal interneurons are the main targets for brainstem inputs adjusting gait (Danner et al., 2017). Here, by extending our previous model, we propose a connectome of the brainstem-spinal circuitry and suggest a mechanistic explanation of the operation of brainstem structures and their roles in controlling speed and gait. We suggest that brainstem control of locomotion is mediated by two pathways, one controlling locomotor speed via connections to rhythm generating circuits in the spinal cord and the other providing gait control by targeting commissural and long propriospinal interneurons.

Organismal locomotion mediates ecological interactions and shapes community dynamics. Locomotion is constrained by intrinsic and environmental factors and integrating these factors should clarify how locomotion affects ecology across scales. We extended general theory based on metabolic scaling and biomechanics to predict the scaling of five locomotor performance traits: routine speed, maximum speed, maximum acceleration, minimum powered turn radius, and angular speed. To test these predictions, we used phylogenetically informed analyses of a new database with 884 species and found support for our quantitative predictions. Larger organisms were faster but less maneuverable than smaller organisms. Routine and maximum speeds scaled with body mass to 0.20 and 0.17 powers, respectively, and plateaued at higher body masses, especially for maximum speed. Acceleration was unaffected by body mass. Minimum turn radius scaled to a 0.19 power, and the 95% CI included our theoretical prediction, as we predicted. Maximum angular speed scaled higher than predicted but in the same direction. We observed universal scaling among locomotor modes for routine and maximum speeds but the intercepts varied; flying organisms were faster than those that swam or ran. Acceleration was independent of size in flying and aquatic taxa but decreased with body mass in land animals, possibly due to the risk of injury large, terrestrial organisms face at high speeds and accelerations. Terrestrial mammals inhabiting structurally simple habitats tended to be faster than those in complex habitats. Despite effects of body size, locomotor mode, and habitat complexity, universal scaling of locomotory performance reveals the general ways organisms move across Earth’s complex environments.

•A lack of Vdr activity in skeletal muscle decreases locomotor functions in mice.•In skeletal muscle, the 1,25-dihydroxyvitamin D3 vitamin D receptor signaling regulates the adenosine triphosphate to pyrophosphate axis.•Extracellular pyrophosphate suppressed calcium deposition in skeletal muscle. During musculoskeletal development, the vitamin D endocrine system is crucial, because vitamin D–dependent calcium absorption is a major regulator of bone growth. Because exercise regimens depend on bone mass, the direct action of active vitamin D (1,25-dihydroxyvitamin D3 [1,25(OH)2D3]) on musculoskeletal performance should be determined. To evaluate the effect of 1,25(OH)2D3 on muscle tissue, the vitamin D receptor (Vdr) gene was genetically inactivated in mouse skeletal muscle and the role of 1,25(OH)2D3-VDR signaling on locomotor function was assessed. The direct action of 1,25(OH)2D3 on muscle development was determined using cultured C2C12 cells with myogenic differentiation. The lack of Vdr activity in skeletal muscle decreased spontaneous locomotor activity, suggesting that the skeletal muscle performance depended on 1,25(OH)2D3-VDR signaling. Bone phenotypes, reduced femoral bone mineral density, and accelerated osteoclast bone resorption were confirmed in mice lacking skeletal muscle Vdr activity. In vitro study revealed that the treatment with 1,25(OH)2D3 decreased the cellular adenosine triphosphate (ATP)–to–adenosine monophosphate ratio without reducing ATP production. Remarkably, protein expressions of connexin 43, an ATP releaser to extracellular space, and ATP metabolizing enzyme ectonucleotide pyrophosphatase phosphodiesterase 1 were increased responding to 1,25(OH)2D3 treatment. Furthermore, the concentration of pyrophosphate in the culture medium, which inhibits tissue calcification, was increased with 1,25(OH)2D3 treatment. In the presence of 1,25(OH)2D3-VDR signaling, calcium accumulation was suppressed in both muscle samples isolated from mice and in cultured C2C12 cells. This study dissected the physiological functions of 1,25(OH)2D3-VDR signaling in muscle and revealed that regulation of ATP dynamics is involved in sustaining locomotor function.

