-
Current Biology : CB Nov 2022In many animals, there is a direct correspondence between the motor patterns that drive locomotion and the motor neuron innervation. For example, the adult C. elegans...
In many animals, there is a direct correspondence between the motor patterns that drive locomotion and the motor neuron innervation. For example, the adult C. elegans moves with symmetric and alternating dorsal-ventral bending waves arising from symmetric motor neuron input onto the dorsal and ventral muscles. In contrast to the adult, the C. elegans motor circuit at the juvenile larval stage has asymmetric wiring between motor neurons and muscles but still generates adult-like bending waves with dorsal-ventral symmetry. We show that in the juvenile circuit, wiring between excitatory and inhibitory motor neurons coordinates the contraction of dorsal muscles with relaxation of ventral muscles, producing dorsal bends. However, ventral bending is not driven by analogous wiring. Instead, ventral muscles are excited uniformly by premotor interneurons through extrasynaptic signaling. Ventral bends occur in anti-phasic entrainment to activity of the same motor neurons that drive dorsal bends. During maturation, the juvenile motor circuit is replaced by two motor subcircuits that separately drive dorsal and ventral bending. Modeling reveals that the juvenile's immature motor circuit is an adequate solution to generate adult-like dorsal-ventral bending before the animal matures. Developmental rewiring between functionally degenerate circuit solutions, which both generate symmetric bending patterns, minimizes behavioral disruption across maturation.
Topics: Animals; Caenorhabditis elegans; Motor Neurons; Interneurons; Locomotion; Larva
PubMed: 36182701
DOI: 10.1016/j.cub.2022.09.002 -
Respiratory Physiology & Neurobiology Sep 2011Many lung and central nervous system disorders require robust and appropriate physiological responses to assure adequate breathing. Factors undermining the efficacy of... (Review)
Review
Many lung and central nervous system disorders require robust and appropriate physiological responses to assure adequate breathing. Factors undermining the efficacy of ventilatory control will diminish the ability to compensate for pathology, threatening life itself. Although most of these same disorders are associated with systemic and/or neuroinflammation, and inflammation affects neural function, we are only beginning to understand interactions between inflammation and any aspect of ventilatory control (e.g. sensory receptors, rhythm generation, chemoreflexes, plasticity). Here we review available evidence, and present limited new data suggesting that systemic (or neural) inflammation impairs two key elements of ventilatory control: chemoreflexes and respiratory motor (versus sensory) plasticity. Achieving an understanding of mechanisms whereby inflammation undermines ventilatory control is fundamental since inflammation may diminish the capacity for natural, compensatory responses during pathological states, and the ability to harness respiratory plasticity as a therapeutic strategy in the treatment of devastating breathing disorders, such as during cervical spinal injury or motor neuron disease.
Topics: Animals; Humans; Motor Neurons; Neuronal Plasticity; Reflex; Respiratory Mechanics; Systemic Inflammatory Response Syndrome
PubMed: 21729770
DOI: 10.1016/j.resp.2011.06.017 -
Brain Structure & Function Jan 2024Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition characterised by a progressive loss of motor neurons controlling voluntary muscle activity.... (Review)
Review
Selective vulnerability of motor neuron types and functional groups to degeneration in amyotrophic lateral sclerosis: review of the neurobiological mechanisms and functional correlates.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition characterised by a progressive loss of motor neurons controlling voluntary muscle activity. The disease manifests through a variety of motor dysfunctions related to the extent of damage and loss of neurons at different anatomical locations. Despite extensive research, it remains unclear why some motor neurons are especially susceptible to the disease, while others are affected less or even spared. In this article, we review the neurobiological mechanisms, neurochemical profiles, and morpho-functional characteristics of various motor neuron groups and types of motor units implicated in their differential exposure to degeneration. We discuss specific cell-autonomous (intrinsic) and extrinsic factors influencing the vulnerability gradient of motor units and motor neuron types to ALS, with their impact on disease manifestation, course, and prognosis, as revealed in preclinical and clinical studies. We consider the outstanding challenges and emerging opportunities for interpreting the phenotypic and mechanistic variability of the disease to identify targets for clinical interventions.
