Dissertations / Theses on the topic 'Spinal motoneuron'
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Narayan, Sreenath. "REANIMATION OF A DENERVATED MUSCLE USING UPPER MOTONEURON INJURED LOWER MOTONEURONS IN SPINAL CORD INJURY PATIENTS: A RAT MODEL." online version, 2006. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=case1133754830.
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Chopek, Jeremy W. "Lumbar spinal cord excitability: flexors vs. extensors, sensitivity to quipazine; effects of activity following spinal transection; and expression of post-synaptic serotonin receptors." American Physiological Society, 2013. http://hdl.handle.net/1993/24099.
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Serotonin (5-HT) is a well-known modulator of spinal cord excitability and motor output. In the spinal cord, the actions of 5-HT are primarily mediated by the 5-HT1AR, 5-HT2Rs and the 5-HT7R. Following a spinal cord transection, which results in a loss of supraspinal input, 5-HT agonists such as quipazine are used to provide excitation to the spinal cord to facilitate locomotor recovery. This is characterized by rhythmic alteration of left and right hindlimbs and ipsilateral flexor and extensor muscles. However, whether 5-HT has a global effect on spinal cord excitability or is confined to a specific motor group (i.e. flexors or extensors) is currently unknown. Furthermore, quipazine is used in conjunction with activity based interventions to enhance recovery following a spinal cord injury. However, the influence of limb activity on the responsiveness of the injured spinal cord to quipazine has not been examined. Lastly, the recovery of locomotion is at least in part thought to occur through an up-regulation of 5-HT receptors, although this has not been investigated in lumbar spinal cord.
Chapter 2 examines whether quipazine had a differential effect on flexor and extensor motor output assessed by recording flexor and extensor reflexes, motoneurons and Ia extracellular field potentials pre- and post-quipazine. It was determined that following an acute spinal transection, quipazine induced a larger flexor monosynaptic reflex (MSR) compared to the extensor MSR due to pre-synaptic but not motoneuron modulation.
Chapter 3 examines the influence of a chronic spinal transection with and without passive cycling on the hindlimb flexor and extensor MSR, both pre- and post-quipazine. It was found that three months post STx, the extensor but not flexor MSR demonstrated a hyperexcitable response, which was attenuated with passive cycling. Further, three months of passive cycling extensor MSR response to quipazine was similar to that seen in the control intact group.
Chapter 4 examined 5-HT receptor expression in flexor and extensor motoneurons three months post spinalization with or without passive cycling. Following a chronic STx, the 5-HT1AR and 5-HT2CR are down regulated, whereas the 5-HT2AR is up-regulated. Passive cycling further enhanced the 5-HT2AR expression as well as up-regulated the 5-HT7R in extensor but not flexor motoneurons.
Chapter 5 discusses the results and significance of these findings in detail.
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Arumugam, Saravanan. "A Study on the Role of NF-kB Signaling Pathway Members in Regulating Survival Motor Neuron Protein level and in the Pathogenesis of Spinal Muscular Atrophy." Doctoral thesis, Universitat de Lleida, 2017. http://hdl.handle.net/10803/400607.
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L’atròfia muscular espinal (AME) és una malaltia neuromuscular causada per mutació o deleció en el gen SMN1, que codifica per la proteïna ubiqua SMN (de l’anglès survival motor neuron). L’AME es caracteritza per atròfia muscular i degeneració de les motoneurones (MN) de la medul·la espinal. Els esdeveniments moleculars que causen la vulnerabilitat específica de les MN amb nivells baixos de proteïna SMN encara no es coneixen. La via de l’NF-κB (nuclear factor-κB) ha destacat recentment ja que sembla jugar un paper cabdal en la supervivència de les MN i en les malalties neurodegeneratives. Els factors de transcripció NF-κB regulen gens relacionats amb molts processos cel·lulars. En aquest treball hem analitzat la capacitat dels membres de la via de l’NF-κB de regular la proteïna Smn i el seu possible rol en la patogènesi de l’AME. L’activació de la via de l’NF-κB està associada a la fosforilació de l’IKKα/IKKβ i la translocació nuclear del factor RelA/p50 (via canònica) o la fosforilació de l’homodímer d’IKKα i la translocació nuclear del factor RelB/p52 (via no canònica). La inhibició de diferents membres d’aquestes vies (tant la canònica com la no canònica) usant la metodologia de transducció amb lentivirus amb shRNA en cultius primaris de MN embrionàries aïllades de ratolí hem demostrat que una reducció selectiva del factor RelA provoca una reducció de la proteïna Smn, mentre que una reducció del factor RelB no té cap efecte en els nivells de l’Smn. En el nostre model cel·lular, la reducció dels nivells de l’IKKα o l’IKKβ provoca un efecte oposat en l’Smn. Mitjançant la tècnica de la RT-PCR hem observat que la transducció de les MN amb l’shIKKβ provoca un augment dels nivells de l’mRNA de Smn, mentre que la transducció amb l’shIKKα o l’shRelA no modifica l’expressió de Smn. El doble knockdown de l’IKKα i l’IKKβ a les MN mostra una reducció de l’Smn. El knockdown selectiu de l’IKKα o l’IKKβ presenta una reducció de la fosforilació del RelA, es coneix que aquesta fosforilació en permet l’alliberament del seu inhibidor al citosol i en facilita la translocació nuclear. També la proteïna CREB, un dels factors de transcripció coneguts de l’Smn, disminueix amb la transducció de les MN amb els shIKKα o amb l’IKKα i l’IKKβ alhora, així com amb l’shRelA. Ara bé, les motoneurones amb l’shIKKβ mostren una reducció de la fosforilació de RelA però un augment dels nivells de CREB. La transducció de les MN amb l’shCREB disminueix els nivells de l’Smn recolzant el paper regulador de CREB en l’Smn. Hem observat una reducció de l’IKKα, l’IKKβ i de la fosforilació de RelA amb la transducció de les MN amb l’shSmn i en les MN del model murí sever de l’AME. Els nostres resultats mostren l’habilitat de la via canònica de l’NF-κB de regular els nivells de l’Smn i que aquesta via també es troba alterada en les MN deficients en la proteïna Smn. En conjunt, aquestes observacions suggereixen que la via de l’NF-κB pot tenir un rol en la patogènesi i ser, a la vegada, una possible diana terapèutica per l’AME.La Atrofia Muscular Espinal (SMA) es un trastorno neuromuscular causado por la mutación o deleción del gen SMN1, el cual codifica para la proteína que se expresa ubicuamente SMN (del inglés Survival Motor