The mammalian suprachiasmatic nucleus (SCN) serves as the master circadian pacemaker, which coordinates daily behavioral and physiological rhythms through functionally diverse neuronal subtypes. Cholecystokinin (CCK) is expressed in a subset of SCN neurons; however, its role in locomotor activity rhythms remains poorly understood. To study the functional contribution of SCN CCK-expressing (SCN ) neurons, we selectively blocked synaptic transmission by injecting a Cre-dependent tetanus toxin (TeNT) viral vector into the SCN of CCK-IRES-Cre mice. Before and after the virus injection, spontaneous locomotor activity was continuously recorded under a 12:12 h light-dark (LD) cycle. Subsequently, we used Cre-dependent fluorescent reporter (mYongHong) to label SCN neurons and performed whole-brain projection mapping to characterize their downstream connectivity. Synaptic inhibition of SCN neurons significantly attenuated the strength of locomotor rhythmicity, resulting in reduced rhythm organization and a more uniform distribution of activity. This disruption was mainly driven by a significant decrease in dark-phase locomotor activity, while light-phase activity remained unchanged. Anatomically, SCN neurons are widely projected along the anterior and posterior axes to multiple hypothalamic, thalamic, and limbic regions, including the medial preoptic area (MPA), paraventricular thalamic nucleus (PVT), paraventricular hypothalamic nucleus (PVH), anterior hypothalamic area (AHC), dorsomedial hypothalamic nucleus (DMH), ventromedial hypothalamic nucleus (VMH), and medial amygdala nucleus (MeA). Quantitative analysis revealed projections to these downstream regions, with moderate variation in projection density across targets. Together, these findings identify SCN neurons as an important neuronal subpopulation, which contributes to the robustness and consolidation of spontaneous locomotor rhythms, likely through a wide range of downstream circuits.

Body-weight supported locomotor training (BWST) promotes recovery of load-bearing stepping in lower mammals, but its efficacy in individuals with a spinal cord injury (SCI) is limited and highly dependent on injury severity. While animal models with complete spinal transections recover stepping with step-training, motor complete SCI individuals do not, despite similarly intensive training. In this review, we examine the significant differences between humans and animal models that may explain this discrepancy in the results obtained with BWST. We also summarize the known effects of SCI and locomotor training on the muscular, motoneuronal, interneuronal, and supraspinal systems in human and non-human models of SCI and address the potential causes for failure to translate to the clinic. The evidence points to a deficiency in neuronal activation as the mechanism of failure, rather than muscular insufficiency. While motoneuronal and interneuronal systems cannot be directly probed in humans, the changes brought upon by step-training in SCI animal models suggest a beneficial re-organization of the systems’ responsiveness to descending and afferent feedback that support locomotor recovery. The literature on partial lesions in humans and animal models clearly demonstrate a greater dependency on supraspinal input to the lumbar cord in humans than in non-human mammals for locomotion. Recent results with epidural stimulation that activates the lumbar interneuronal networks and/or increases the overall excitability of the locomotor centers suggest that these centers are much more dependent on the supraspinal tonic drive in humans. Sensory feedback shapes the locomotor output in animal models but does not appear to be sufficient to drive it in humans.

Our understanding of the central pattern generator (CPG) for locomotion is primarily based on motor output analyses in isolated neonatal rodent preparations. Recent studies show that biomimetic neural modulation protocols, which mimic biological signals, outperform traditional methods in sustaining long-lasting fictive locomotor rhythms. However, fine-tuning such protocols requires extensive experimental trials, highlighting the urgent need for an automated CPG signal analysis tool. This study introduces the Peak-based Oscillation Classification Algorithm (POCA) for analyzing CPG signals using a novel peak-based feature extraction and machine learning. Although epoch-based feature extraction is widely applied in other biological oscillation analyses, they are suboptimal for CPG signals due to issue like challenging annotation and indirect feature representation. POCA addresses these limitations by extracting features directly from individual oscillation peaks, enabling more accurate and interpretable classification of locomotor versus non-locomotor activity. Using datasets from three independent stimulation protocols, a thresholding method using “peak prominence” feature achieved an F1 score of 0.911 and accuracy of 0.957, demonstrating the effectiveness of “peak prominence” as a key discriminative feature. A radial basis function kernel Support Vector Machine, incorporating additional peak features, further improved performance to an F1 score of 0.923 and accuracy of 0.966. The locomotor rhythm characterization results, based on oscillation detection, also aligned closely with human-expert assessments. The proposed POCA algorithm provides a robust, scalable tool for CPG signal analysis, facilitating large-scale evaluation of biomimetic protocols. The novel peak-based feature extraction framework also offers a versatile strategy for broader biological oscillation detection tasks.

A successful guaranteed launch of a mainline diesel locomotive is one of the most important and urgent problems of the rolling stock operation. Improvement of the start-up system of the main diesel locomotive when using a supercapacitor allows multiple restarts of diesel locomotives, meaning that the operation of the diesel locomotive can be stopped several times without wasting fuel in idle operations. In this study, we simulated the electric starting circuit of a diesel locomotive with a block of supercapacitors using the Matlab Simulink program. The simulation results show that using only a supercapacitor in the start-up system is impossible. Even though the supercapacitor produces the required current and voltage, its operating time is extremely insufficient. Using a storage battery along with a supercapacitor in the diesel locomotive start-up system is most effective. This reduces the peak current load on the standard battery. The article suggests an effective principle for starting a mainline diesel locomotive and provides an effective circuit solution involving a supercapacitor. Based on the booster stabilizer scheme, a new scheme was modeled to study the successful launch of a diesel locomotive that has various start-up systems. Applying a supercapacitor in the start-up system of a main diesel locomotive is proposed and the results of its use are presented. In addition, this study defines the basic requirements for using a system based on a battery in conjunction with a supercapacitor. Characteristics such as the temperature range of the system are shown.