Topics: Humans; Animals; Amyotrophic Lateral Sclerosis; Motor Neurons; Disease Models, Animal
PubMed: 37999738
DOI: 10.1007/s00429-023-02728-6 -
Arquivos de Neuro-psiquiatria Oct 2016Motor neuron disease is one of the major groups of neurodegenerative diseases, mainly represented by amyotrophic lateral sclerosis. Despite wide genetic and biochemical... (Review)
Review
Motor neuron disease is one of the major groups of neurodegenerative diseases, mainly represented by amyotrophic lateral sclerosis. Despite wide genetic and biochemical data regarding its pathophysiological mechanisms, motor neuron disease develops under a complex network of mechanisms not restricted to the unique functions of the alpha motor neurons but which actually involve diverse functions of glial cell interaction. This review aims to expose some of the leading roles of glial cells in the physiological mechanisms of neuron-glial cell interactions and the mechanisms related to motor neuron survival linked to glial cell functions.
Topics: Amyotrophic Lateral Sclerosis; Glutamic Acid; Humans; Medical Illustration; Motor Neurons; Nerve Growth Factors; Neuroglia
PubMed: 27759812
DOI: 10.1590/0004-282X20160117 -
Histology and Histopathology Oct 2018Counting motor neurons within the spinal cord and brainstem represents a seminal step to comprehend the anatomy and physiology of the final common pathway sourcing from... (Review)
Review
Counting motor neurons within the spinal cord and brainstem represents a seminal step to comprehend the anatomy and physiology of the final common pathway sourcing from the CNS. Motor neuron loss allows to assess the severity of motor neuron disorders while providing a tool to assess disease modifying effects. Counting motor neurons at first implies gold standard identification methods. In fact, motor neurons may occur within mixed nuclei housing a considerable amount of neurons other than motor neurons. In the present review, we analyse various approaches to count motor neurons emphasizing both the benefits and bias of each protocol. A special emphasis is placed on discussing automated stereology. When automated stereology does not take into account site-specificity and does not distinguish between heterogeneous neuronal populations, it may confound data making such a procedure a sort of "guide for the perplex". Thus, if on the one hand automated stereology improves our ability to quantify neuronal populations, it may also hide false positives/negatives in neuronal counts. For instance, classic staining for antigens such as SMI-32, SMN and ChAT, which are routinely considered to be specific for motor neurons, may also occur in other neuronal types of the spinal cord. Even site specificity within Lamina IX may be misleading due to neuronal populations having a size and shape typical of motor neurons. This is the case of spinal border cells, which often surpass the border of Lamina VII and intermingle with motor neurons of Lamina IX. The present article discusses the need to join automated stereology with a dedicated knowledge of each specific neuroanatomical setting.
Topics: Animals; Automation, Laboratory; Biomarkers; Cell Count; Humans; Immunohistochemistry; Microscopy; Motor Neuron Disease; Motor Neurons; Predictive Value of Tests; Prognosis; Reproducibility of Results; Severity of Illness Index; Spinal Cord
PubMed: 29537481
DOI: 10.14670/HH-11-983 -
STAT3 promotes motor neuron differentiation by collaborating with motor neuron-specific LIM complex.Proceedings of the National Academy of... Jul 2013The motor neuron (MN)-hexamer complex consisting of LIM homeobox 3, Islet-1, and nuclear LIM interactor is a key determinant of motor neuron specification and...