Neuron). La AME se caracteriza por atrofia muscular y degeneración de las motoneuronas de la médula espinal (MN). Los eventos moleculares detrás de la vulnerabilidad selectiva de las MN con niveles bajos de la proteína SMN se desconocen. La vía del factor nuclear-kB (NF-kB) ha sido implicada recientemente en la supervivencia de las MNs, así como en trastornos neurodegenerativos. Los factores de transcripción NF-kB regulan genes relacionados con varios procesos celulares. En este trabajo hemos analizado la capacidad de los miembros de la vía del NF-κB de regular la proteína SMN y su posible rol en la patogénesis del AME. La activación de la vía del NF-κB está asociada a la fosforilación de IKKα / IKKβ y la translocación nuclear del factor RelA/ p50 (vía canónica) o la fosforilación del homodímero de IKKα y la translocación nuclear del factor RelB / p52 (vía no canónica). Hemos realizado la inhibición de diferentes miembros de estas vías (tanto la canónica como la no canónica) usando la metodología de shRNA, y la transducción mediante el uso de lentivirus, en cultivos primarios de MN embrionarias aisladas de ratón. Hemos demostrado que una reducción selectiva del factor RelA provoca una reducción de la proteína SMN, mientras que una reducción del factor RelB no tiene ningún efecto en los niveles de la SMN. En nuestro modelo celular, la reducción de las proteínas IKKα o IKKβ mostró efectos opuestos sobre la proteína Smn. Mediante la técnica de PCR, hemos observado que la transducción de las MN con el shIKKβ provoca un aumento de los niveles de mRNA de SMN, mientras que la transducción con el shIKKα o el shRelA no cambian los niveles de RNA de SMN. El doble knockdown de IKKα e IKKβ en las MN muestra una reducción de SMN. El knockdown selectivo de IKKα o IKKβ presenta una reducción de la fosforilación del RelA, esta fosforilación permite la liberación de su inhibidor en el citosol y facilita la translocación nuclear. La proteína CREB, uno de los factores de transcripción conocidos para SMN, disminuye con la transducción de las MN con shIKKα o con IKKα e IKKβ a la vez, así como con shRelA. Ahora bien, las motoneuronas transducidas con shIKKβ muestran una reducción de la fosforilación de RelA pero un aumento de los niveles de la proteína CREB. La transducción de las MN con el shCREB disminuyó los niveles de la proteína SMN apoyando el papel regulador de CREB sobre SMN.
Spinal Muscular Atrophy (SMA) is a neuromuscular disorder caused by mutation or loss in SMN1 gene, encoding the ubiquitously expressed Survival Motor Neuron (SMN) protein. SMA is characterized by muscle atrophy, and spinal cord motoneurons (MNs) degeneration. The molecular events behind the selective vulnerability of these MNs to low level of SMN protein are still unknown. The nuclear factor-κB (NF-κB) pathway has recently been emerged having a vital role related to MN survival, and in neurodegenerative disorders. The NF-κB transcription factors regulate genes related to several cellular processes. In the present work, we have analyzed the ability of NF-κB pathway members to regulate Smn and their possible role in SMA pathogenesis. The NF-κB pathway activation is associated with IKKα/IKKβ phosphorylation, and RelA/p50 nuclear translocation (canonical) or IKKα homodimer phosphorylation, and RelB/p52 nuclear translocation (non-canonical). The inhibition of different protein members of both canonical, and non-canonical pathways using shRNA lentiviral transduction methodology in a primary culture of isolated embryonic spinal cord MNs reveals that the selective reduction of RelA induced the reduction of Smn whereas RelB protein reduction had no effect on Smn. In our culture system, reduction of IKKα or IKKβ proteins showed opposite effects on Smn. RT-PCR studies indicate that the shIKKβ-transduced MNs showed increased Smn mRNA levels, whereas it was not observed changes in Smn mRNA in the case of shIKKα- or shRelA-transduced MNs. The double knock-down of IKKα and IKKβ in MNs showed Smn reduction. The knockdown of IKKα and/or IKKβ showed a decrease in RelA phosphorylation, where the phosphorylation of RelA enable RelA/p50 release from its inhibitor in the cytoplasm and facilitates their nuclear translocation. Also, the CREB, one of the transcription factors for Smn was decreased in shIKKα, or in shIKKα- plus IKKβ-transduced MNs, and as well as in shRelA-transduced MNs. But, the shIKKβ MNs exhibited reduced p-RelA but increased CREB level. The shCREB-transduced MNs decreased Smn level, authenticating the regulatory role of CREB on Smn. We observed a reduction in IKKα, IKKβ and p-RelA levels in shSmn-tranduced MNs, and in MNs from a severe type SMA mouse model. Our results show the ability of NF-κB canonical pathway to regulate Smn level and, conversely, this pathway is also altered in Smn-deficient MNs. Together, these observations suggest that the NF-κB pathway has a role in SMA pathogenesis, and could be a therapeutic target for SMA.
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Sowd, Matthew Michael. "Analyzing Non-Unique Parameters in a Cat Spinal Cord Motoneuron Model." Thesis, Georgia Institute of Technology, 2006. http://hdl.handle.net/1853/11545.
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When modeling a neuron, modelers often focus on the values of parameters that produce a desired output. However, if these parameters are not unique, there could be a number of parameter sets that produce the same output. Thus, even though the values of the various maximum conductances, half activation voltages and so on differ, as a set they can produce the same spike height, firing rates, and so forth.
To examine whether or not parameter sets are unique, a 3-compartment motoneuron model was created that has 15 target outputs and 59 parameters. Using parameter searches, over one hundred parameter sets were created for this model that produced the same output (within tolerances). Parameter values vary between parameter sets and indicate that the parameter values are not unique. In addition, some parameters are more tightly constrained than others. Principal component analysis is used to examine the dimensionality of the input and output spaces.
However, neurons are more than static output generators. For example, a variety of neuromodulatory influences are known to shift parameter values to alter neuronal output. Thus the question arises as to whether this non-uniqueness extends from model outputs to the models sensitivities to its parameters. In this work, the non-unique parameter sets are further analyzed using sensitivity analyses and output correlations to show that these values vary significantly between these parameter sets. Therefore, each of these models will react to parameter variation differently.
