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Philosophical Transactions of the Royal... Sep 2018The intrinsic oscillatory activity of central pattern generators underlies motor rhythm. We review and discuss recent findings that address the origin of motor rhythm.... (Review)
Review
The intrinsic oscillatory activity of central pattern generators underlies motor rhythm. We review and discuss recent findings that address the origin of motor rhythm. These studies propose that the A- and mid-body B-class excitatory motor neurons at the ventral cord function as non-bursting intrinsic oscillators to underlie body undulation during reversal and forward movements, respectively. Proprioception entrains their intrinsic activities, allows phase-coupling between members of the same class motor neurons, and thereby facilitates directional propagation of undulations. Distinct pools of premotor interneurons project along the ventral nerve cord to innervate all members of the A- and B-class motor neurons, modulating their oscillations, as well as promoting their bi-directional coupling. The two motor sub-circuits, which consist of oscillators and descending inputs with distinct properties, form the structural base of dynamic rhythmicity and flexible partition of the forward and backward motor states. These results contribute to a continuous effort to establish a mechanistic and dynamic model of the sensorimotor system. exhibits rich sensorimotor functions despite a small neuron number. These findings implicate a circuit-level functional compression. By integrating the role of rhythm generation and proprioception into motor neurons, and the role of descending regulation of oscillators into premotor interneurons, this numerically simple nervous system can achieve a circuit infrastructure analogous to that of anatomically complex systems. has manifested itself as a compact model to search for general principles of sensorimotor behaviours.This article is part of a discussion meeting issue 'Connectome to behaviour: modelling at cellular resolution'.
Topics: Animals; Caenorhabditis elegans; Interneurons; Locomotion; Motor Neurons; Periodicity
PubMed: 30201835
DOI: 10.1098/rstb.2017.0370 -
Neurobiology of Disease Dec 2018Mechanisms underlying α-synuclein (αSyn) mediated neurodegeneration are poorly understood. Intramuscular (IM) injection of αSyn fibrils in human A53T transgenic M83...
Mechanisms underlying α-synuclein (αSyn) mediated neurodegeneration are poorly understood. Intramuscular (IM) injection of αSyn fibrils in human A53T transgenic M83 mice produce a rapid model of α-synucleinopathy with highly predictable onset of motor impairment. Using varying doses of αSyn seeds, we show that αSyn-induced phenotype is largely dose-independent. We utilized the synchrony of this IM model to explore the temporal sequence of αSyn pathology, neurodegeneration and neuroinflammation. Longitudinal tracking showed that while motor neuron death and αSyn pathology occur within 2 months post IM, astrogliosis appears at a later timepoint, implying neuroinflammation is a consequence, rather than a trigger, in this prionoid model of synucleinopathy. Initiating at 3 months post IM, immune activation dominates the pathologic landscape in terminal IM-seeded M83 mice, as revealed by unbiased transcriptomic analyses. Our findings provide insights into the role of neuroinflammation in αSyn mediated proteostasis and neurodegeneration, which will be key in designing potential therapies.
Topics: Animals; Brain; Female; Humans; Inflammation; Male; Mice; Mice, Transgenic; Motor Neurons; Nerve Degeneration; Spinal Cord; alpha-Synuclein
PubMed: 30195075
DOI: 10.1016/j.nbd.2018.09.005 -
Cell and Tissue Research Oct 2020Glial cell line-derived neurotrophic factor (GDNF) is a 134 amino acid protein belonging in the GDNF family ligands (GFLs). GDNF was originally isolated from rat glial... (Review)
Review
Glial cell line-derived neurotrophic factor (GDNF) is a 134 amino acid protein belonging in the GDNF family ligands (GFLs). GDNF was originally isolated from rat glial cell lines and identified as a neurotrophic factor with the ability to promote dopamine uptake within midbrain dopaminergic neurons. Since its discovery, the potential neuroprotective effects of GDNF have been researched extensively, and the effect of GDNF on motor neurons will be discussed herein. Similar to other members of the TGF-β superfamily, GDNF is first synthesized as a precursor protein (pro-GDNF). After a series of protein cleavage and processing, the 211 amino acid pro-GDNF is finally converted into the active and mature form of GDNF. GDNF has the ability to trigger receptor tyrosine kinase RET phosphorylation, whose downstream effects have been found to promote neuronal health and survival. The binding of GDNF to its receptors triggers several intracellular signaling pathways which play roles in promoting the development, survival, and maintenance of neuron-neuron and neuron-target tissue interactions. The synthesis and regulation of GDNF have been shown to be altered in many diseases, aging, exercise, and addiction. The neuroprotective effects of GDNF may be used to develop treatments and therapies to ameliorate neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). In this review, we provide a detailed discussion of the general roles of GDNF and its production, delivery, secretion, and neuroprotective effects on motor neurons within the mammalian neuromuscular system.