The motor neuron (MN)-hexamer complex consisting of LIM homeobox 3, Islet-1, and nuclear LIM interactor is a key determinant of motor neuron specification and differentiation. To gain insights into the transcriptional network in motor neuron development, we performed a genome-wide ChIP-sequencing analysis and found that the MN-hexamer directly regulates a wide array of motor neuron genes by binding to the HxRE (hexamer response element) shared among the target genes. Interestingly, STAT3-binding motif is highly enriched in the MN-hexamer-bound peaks in addition to the HxRE. We also found that a transcriptionally active form of STAT3 is expressed in embryonic motor neurons and that STAT3 associates with the MN-hexamer, enhancing the transcriptional activity of the MN-hexamer in an upstream signal-dependent manner. Correspondingly, STAT3 was needed for motor neuron differentiation in the developing spinal cord. Together, our studies uncover crucial gene regulatory mechanisms that couple MN-hexamer and STAT-activating extracellular signals to promote motor neuron differentiation in vertebrate spinal cord.
Topics: Animals; Cell Differentiation; Enhancer Elements, Genetic; Genome; LIM-Homeodomain Proteins; Mice; Motor Neurons; Protein Binding; STAT3 Transcription Factor
PubMed: 23798382
DOI: 10.1073/pnas.1302676110 -
Physiology (Bethesda, Md.) May 2018Autophagy is a cellular digestion process that contributes to cellular homeostasis and adaptation by the elimination of proteins and damaged organelles. Evidence... (Review)
Review
Autophagy is a cellular digestion process that contributes to cellular homeostasis and adaptation by the elimination of proteins and damaged organelles. Evidence suggests that dysregulation of autophagy plays a role in neurodegenerative diseases, including motor neuron disorders. Herein, we review emerging evidence indicating the roles of autophagy in physiological motor neuron processes and its function in specific compartments. Moreover, we discuss the involvement of autophagy in the pathogenesis of motor neuron diseases, including spinal cord injury and aging, and recent developments that offer promising therapeutic approaches to mitigate effects of dysregulated autophagy in health and disease.
Topics: Animals; Autophagy; Homeostasis; Humans; Motor Neurons; Neurodegenerative Diseases
PubMed: 29638184
DOI: 10.1152/physiol.00008.2018 -
NeuroImage. Clinical 2020The thalamus is a key cerebral hub relaying a multitude of corticoefferent and corticoafferent connections and mediating distinct extrapyramidal, sensory, cognitive and...
The thalamus is a key cerebral hub relaying a multitude of corticoefferent and corticoafferent connections and mediating distinct extrapyramidal, sensory, cognitive and behavioural functions. While the thalamus consists of dozens of anatomically well-defined nuclei with distinctive physiological roles, existing imaging studies in motor neuron diseases typically evaluate the thalamus as a single structure. Based on the unique cortical signatures observed in ALS and PLS, we hypothesised that similarly focal thalamic involvement may be observed if the nuclei are individually evaluated. A prospective imaging study was undertaken with 100 patients with ALS, 33 patients with PLS and 117 healthy controls to characterise the integrity of thalamic nuclei. ALS patients were further stratified for the presence of GGGGCC hexanucleotide repeat expansions in C9orf72. The thalamus was segmented into individual nuclei to examine their volumetric profile. Additionally, thalamic shape deformations were evaluated by vertex analyses and focal density alterations were examined by region-of-interest morphometry. Our data indicate that C9orf72 negative ALS patients and PLS patients exhibit ventral lateral and ventral anterior involvement, consistent with the 'motor' thalamus. Degeneration of the sensory nuclei was also detected in C9orf72 negative ALS and PLS. Both ALS groups and the PLS cohort showed focal changes in the mediodorsal-paratenial-reuniens nuclei, which mediate memory and executive functions. PLS patients exhibited distinctive thalamic changes with marked pulvinar and lateral geniculate atrophy compared to both controls and C9orf72 negative ALS. The considerable ventral lateral and ventral anterior pathology detected in both ALS and PLS support the emerging literature of extrapyramidal dysfunction in MND. The involvement of sensory nuclei is consistent with sporadic reports of sensory impairment in MND. The unique thalamic signature of PLS is in line with the distinctive clinical features of the phenotype. Our data confirm phenotype-specific patterns of thalamus involvement in motor neuron diseases with the preferential involvement of nuclei mediating motor and cognitive functions. Given the selective involvement of thalamic nuclei in ALS and PLS, future biomarker and natural history studies in MND should evaluate individual thalamic regions instead overall thalamic changes.