This work concludes that parameter sets are non-unique but have varying sensitivity analyses and output correlations. The ramifications of this are discussed for both modelers and neuroscientists.
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Rademacher, Sebastian [Verfasser]. "Cytoskeletal dysregulation in the motoneuron disease Spinal Muscular Atrophy (SMA) / Sebastian Rademacher." Hannover : Bibliothek der Tierärztlichen Hochschule Hannover, 2017. http://d-nb.info/1136298002/34.
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Zelano, Johan. "Adhesion molecules and synapse remodeling during motoneuron regeneration." Stockholm : Department of Neuroscience, Karolinska Institutet, 2009. http://diss.kib.ki.se/2009/978-91-7409-623-1/.
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Van, Ryswyk Liesl, and Ryswyk Liesl Van. "A Question of Identity: Genes that Distinguish Motoneurons from Interneurons." Thesis, University of Oregon, 2012. http://hdl.handle.net/1794/12539.
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The question of how a single cell can grow, divide, and ultimately acquire a distinct function within an adult animal is central to the field of developmental biology. An elegant way to address this question is by studying the specification of a specific cell type, for example, vertebrate motoneurons. For an animal to be able to move and behave appropriately, individual motoneurons (MNs) must correctly innervate specific muscles. For this to happen, MNs must first be specified and then must differentiate into distinct subtypes, each of which is classified in part by the muscle it innervates. MN subtype specification is dependent on both the acquisition of MN-specific characteristics as well as the failure to acquire characteristics specific to interneurons, cells that only innervate other neurons. The entire process of specification is initiated in progenitor cells and relies on the correct spatial and temporal expression of specific genes.
Previous work in various vertebrate models has identified some of the key genes involved in MN specification, most notably transcription factors such as olig2, nkx6s, lhxs, mnxs, and islet1. In this dissertation, I use the zebrafish model to demonstrate novel roles in MN specification for two of these families of transcription factors - the lhxs and the mnxs. I provide evidence that both lhx3 and lhx4 are necessary for normal MN and ventral interneuron (IN) development and work by preventing MNs from expressing IN-specific characteristics. I also show that mnx1, mnx2a, and mnx2b are necessary in MNs both to promote the acquisition of some MN subtype-specific characteristics and to prevent the acquisition of some IN-specific characteristics and appear to be working in part through interactions with islet1. Finally, I identify an intermediate filament gene, inab, as being expressed in a subset of zebrafish MNs and a ventral IN and as having a potential role in the axon outgrowth of a specific MN subtype. Together, this work provides evidence for a mechanism of MN specification dependent on the expression of genes that both promote aspects of MN fate and inhibit aspects of IN fate.
This dissertation includes previously unpublished co-authored material.
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柴宏 and Hong Chai. "Survival and regeneration of spinal motoneuron after ventral root avulsion in adult rat." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2000. http://hub.hku.hk/bib/B3124158X.
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Chai, Hong. "Survival and regeneration of spinal motoneuron after ventral root avulsion in adult rat /." Hong Kong : University of Hong Kong, 2000. http://sunzi.lib.hku.hk/hkuto/record.jsp?
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Obeidat, Ahmed Zayed. "New Insights into the Spinal Recurrent Inhibitory Pathway Normally and After Motoneuron Regeneration." Wright State University / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=wright1369702090.
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Yuan, Chun-Su. "ELECTROPHYSIOLOGICAL ANALYSIS OF THE RECURRENT RENSHAW CIRCUIT (MOTONEURON, INHIBITION, SPIKE-TRIGGERED AVERAGE, SPINAL CORD)." Diss., The University of Arizona, 1986. http://hdl.handle.net/10150/188170.
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One goal of the neurophysiological approach to the study of nervous systems is to analyze neuronal circuitry in terms of the synaptic actions of one cell on another, particularly in instances in which both cells are functionally identifiable and components of a circuit whose overall structural and functional properties can be analyzed with experimental techniques. The present project contributed to this type of effort by providing an analysis of the recurrent Renshaw circuit, a prominent pathway in the mammalian spinal cord which includes recurrent motoneuronal collaterals, Renshaw cells and other interneurons, which, in turn, project to motoneurons. The project describes the use of a relatively new data processing technique, spike-triggered averaging, to study the effects of the single impulses of single motor axons on the postsynaptic activity of single motoneurons which were responsive to the test impulses by way of components of the recurrent Renshaw circuit. The experimental paradigm involved intracellular recording from single motoneurons in low-spinal cats, either anesthetized with chloralose-urethane or unanesthetized after their ischemic decapitation. The synaptic noise recorded in each motoneuron served as the input to a signal averager which was triggered by brief electrical shocks used to activate single antidromic impulses in single motor axons, either by way of an intra-axonally positioned microelectrode in the muscle nerve or by microstimulation of the muscle supplied by the axon. The resultant average revealed the motoneuron's response to each single antidromic impulse; a recurrent inhibitory postsynaptic potential, recorded for the first-ever time in this project and termed a single-axon RIPSP. The experimental results described in the report include: first, the measurement, incidence and characterization of single-axon RIPSPs; and second, their use to test a hypothesis concerned with the distribution of Renshaw-cell effects within the spinal cord. The single-axon RIPSP measurement was shown to be the clearest example yet provided in the neurophysiological literature that spike-triggered averaging can be used to detect synaptic activity crossing two or more synapses within the central nervous system. Furthermore, the hypothesis was confirmed that Renshaw-cell effects within a single spinal motor nucleus are distributed according to the principle of topographic specificity.
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Moore, N. J. "Recurrent excitation and inhibition in the Renshaw cell-motoneuron circuit of the lumbar spinal cord." Thesis, University College London (University of London), 2015. http://discovery.ucl.ac.uk/1458605/.