Topics: Biological Transport; Glial Cell Line-Derived Neurotrophic Factor; Humans; Motor Neurons; Signal Transduction
PubMed: 32897420
DOI: 10.1007/s00441-020-03287-6 -
Brain : a Journal of Neurology Apr 2020Motor neuron diseases (MNDs) encompass an extensive and heterogeneous group of upper and/or lower motor neuron degenerative disorders, in which the particular clinical... (Review)
Review
Motor neuron diseases (MNDs) encompass an extensive and heterogeneous group of upper and/or lower motor neuron degenerative disorders, in which the particular clinical outcomes stem from the specific neuronal component involved in each condition. While mutations in a large number of molecules associated with lipid metabolism are known to be implicated in MNDs, there remains a lack of clarity regarding the key functional pathways involved, and their inter-relationships. This review highlights evidence that defines defects within two specific lipid (cholesterol/oxysterol and phosphatidylethanolamine) biosynthetic cascades as being centrally involved in MND, particularly hereditary spastic paraplegia. We also identify how other MND-associated molecules may impact these cascades, in particular through impaired organellar interfacing, to propose 'subcellular lipidome imbalance' as a likely common pathomolecular theme in MND. Further exploration of this mechanism has the potential to identify new therapeutic targets and management strategies for modulation of disease progression in hereditary spastic paraplegias and other MNDs.
Topics: Animals; Humans; Lipid Metabolism; Motor Neurons; Neurodegenerative Diseases
PubMed: 31848577
DOI: 10.1093/brain/awz382 -
Current Opinion in Neurobiology Feb 2017Execution of motor behaviors relies on the ability of circuits within the nervous system to engage functionally relevant subtypes of spinal motor neurons. While much... (Review)
Review
Execution of motor behaviors relies on the ability of circuits within the nervous system to engage functionally relevant subtypes of spinal motor neurons. While much attention has been given to the role of networks of spinal interneurons on setting the rhythm and pattern of output from locomotor circuits, recent studies suggest that motor neurons themselves can exert an instructive role in shaping the wiring and functional properties of locomotor networks. Alteration in the distribution of motor neuron subtypes also appears to have contributed to evolutionary transitions in the locomotor strategies used by land vertebrates. This review describes emerging evidence that motor neuron-derived cues can have a profound influence on the organization, wiring, and evolutionary diversification of locomotor circuits.
Topics: Animals; Interneurons; Locomotion; Motor Neurons; Vertebrates
PubMed: 27907815
DOI: 10.1016/j.conb.2016.11.005 -
Cell Adhesion & Migration 2012Spinal motor neurons are critical to the ability of animals to move and thus essential to survival. Motor neurons that project axons to distinct limb-muscle targets are... (Review)
Review
Spinal motor neurons are critical to the ability of animals to move and thus essential to survival. Motor neurons that project axons to distinct limb-muscle targets are topographically organized such that central nervous system position reflects the location of the muscle in the limb. The central positioning of limb-projecting motor neurons arises during development through motor neuron migration followed by a period of coalescence into discrete groupings of motor neurons which project axons to an individual muscle. These so-called motor pools are a common feature of motor organization in higher vertebrates. Recent work has highlighted the critical role for armadillo family member catenin-dependent functions of the cadherin family of cell adhesion molecules in directing the organization of motor neurons. Cadherin function appears to be important for both the motor neuron migration and coalescence phases of the emergence of motor neuron topography. Here, I review this recent work in the context of our understanding of the general development of spinal motor neurons.
Topics: Animals; Cadherins; Catenins; Cell Adhesion; Cell Division; Cell Movement; Chick Embryo; Motor Neurons; Protein Binding; Protein Interaction Mapping; Signal Transduction; Spinal Cord
PubMed: 22902765
DOI: 10.4161/cam.21044 -
PloS One 2013Loss of the survival motor neuron gene (SMN1) is responsible for spinal muscular atrophy (SMA), the most common inherited cause of infant mortality. Even though the SMA...
Loss of the survival motor neuron gene (SMN1) is responsible for spinal muscular atrophy (SMA), the most common inherited cause of infant mortality. Even though the SMA phenotype is traditionally considered as related to spinal motor neuron loss, it remains debated whether the specific targeting of motor neurons could represent the best therapeutic option for the disease. We here investigated, using stereological quantification methods, the spinal cord and cerebral motor cortex of ∆7 SMA mice during development, to verify extent and selectivity of motor neuron loss. We found progressive post-natal loss of spinal motor neurons, already at pre-symptomatic stages, and a higher vulnerability of motor neurons innervating proximal and axial muscles. Larger motor neurons decreased in the course of disease, either for selective loss or specific developmental impairment. We also found a selective reduction of layer V pyramidal neurons associated with layer V gliosis in the cerebral motor cortex. Our data indicate that in the ∆7 SMA model SMN loss is critical for the spinal cord, particularly for specific motor neuron pools. Neuronal loss, however, is not selective for lower motor neurons. These data further suggest that SMA pathogenesis is likely more complex than previously anticipated. The better knowledge of SMA models might be instrumental in shaping better therapeutic options for affected patients.