Topics: Aged; Amyotrophic Lateral Sclerosis; Atrophy; Brain; C9orf72 Protein; Female; Humans; Male; Middle Aged; Motor Neuron Disease; Motor Neurons; Mutation; Thalamic Nuclei
PubMed: 32554322
DOI: 10.1016/j.nicl.2020.102300 -
Journal of Neuroscience Methods Apr 2021Previous assessments of mitochondrial volume density within motor neurons used electron microscopy (EM) to image mitochondria. However, adequate identification and...
BACKGROUND
Previous assessments of mitochondrial volume density within motor neurons used electron microscopy (EM) to image mitochondria. However, adequate identification and sampling of motor neurons within a particular motor neuron pool is largely precluded using EM. Here, we present an alternative method for determining mitochondrial volume density in identified motor neurons within the phrenic motor neuron (PhMN) pool, with greatly increased sampling.
NEW METHOD
This novel method for assessing mitochondrial volume density in PhMNs uses a combination of intrapleural injection of Alexa 488-conjugated cholera toxin B (CTB) to retrogradely label PhMNs, followed by intrathecal application of MitoTracker Red to label mitochondria. This technique was validated by comparison to 3D EM determination of mitochondrial volume density as a "gold standard".
RESULTS
A mean mitochondrial volume density of ∼11 % was observed across PhMNs using the new MitoTracker Red method. This compared favourably with mitochondrial volume density (∼11 %) measurements using EM.
COMPARISON WITH EXISTING METHOD
The range, mean and variance of mitochondrial volume density estimates in PhMNs were not different between EM and fluorescent imaging techniques.
CONCLUSIONS
Fluorescent imaging may be used to estimate mitochondrial volume density in a large sample of motor neurons, with results similar to EM, although EM did distinguish finer mitochondrion morphology compared to MitoTracker fluorescence. Compared to EM methods, the assessment of a larger sample size and unambiguous identification of motor neurons belonging to a specific motor neuron pool represent major advantages over previous methods.
Topics: Cholera Toxin; Mitochondrial Size; Motor Neurons; Phrenic Nerve
PubMed: 33549636
DOI: 10.1016/j.jneumeth.2021.109093 -
Journal of Applied Physiology... Dec 2014A surface EMG signal represents the linear transformation of motor neuron discharge times by the compound action potentials of the innervated muscle fibers and is often... (Review)
Review
A surface EMG signal represents the linear transformation of motor neuron discharge times by the compound action potentials of the innervated muscle fibers and is often used as a source of information about neural activation of muscle. However, retrieving the embedded neural code from a surface EMG signal is extremely challenging. Most studies use indirect approaches in which selected features of the signal are interpreted as indicating certain characteristics of the neural code. These indirect associations are constrained by limitations that have been detailed previously (Farina D, Merletti R, Enoka RM. J Appl Physiol 96: 1486-1495, 2004) and are generally difficult to overcome. In an update on these issues, the current review extends the discussion to EMG-based coherence methods for assessing neural connectivity. We focus first on EMG amplitude cancellation, which intrinsically limits the association between EMG amplitude and the intensity of the neural activation and then discuss the limitations of coherence methods (EEG-EMG, EMG-EMG) as a way to assess the strength of the transmission of synaptic inputs into trains of motor unit action potentials. The debated influence of rectification on EMG spectral analysis and coherence measures is also discussed. Alternatively, there have been a number of attempts to identify the neural information directly by decomposing surface EMG signals into the discharge times of motor unit action potentials. The application of this approach is extremely powerful, but validation remains a central issue.
Topics: Electromyography; Humans; Motor Neurons; Neuromuscular Junction
PubMed: 25277737
DOI: 10.1152/japplphysiol.00162.2014