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Motor output from spinal motoneurons is influenced by interneuron networks in the ventral horn of the spinal cord. This thesis presents electrophysiologi- cal investigations of two separate but complementary aspects of the neuronal networks that influence this motor output. The first investigation focuses on inhibition of lumbar motoneurons. The second characterises the excitatory synapse formed by motoneuron axon collaterals onto Renshaw cells, which are interneurons that mediate recurrent inhibition onto motoneurons. Previous studies on neonatal rats have shown that inhibition of motoneu- rons is mediated a mixed GABAergic and glycinergic response. Whole- cell voltage-clamp recordings of spinal motoneurons obtained from juvenile (P 8 − 14) mice demonstrated that motoneuron inhibition is mostly mediated by glycine. GABA currents were not co-detected with glycine during this age range in the mouse. Further experiments, in which the relative content of pre-synaptic GABA and glycine was manipulated, showed that GABA is not co-released with glycine by premotor interneurons. Quantal analysis of paired recordings of pre-synaptic motoneurons and post-synaptic Renshaw cells showed that this excitatory synapse exhibits a large number of release sites and a high probability of release. This is suggestive of highly reliable synaptic transmission between the two cell types. Comparison of the number of release sites estimated from paired recordings with those estimated from responses evoked by ventral root stimulation revealed that on average six motoneurons project onto every Renshaw cell. We conclude that: • In mature animals motoneuron inhibition is mainly glycinergic. • The Renshaw cell to motoneuron synapse has a high efficiency of transmission. • The degree of convergence of motoneurons to Renshaw cells is very high. The last two conclusions suggest that firing in motoneurons pools reliably induces firing in the population of connected Renshaw cells.
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McWhorter, Michelle L. "Development and analysis of a Zebrafish model of spinal muscular atrophy." Columbus, Ohio : Ohio State University, 2005. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1133212697.
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Periyakaruppiah, Ambika. "Study of Survival Motor Neuron protein regulation and the role of autophagy in Spinal Muscular Atrophy." Doctoral thesis, Universitat de Lleida, 2015. http://hdl.handle.net/10803/296677.
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Spinal muscular atrophy (SMA) is a genetic disorder caused by loss of the Survival motor neuron 1 gene (SMN1), lead to reduced SMN protein level and selective dysfunction of MNs. SMN reduction causes neurite degeneration and cell death without classical apoptotic features, but the direct events leading to MN degeneration in SMA are still unknown. Autophagy is being a primary target for the treatment of many neurodegenerative diseases. The objective of the present study is to analyze the role of autophagy in SMA pathology, the mechanisms that regulate SMN protein degradation and the origin of neurodegeneration in spinal cord MNs. To this end, we have reduced the Smn protein by using the lentivirus knockdown method. In Smn-reduced MNs from lentivirus Smn knockdown and SMA type I transgenic mice models, we have observed the increase of autophagy markers and autophagosome accumulation. Treatment with autophagy activators or inhibitors or proteasome inhibitors or calpain knockdown induce changes of Smn protein level in MNs suggesting the role of autophagy and proteasome in the regulation of Smn protein in these cells. Therefore the results contribute to new insight about Smn protein regulation in MNs and the possible role of autophagy in SMA neurodegeneration.L'atròfia muscular espinal (SMA) és un trastorn genètic, causada per la pèrdua o la mutació del gen de la supervivencia de les neurones motores 1 (SMN1), cosa que condueix a una reducció dels nivells de la proteïna SMN i una disfunció selectiva de les MN. S’ha descrit que la reducció d’SMN causa la degeneració de les neurites i la mort cel•lular sense les característiques apoptòtiques clàssiques, però els esdeveniments directes que condueixen a la degeneració de les MN en l’SMA encara són desconeguts. L’autofàgia és una diana principal per al tractament de moltes malalties neurodegeneratives. L'objectiu d’aquest estudi és analitzar el paper de l'autofàgia en la patologia de l’SMA, els mecanismes que regulen la degradació de la proteïna SMN i l'origen de la neurodegeneració en les MN de la medul•la espinal. Amb aquesta finalitat, hem reduït la proteïna SMN utilitzant el mètode de silenciament amb lentivirus. Hem analitzat els canvis en els marcadors d’autofàgia en les MN en cultiu amb l’SMN reduïda amb lentivirus i en cultius de MN de models de ratolins transgènics de SMA de tipus I. Hem observat que la reducció de l’SMN provoca un augment dels marcadors d’autofàgia i l'acumulació d’autofagosomes. A més, el tractament amb activadors de l'autofàgia, inhibidors de l'autofàgia o inhibidors del proteasoma o calpaïna indueix canvis en els nivells de la proteïna SMN en les MN, la qual cosa suggereix un paper de l'autofàgia i el proteasoma en la regulació de la proteïna SMN en aquestes cèl•lules. Conjuntament, aquests resultats contribueixen a una nova visió sobre la regulació de la proteïna SMN en les MN i sobre el possible paper de l'autofàgia en la neurodegeneració en l’ SMA.
La atrofia muscular espinal (AME) es un trastorno genético causado por la pérdida de la supervivencia de las neuronas motoras del gen 1 (SMN1) que conduce a la reducción de nivel de proteína SMN y a la disfunción selectiva de los MNs. La reducción de SMN causa la degeneración de axones y la muerte celular sin características apoptóticas clásicas; sin embargo, los motivos directos que conducen a la degeneración del MN en AME aún se desconocen. La autofagia está siendo un objetivo principal para el tratamiento de muchas enfermedades neurodegenerativas. El objetivo del presente estudio es analizar el papel de la autofagia en la patología de la AME, los mecanismos que regulan la degradación de la proteína SMN y el origen de la neurodegeneración de los MNs en la médula espinal. Con este fin, hemos reducido la proteína SMN utilizando un método de reducción lentiviral. En la Smn reducida mediante el método de reducción lentiviral y modelos de ratones transgénicos AME de tipo I, hemos observado el aumento de los marcadores de autofagia y la acumulación de autofagosoma. El tratamiento con activadores o inhibidores de la autofagia o inhibidores del proteasoma o calpaína reducida induce cambios del nivel de la proteína SMN en los MNs que demuestran el papel de la autofagia y del proteasoma en la regulación de la proteína SMN en estas células. Por lo tanto, los resultados contribuyen a una nueva visión sobre la regulación de las proteínas Smn en el MN y el posible papel de la autofagia en la neurodegeneración de AME.
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Richards, Dannette Shanon. "CHARACTERIZATION OF EXCITATORY AMINO ACID NEUROTRANSMITTERS AT MOTONEURON SYNAPSES CONTACTING RENSHAW CELLS." Wright State University / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=wright1260896604.
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Romer, Shannon Hunt. "The Organization of Kv2.1 ChannelProteins in the Membrane of Spinal Motoneurons:Regulation by Injury and Cellular Activity." Wright State University / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=wright1425136084.
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Hensel, Niko [Verfasser]. "Analysis and inhibition of dysregulated pathways in a mouse model of the motoneuron disease Spinal Muscular Atrophy / Niko Hensel." Hannover : Bibliothek der Tierärztlichen Hochschule Hannover, 2014. http://d-nb.info/105431201X/34.