Topics: Animals; Cerebral Cortex; Cholinergic Neurons; Disease Models, Animal; Gliosis; Mice; Mice, Knockout; Motor Cortex; Motor Neurons; Muscular Atrophy, Spinal; Pyramidal Cells; Spinal Cord; Survival of Motor Neuron 1 Protein
PubMed: 24324819
DOI: 10.1371/journal.pone.0082654 -
Cell and Tissue Research Dec 2020The stomach acts as a buffer between the ingestion of food and its processing in the small intestine. It signals to the brain to modulate food intake and it in turn... (Review)
Review
The stomach acts as a buffer between the ingestion of food and its processing in the small intestine. It signals to the brain to modulate food intake and it in turn regulates the passage of a nutrient-rich fluid, containing partly digested food, into the duodenum. These processes need to be finely controlled, for example to restrict reflux into the esophagus and to transfer digesta to the duodenum at an appropriate rate. Thus, the efferent pathways that control gastric volume, gastric peristalsis and digestive juice production are critically important. We review these pathways with an emphasis on the identities of the final motor neurons and comparisons between species. The major types of motor neurons arising from gastric enteric ganglia are as follows: immunohistochemically distinguishable excitatory and inhibitory muscle motor neurons; four neuron types innervating mucosal effectors (parietal cells, chief cells, gastrin cells and somatostatin cells); and vasodilator neurons. Sympathetic efferent neurons innervate intramural arteries, myenteric ganglia and gastric muscle. Vagal efferent neurons with cell bodies in the brain stem do not directly innervate gastric effector tissues; they are pre-enteric neurons that innervate each type of gastric enteric motor neuron. The principal transmitters and co-transmitters of gastric motor neurons, as well as key immunohistochemical markers, are the same in rat, pig, human and other species.
Topics: Animals; Efferent Pathways; Humans; Motor Neurons; Rats; Stomach
PubMed: 33156383
DOI: 10.1007/s00441-020-03294-7 -
Annals of Clinical and Translational... Jul 2020To investigate disease spread in amyotrophic lateral sclerosis (ALS), and determine the influence of lower (LMN) and upper motor neuron (UMN) involvement.
OBJECTIVE
To investigate disease spread in amyotrophic lateral sclerosis (ALS), and determine the influence of lower (LMN) and upper motor neuron (UMN) involvement.
METHODS
We assessed disease spread in ALS in 1376 consecutively studied patients, from five European centers, applying an agreed proforma to assess LMN and UMN signs. We defined the pattern of disease onset and progression from predominant UMN or lower motor neuron (LMN) dysfunction in bulbar, upper limbs, lower limbs, and thoracic regions Non-linear regression analysis was applied to fit the data to a model that described the relation between two random variables, graphically represented by an inverse exponential curve. We analyzed the probability, rate of spread, and both combined (area under the curve).
RESULTS
We found that progression was more likely and quicker to or from the region of onset to close spinal regions. When the disease had a limb onset, bulbar motor neurons were more resistant. Furthermore, in the same time frame more patients progressed from bulbar to lower limbs than vice-versa, whether predominantly UMN or LMN involvement. Patients with initial thoracic involvement had a higher probability for rapid change. The presence of predominant UMN signs was associated with a faster caudal progression.
INTERPRETATION
Contiguous progression was leading pattern, and predominant UMN involvement is important in shortening the time for cranial-caudal spread. Our results can best be fitted to a model of independent LMN and UMN degeneration, with regional progression of LMN degeneration mostly by contiguity. UMN lesion causes an acceleration of rostral-caudal LMN loss.
Topics: Aged; Amyotrophic Lateral Sclerosis; Disease Progression; Female; Follow-Up Studies; Humans; Male; Middle Aged; Motor Neurons
PubMed: 32558369
DOI: 10.1002/acn3.51098 -
Development (Cambridge, England) Aug 2020Spinal cord pMN progenitors sequentially produce motor neurons and oligodendrocyte precursor cells (OPCs). Some OPCs differentiate rapidly as myelinating...
Spinal cord pMN progenitors sequentially produce motor neurons and oligodendrocyte precursor cells (OPCs). Some OPCs differentiate rapidly as myelinating oligodendrocytes, whereas others remain into adulthood. How pMN progenitors switch from producing motor neurons to OPCs with distinct fates is poorly understood. pMN progenitors express , which encodes a transcriptional repressor, during motor neuron and OPC formation. To determine whether controls pMN cell fate specification, we used zebrafish as a model system to investigate function. Our analysis revealed that mutant embryos have fewer motor neurons resulting from a premature switch from motor neuron to OPC production. Additionally, mutant larvae have excess oligodendrocytes and a concomitant deficit of OPCs. Notably, pMN cells of mutant embryos have elevated Shh signaling, coincident with the motor neuron to OPC switch. Inhibition of Shh signaling restored the number of motor neurons to normal but did not rescue the proportion of oligodendrocytes. These data suggest that Prdm8 regulates the motor neuron-OPC switch by controlling the level of Shh activity in pMN progenitors, and also regulates the allocation of oligodendrocyte lineage cell fates.This article has an associated 'The people behind the papers' interview.
Topics: Animals; Cell Differentiation; DNA-Binding Proteins; Hedgehog Proteins; Histone Methyltransferases; Mice; Mice, Transgenic; Motor Neurons; Neural Stem Cells; Oligodendroglia; Signal Transduction
PubMed: 32680935
DOI: 10.1242/dev.191023