In vertebrates, dopamine neurons are classically known to modulate locomotion via their ascending projections to the basal ganglia that project to brainstem locomotor networks. An increased dopaminergic tone is associated with increase in locomotor activity. In pathological conditions where dopamine cells are lost, such as in Parkinson's disease, locomotor deficits are traditionally associated with the reduced ascending dopaminergic input to the basal ganglia. However, a descending dopaminergic pathway originating from the was recently discovered. It innervates the mesencephalic locomotor region (MLR) from basal vertebrates to mammals. This pathway was shown to increase locomotor output in lampreys, and could very well play an important role in mammals. Here, we provide a detailed account on the newly found dopaminergic pathway in lamprey, salamander, rat, monkey, and human. In lampreys and salamanders, dopamine release in the MLR is associated with the activation of reticulospinal neurons that carry the locomotor command to the spinal cord. Dopamine release in the MLR potentiates locomotor movements through a D1-receptor mechanism in lampreys. In rats, stimulation of the elicited dopamine release in the pedunculopontine nucleus, a known part of the MLR. In a monkey model of Parkinson's disease, a reduced dopaminergic innervation of the brainstem locomotor networks was reported. Dopaminergic fibers are also present in human pedunculopontine nucleus. We discuss the conserved locomotor role of this pathway from lamprey to mammals, and the hypothesis that this pathway could play a role in the locomotor deficits reported in Parkinson's disease.

[This corrects the article DOI: 10.3389/fnmol.2025.1469467.].

RationaleThe phenylalkylamine hallucinogen (-)-2,5-dimethoxy-4-methylamphetamine (DOM) exhibits an inverted U-shaped dose-response curve for both head twitch response (HTR) and locomotor activity in mice. Accumulated studies suggest that HTR and locomotor hyperactivity induced by DOM are mainly caused by the activation of serotonin 5-hydroxytryptamine 2 A receptor (5-HT2A receptor). However, the mechanisms underlying the biphasic dose response of HTR and locomotor activity induced by DOM, particularly at high doses, remain unclear.ObjectivesThe primary objective of this study is to investigate the modulation of 5-HT2A/2C/1A receptors in HTR and locomotor activity, while also exploring the potential receptor mechanisms underlying the biphasic dose response of DOM.MethodsIn this study, we employed pharmacological methods to identify the specific 5-HT receptor subtypes responsible for mediating the biphasic dose-response effects of DOM on HTR and locomotor activity in C57BL/6J mice.ResultsThe 5-HT2A receptor selective antagonist (R)-[2,3-di(methoxy)phenyl]-[1-[2-(4-fluorophenyl)ethyl]piperidin-4-yl]methanol (M100907) (500 µg/kg, i.p.) fully blocked the HTR at every dose of DOM (0.615–10 mg/kg, i.p.) in C57BL/6J mice. M100907 (50 µg/kg, i.p.) decreased the locomotor hyperactivity induced by a low dose of DOM (0.625, 1.25 mg/kg, i.p.), but had no effect on the locomotor hypoactivity induced by a high dose of DOM (10 mg/kg) in C57BL/6J mice. The 5-HT2C antagonist 6-chloro-5-methyl-1-[(2-[2-methylpyrid-3yloxy]pyrid-5yl)carbamoyl]indoline (SB242084) (0.3, 1 mg/kg, i.p.) reduced the HTR induced by a dose of 2.5 mg/kg DOM, but did not affect the response to other doses. SB242084 (1 mg/kg, i.p.) significantly increased the locomotor activity induced by DOM (0.615–10 mg/kg, i.p.) in mice. The 5-HT1A antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]N-(2-pyridinyl) cyclohexane carboxamide maleate (WAY100635) (1 mg/kg, i.p.) increased both HTR and locomotor activity induced by DOM in mice. The 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (1 mg/kg, i.p.) significantly reduced both the HTR and locomotor activity induced by DOM in mice. Additionally, pretreatment with the Gαi/o inhibitor PTX (0.25 µg/mouse, i.c.v.) enhanced the HTR induced by DOM and attenuated the effect of DOM on locomotor activity in mice.ConclusionsReceptor subtypes 5-HT2C and 5-HT1A are implicated in the inverted U-shaped dose-response curves of HTR and locomotor activity induced by DOM in mice. The biphasic dose-response function of HTR and locomotor activity induced by DOM has different mechanisms in mice.