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Kastanenka, Ksenia V. "IN VIVO ACTIVATION OF CHANNELRHODOPSIN-2 USED TO DETERMINE THE ROLE OF SPONTANEOUS NEURAL ACTIVITY IN AXONAL GUIDANCE." Case Western Reserve University School of Graduate Studies / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=case1307741269.
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Guzulaitis, Robertas. "The organisation principles of spinal neural network: temporal integration of somatosensory input and distribution of network activity." Doctoral thesis, Lithuanian Academic Libraries Network (LABT), 2013. http://vddb.laba.lt/obj/LT-eLABa-0001:E.02~2013~D_20130925_093153-76748.
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Spinal cord integrates somatosensory information and generates coordinated motor responses. Temporal integration can be used for discrimination of important stimuli from noise. Here it is shown that temporal integration of somatosensory inputs in sub second time scale is possible without changes of intrinsic properties of motoneurons. The activity of premotor neurons increases during temporal integration and can be a mechanism for short term information storage in spinal cord. Suppression of motor activity after painful somatosensory stimulus is called cutaneous silent period. This motor suppression is well described in humans and used for diagnostics. However it is not known if the suppression of motor activity is due to inhibition of motoneurons or reduction of excitatory drive from premotor neurons. Here it is shown that motoneurons are inhibited during cutaneous silent period. Neural networks of spinal cord not only process somatosensory information but generate locomotion and reflexes too. It is accepted that neural networks controlling front and hind limb movements are located in cervical and lumbar enlargements respectfully. Here it is shown that thoracic segments of spinal cord contribute to hind limb movements as well. It means that neural network generating movements is much more widely distributed than previously thought.Nugaros smegenys gauna somatosensorinę informaciją, ją integruoja ir generuoja motorinius atsakus. Disertacijoje parodoma, kad somatosensorinių įėjimų viršsekundinė laikinė integracija nugaros smegenų neuronų tinkle vyksta ne dėl motorinių neuronų vidinių savybių kitimo. Laikinės integracijos metu padidėja priešmotorinių neuronų aktyvumas ir tai gali lemti informacijos apie somatosensorinį įėjimą saugojimą. Somatosensorinis tylos periodas – tai motorinio aktyvumo slopinimas po skausmingo stimulo. Jis plačiai aprašytas žmonėse, bei taikomas diagnostikoje. Nepaisant plataus taikymo, somatosensorinio tylos periodo mechanizmai nėra ištirti – nebuvo žinoma ar šis motorinio aktyvumo slopinimas vyksta slopinant motorinius neuronus, ar eliminuojant motorinių neuronų žadinimą. Disertacijoje parodoma, kad somatosensorinio tylos periodo metu motoriniai neuronai yra slopinami. Be somatosensorinės informacijos apdorojimo nugaros smegenų neuronų tinklai užtikrina judėjimo ir refleksų valdymą. Yra priimta, kad priekines ir užpakalines galūnes valdantys neuronų tinklai išsidėstę atitinkamai nugaros smegenų kaklinės ir strėnų sričių išplatėjimuose. Disertacijoje parodoma, kad ir krūtininiai nugaros smegenų segmentai prisideda prie užpakalinių galūnių motorinio aktyvumo generavimo. Tai leidžia manyti, kad neuronų tinklas generuojantis judesius yra išplitęs labiau, nei manyta iki šiol.
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Fuente, Ruiz Sandra de la. "Development of new therapeutic strategies for Spinal Muscular Atrophy." Doctoral thesis, Universitat de Lleida, 2020. http://hdl.handle.net/10803/669753.
Full textAbstract:
L'Atròfia Muscular Espinal (AME) és una malaltia neurodegenerativa greu i la primera causa genètica de mort infantil. S'origina per la pèrdua o mutació del gen Survival Motor Neuron 1 (SMN1) que causa una deficiència de la proteïna de Survival Motor Neuron (SMN). La reducció d'aquesta proteïna condueix principalment a la degeneració de les motoneurones (MNs) de la medul·la espinal i, en conseqüència, produeix atròfia i feblesa del múscul esquelètic. Actualment, només es coneix parcialment quins mecanismes cel·lulars i moleculars exactes són els responsables de la pèrdua de funció de les MNs. La reducció de SMN causa degeneració de les neurites i mort cel·lular sense característiques apoptótiques clàssiques. L'autofàgia és un procés important i altament regulat, essencial per a l'eliminació d'orgànuls danyats i substàncies o proteïnes tòxiques a través de la degradació amb els lisosomes. L'autofàgia és especialment important en cèl·lules post-mitòtiques, com les MNs, on l'acumulació d’autofagosomes provoca la interrupció del transport axonal, la interferència del trànsit intracel·lular i la degeneració de les neurites.
El que és ben sabut en l'AME és que el nivell intracel·lular de proteïna SMN defineix l'inici i la gravetat de la malaltia i això està parcialment determinat pel nombre de còpies del gen SMN2, la duplicació centromérica de SMN i el principal modificador de l'AME. Per aquesta raó, comprendre els processos que regulen la degradació de SMN amb la finalitat d'identificar compostos que augmentin els nivells de proteïnes és el principal objectiu en el desenvolupament terapèutic per a l’AME. Les calpaínes són una família de proteases dependents de calci que s'han relacionat amb trastorns musculars i malalties neurodegeneratives. Específicament, s'ha descrit en el múscul que SMN pot ser proteolizada per calpaína. L'activitat de la calpaína també està involucrada en la regulació de l'autofàgia mitjançant la modulació de múltiples de les proteïnes involucrades en el procés.
L'objectiu en el present treball ha estat analitzar la desregulació de l'autofàgia i determinar la participació de la calpaína en la regulació de la proteïna SMN en les MNs per a aprofundir en l'origen de la neurodegeneración i desenvolupar un nou enfocament terapèutic per a l'AME. Per aquesta finalitat, hem analitzat marcadors autofágics en diferents models in vitro d’AME, tant de ratolí com d'humà. Els resultats van mostrar que, tant els autofagosomes com els nivells de LC3 es troben augmentats en les mostres d’AME en comparació amb els controls, la qual cosa suggereix una desregulació del procés d'autofàgia al llarg de la progressió de la malaltia. A més, la reducció dels nivells endògens de calpaína utilitzant un shRNA van mostrar un augment dels nivells de Smn i LC3, alhora que prevenia la degeneració neurítica que es produeix en les MNs de ratolí afectats per AME. Es van obtenir resultats similars en experiments in vitro utilitzant un inhibidor farmacològic de calpaína, la calpeptina. Tanmateix, l'activació de la calpaína produïda per condicions despolarizants induïa la proteólisis de l’α-fodrina i de SMN, la qual cosa confirma que calpain regula directament els nivells de proteïna SMN en les MNs. A més, el tractament amb calpeptina in vivo va millorar significativament l'esperança de vida i la funció motora de dos models de ratolins amb AME, la qual cosa demostra la utilitat potencial dels inhibidors de la calpaína en la teràpia per a la malaltia. Finalment, l'anàlisi de la via de la calpaína en ratolins i models cel·lulars humans d’AME va indicar un augment de l'activitat de la calpaína en les MNs amb nivells reduïts de SMN. Per tant, els nostres resultats demostren que l'activitat de la calpaína es troba sobreactivada en les MNs d’AME i que la seva inhibició pot tenir un efecte beneficiós sobre el fenotip de la malaltia a través de l'augment de SMN i la regulació del procés d'autofàgia en les MNs de la medul·la espinal.La atrofia muscular espinal (AME) es una enfermedad neurodegenerativa grave y la primera causa genética de muerte infantil. Se origina por la pérdida o mutación del gen Survival Motor Neuron 1 (SMN1) que causa una deficiencia de la proteína de Survival Motor Neuron (SMN). La reducción de esta proteína conduce predominantemente a la degeneración de las motoneuronas (MNs) de la médula espinal y, en consecuencia, produce atrofia y debilidad del músculo esquelético. Actualmente, solo se conoce parcialmente que mecanismos celulares y moleculares exactos son los responsables de la pérdida de función de las MNs. La reducción de SMN causa degeneración de neuritas y muerte celular sin características apoptóticas clásicas. La autofagia es un proceso importante y altamente regulado, esencial para la eliminación de orgánulos dañados y sustancias o proteínas tóxicas a través de la degradación con los lisosomas. La autofagia es especialmente importante en células post-mitóticas, como las MNs, donde la acumulación de autofagosomas provoca la interrupción del transporte axonal, la interferencia del tráfico intracelular y la degeneración de las neuritas. Lo que es bien sabido en la AME es que el nivel intracelular de proteína SMN define el inicio y la gravedad de la enfermedad y esto está parcialmente determinado por el número de copias del gen SMN2, la duplicación centromérica de SMN y el principal modificador de la AME. Por esa razón, comprender los procesos que regulan la degradación de SMN con la finalidad de identificar compuestos que aumentan los niveles de proteínas es el principal objetivo en el desarrollo terapéutico de AME. Las calpaínas son una familia de proteasas dependientes de calcio que se han relacionado con trastornos musculares y enfermedades neurodegenerativas. Específicamente, se ha descrito en el músculo que SMN puede ser proteolizada por calpaína. La actividad de la calpaína también está involucrada en la regulación de la autofagia mediante la modulación de múltiples de las proteínas involucradas en el proceso. El objetivo en el presente trabajo ha sido analizar la desregulación de la autofagia y determinar la participación de la calpaína en la regulación de la proteína SMN en las MNs para profundizar en el origen de la neurodegeneración y desarrollar un nuevo enfoque terapéutico para la AME. Con este fin, hemos analizado marcadores autofágicos en diferentes modelos in vitro de AME, tanto de ratón como de humano. Los resultados mostraron que los autofagosomas y los niveles de LC3 se encuentran aumentados en las muestras de AME en comparación con los controles, lo que sugiere una desregulación del proceso de autofagia a lo largo de la progresión de la enfermedad. Además, la reducción de los niveles endógenos de calpaína utilizando un shRNA muestraron un aumento de los niveles de Smn y LC3, a la vez que previene la degeneración neuritica que se produce en las MNs de ratón afectados por AME. Se obtuvieron resultados similares en experimentos in vitro utilizando un inhibidor farmacológico de calpaína, la calpeptina. Asimismo, la activación de calpaína producida por condiciones despolarizantes inducia la proteólisis de α-fodrina y de SMN, lo que confirma que calpain regula directamente los niveles de proteína SMN en las MNs. Además, el tratamiento con calpeptina in vivo mejoró significativamente la esperanza de vida y la función motora de dos modelos de ratones con AME, lo que demuestra la utilidad potencial de los inhibidores de la calpaína en la terapia para la enfermedad. Finalmente, el análisis de la vía de la calpaína en ratones y modelos celulares humanos de AME indicó un aumento de la actividad de la calpaína en las MNs con niveles reducidos de SMN. Por lo tanto, nuestros resultados demuestran que la actividad de la calpaína se encuentra sobreactivada en las MNs de AME y su inhibición puede tener un efecto beneficioso sobre el fenotipo de la enfermedad a través del aumento de SMN y la regulación del proceso de autofagia en las MNs de la médula espinal.
Spinal Muscular Atrophy (SMA) is a severe neurodegenerative disease and the first genetic cause of infant death. It is originated by the deletion or mutation of Survival Motor Neuron 1 (SMN1) gene causing a Survival Motor Neuron (SMN) protein deficiency. The reduction of this protein predominantly leads to the degeneration of spinal cord motoneurons (MNs) and consequently produces skeletal muscle atrophy and weakness. The exact cellular and molecular mechanisms responsible for MN loss of function are only partially known. SMN reduction causes neurite degeneration and cell death without classical apoptotic features. Autophagy is an important and highly regulated process, essential for the removal of damaged organelles and toxic substances or proteins through lysosome degradation. This mechanism is specifically important in post-mitotic cells like MNs where autophagosome accumulation causes axonal transport disruption, interference of intracellular space trafficking, and neurite degeneration. What is well known in SMA is that intracellular SMN protein levels are critical to define the disease onset and severity, and this is partially determined by the number of copies of SMN2, the centromeric duplication of the SMN gene and the main modifier of SMA. For that reason, understanding the processes of SMN stability and degradation to identify compounds that increase protein levels is a major goal in SMA therapeutics development. Calpains are a family of calcium-dependent proteases that have been related to muscle disorders and neurodegenerative diseases. Specifically, it has been described in muscle that SMN can be a proteolytic target of calpain. Calpain activity is also involved in autophagy regulation by modulation of multiple proteins involved in the process. The objectives in the present work have been to analyze the autophagy deregulation and determine the involvement of calpain in SMN protein regulation on MNs, in order to deepen in the origin of neurodegeneration and to develop a new therapeutic approach for SMA disease. To this end, we have analyzed autophagic markers in different mouse and human SMA in vitro models. The results showed that autophagosomes and LC3 levels were increased in SMA samples compared to controls, suggesting a deregulation of the autophagy process throughout the disease progression. Moreover, calpain knockdown using an shRNA approach showed an increase of both, Smn and LC3 levels and prevented neurite degeneration occurred in SMA affected mouse MNs. Similar results were obtained in in vitro experiments using a pharmacological calpain inhibitor, calpeptin. Likewise, calpain activation produced by depolarized conditions induced α-fodrin and SMN proteolysis, confirming that calpain directly regulates the SMN protein level in MNs. Additionally, calpeptin in vivo treatment significantly improved the lifespan and motor function of two severe SMA mouse models, demonstrating the potential utility of calpain inhibitors in SMA therapeutics. Finally, the analysis of calpain pathway members in mice and human cellular SMA models indicated an increase of calpain activity in SMN-reduced MNs. Thus, our results show that calpain activity is increased in SMA MNs and its inhibition may have a beneficial effect on the SMA phenotype through the increase of SMN and the regulation of the autophagy process in spinal cord MNs.
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Bose, Prodip Kumar. "Wobbler mouse : early detection of motoneuron disease, therapeutic evaluation of nutrition, neuropeptides & their antagonists, and the effects on neuronal sprouting in cervical spinal cord /." Hong Kong : University of Hong Kong, 1997. http://sunzi.lib.hku.hk/hkuto/record.jsp?B19118168.
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Walter, Lisa Marie [Verfasser], Peter [Akademischer Betreuer] Claus, Evgeni [Akademischer Betreuer] Ponimaskin, Anaclet [Akademischer Betreuer] Ngezahayo, and Laxman [Akademischer Betreuer] Gangwani. "Dynamics and regulation of the actin cytoskeleton in the motoneuron disease Spinal Muscular Atrophy (SMA) / Lisa Marie Walter ; Peter Claus, Evgeni Ponimaskin, Anaclet Ngezahayo, Laxman Gangwani." Hannover : Stiftung Tierärztliche Hochschule Hannover, 2020. http://d-nb.info/1217249508/34.
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Zanon, Renata Graciele. "Influencia da modulação da expressão do MHC I sobre a astroglicose reativa e plasticidade sinaptica." [s.n.], 2009. http://repositorio.unicamp.br/jspui/handle/REPOSIP/316479.
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Orientador: Alexandre Leite Rodrigues de OliveiraTese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia
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Resumo: O complexo de histocompatibilidade principal de classe I (MHC I) é uma molécula originalmente do Sistema Imunológico. A presença desses elementos no Sistema Nervoso Central (SNC) parece estar relacionada a diferentes funções, apresentando papel importante no refinamento sináptico durante o desenvolvimento do SNC e sendo fundamental no processo de eliminação sináptica após uma lesão nervosa no adulto. No intuito de investigarmos os processos de plasticidade sináptica e reatividade glial no microambiente da medula espinal foram utilizados dois imunomoduladores empregados no tratamento da Esclerose Múltipla, o interferon beta (IFN beta) e o acetato de glatirâmer (AG). O IFN beta, potencialmente capaz de influenciar a expressão de MHC I, foi utilizado in vivo, juntamente com axotomia periférica e in vitro, enquanto o AG foi utilizado para testes in vitro. Para tanto, camundongos C57BL/6J foram tratados com 10.000 UI de IFN beta durante 2 semanas, antes e depois da transecção unilateral do nervo isquiático. Os camundongos foram submetidos à eutanásia e suas medulas espinais lombares processadas para imunohistoquímica (anti-MHC I, sinaptofisina, GFAP - glial fibrillary acidc protein, ezrina e iba1), hibridação in situ (sondas para GFAP e microglobulina beta-2), Western blotting (GFAP e MHC I) e microscopia eletrônica de transmissão. Grupos axotomizados, placebo e não tratado foram utilizados como controles. Adicionalmente ao estudo in vivo, foram estabelecidas culturas purificadas de astrócitos para o tratamento com diferentes doses de IFN beta (0, 100, 500 ou 1000 UI/ml) ou AG (0, 1.2, 2.5 ou 5.0µg/ml) durante 5 dias. As culturas tratadas com IFN beta foram submetidas à imunohistoquímica para MHC I, ezrina, GFAP, enquanto nas culturas tratadas com AG foi realizado o estudo para verificar a reatividade e proliferação através da marcação anti-GFAP e DAPI (para identificação dos núcleos das células). In vivo, os resultados mostraram um aumento do RNAm e da expressão protéica para MHC I após axotomia, sendo que este incremento foi maior no grupo tratado com INF. Observou-se a intensificação da expressão das proteínas que expressam a reatividade astrocitária, GFAP e ezrina, concomitantemente à diminuição da imunomarcação para sinaptofisina, especialmente no grupo tratado. O tratamento realizado não influenciou a reatividade da microglia. A análise do material in vitro também mostrou, após o tratamento com IFN beta, um aumento da expressão de MHC I e GFAP, bem como de ezrina. As doses que mais estimularam a elevação da expressão dos marcadores estudados foram as de 500 e 1000 UI/ml. Dado que não ocorreu para o tratamento com o acetato de glatirâmer. Assim, o tratamento com AG não alterou o nível de reatividade astrocitária, apesar de estimular a proliferação celular. A ultraestrutura das sinapses mostrou uma intensa retração dos terminais pré-sinápticos em contato com os motoneurônios alfa, induzida pela axotomia mais o tratamento com IFN beta. Em conjunto, esses resultados reforçam a importância da expressão de moléculas de MHC I em resposta à lesão nervosa e seu papel como mecanismo de comunicação entre neurônio e glia, além de reafirmar que os astrócitos são elementos ativos no processo de plasticidade sináptica.
Abstract: The class I main histocompatibility complex (MHC I) is a molecule originally restricted to Immune System. The presence of such element in the Central Nervous System (CNS) may indicate other functions, including an important role in the synaptic refinement during the development of the CNS as well as in the synaptic elimination process after a peripheral nerve injury in the adult. To investigate the synaptic plasticity and glial reactivity in the spinal cord, two immunomodulators, widely used for treating Multiple Sclerosis, were applied, namely the Interferon beta (IFN beta) and the glatiramer acetate (GA). The IFN beta was used in order to upregulate the MHC I expression in vivo, after a peripheral axotomy, and also in vitro. GA treatment was only used for in vitro experiments. C57BL/6J mice were injected with 10,000 IU of IFN beta for 2 weeks, before and after the nerve transection. The animals were sacrificed and the lumbar spinal cords were processed for immunohistochemistry (MHC I, synapthophysin, GFAP, ezrin and Iba-1 antisera), in situ hybridization (beta 2 immunoglobulin, a component of the MHC I molecule, and GFAP), Western blotting (GFAP and MHC I) and transmission electron microscopy. Placebo and non-treated axotomized groups were used as controls. Additionally to the in vivo study, primary cultures of astrocytes were established and treated during five consecutive days with different doses of IFN beta (0, 100 IU, 500 IU and 1000 IU/ml). In this case, some cultures were treated with GA (0, 1.2, 2,5 and 5.0 µg/ml). INF treated cultures were processed for immunocitochemistry (MHC I, GFAP and ezrin antisera). GA treated cultures were evaluated with anti-GFAP antibody and cell proliferation was accessed with DAPI staining. In vivo, the results showed an upregulation of MHC I mRNA and protein expression after axotomy, that was stronger in the IFN treated group. We observed a greater GFAP and ezrin expression, coupled with a decrease of synapthophysin immunoreactivity. Such alterations were more evident in the IFN treated group. Interestingly, the IFN beta treatment did not interfere in the microglial reactivity. The in vitro analysis also showed a sharp upregulation of MHC I, GFAP and ezrin, mostly when the cultures were subjected to 500 and 1000 IU/ml of IFN beta. Regarding the GA treatment, the results showed that treatment did not change the level of astroglial reactivity despite stimulating cellular proliferation. The ultrastructural analysis of synapses showed a larger pruning of presynaptic terminals in contact with alpha motoneurons, induced by axotomy plus IFN beta treatment. Together, our results reinforce the importance of the MHC I expression as a response to nerve injury and its role as a communication mechanism between neurons and surrounding glial cells. Furthermore, the present data confirm that astrocytes are active elements during the synaptic plasticity process.
Doutorado
Anatomia
Biologia Celular e Estrutural
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Cerveró, Cebrià Clàudia. "Atròfia muscular espinal: mecanismes patogènics i estratègies terapèutiques en models murins de la malaltia." Doctoral thesis, Universitat de Lleida, 2016. http://hdl.handle.net/10803/399028.
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L’atròfia muscular espinal (AME) és una malaltia genètica que cursa amb mort de motoneurones espinals i atròfia muscular.
S’ha caracteritzat un model murí d’AME, l’Smn2B/-, amb una clínica menys severa que la mostrada per altres models més extensament utilitzats. S’ha evidenciat una alteració multisistèmica acompanyant a la clàssicament coneguda del sistema neuromuscular.
S’han estudiat les sinapsis colinèrgiques tipus C en l’AME i testat el paper del PRE-084 (agonista del receptor sigma-1 present en aquestes) com a possible teràpia en els models SMNΔ7 i Smn2B/-. Malgrat no conferir neuroprotecció, el PRE-084 ha evitat la gliosi pròpia de l’AME.
Finalment, s’ha testat l’efectivitat de l’AICAR, agent mimètic de l’exercici físic, en ratolins SMNΔ7. L’AICAR ha mitigat l’atròfia muscular, els defectes estructurals en les unions neuromusculars i la pèrdua de sinapsis glutamatèrgiques en el soma de les motoneurones, però no ha evitat la mort neuronal ni la reacció glial en la medul·la espinal.La atrofia muscular espinal (AME) es una enfermedad genética que cursa con muerte de motoneuronas espinales y atrofia muscular. Se ha caracterizado un modelo murino de AME, el Smn2B/-, con una clínica menos severa que la mostrada por otros modelos más extensamente utilizados. Se ha evidenciado una alteración multisistémica acompañando a la clásicamente conocida del sistema neuromuscular. Se han estudiado las sinapsis colinérgicas de tipo C en la AME y testado el papel del PRE-084 (agonista del receptor sigma-1 presente en estas) como posible terapia en los modelos SMNΔ7 y Smn2B/-. A pesar de no conferir neuroprotección, el PRE-084 ha evitado la gliosis propia de la AME. Finalmente, se ha testado la efectividad del AICAR, agente mimético del ejercicio físico, en ratones SMNΔ7. El AICAR ha mitigado la atrofia muscular, los defectos estructurales en las uniones neuromusculares y la pérdida de sinapsis glutamatérgicas en el soma de las motoneuronas, pero no ha evitado la muerte neuronal ni la reacción glial en la medula espinal.
The spinal muscular atrophy (SMA) is a genetic disease that affects spinal motor neurons causing its death and muscle atrophy. This study is divided in three parts. First. Characterization of the Smn2B/- mice, a mild SMA phenotype model. A multisistemic affectation was reported to accompany the better known neuromuscular alteration in these mice. Second. Study of C-type cholinergic synapses in the SMA and therapeutic trial with the sigma-1 receptor agonist PRE-084 (molecule present in C boutons) in the SMNΔ7 and Smn2B/- mice. Although PRE-084 did not confer neuroprotection, it prevented the SMA characteristic reactive gliosis. Third. Treatment with AICAR, an exercise mimetic agent, in SMNΔ7 mice. AICAR mitigated muscular atrophy and structural defects in neuromuscular junctions and prevented loss of glutamatergic synapses in the motoneuron soma but it did not protect against neuronal death and reactive gliosis.
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Guzulaitis, Robertas. "Nugaros smegenų neuronų tinklo veikimo principai: somatosensorinės informacijos integracija ir aktyvumo išplitimas." Doctoral thesis, Lithuanian Academic Libraries Network (LABT), 2013. http://vddb.laba.lt/obj/LT-eLABa-0001:E.02~2013~D_20130925_093406-59707.
Full textAbstract:
Nugaros smegenys gauna somatosensorinę informaciją, ją integruoja ir generuoja motorinius atsakus. Disertacijoje parodoma, kad somatosensorinių įėjimų viršsekundinė laikinė integracija nugaros smegenų neuronų tinkle vyksta ne dėl motorinių neuronų vidinių savybių kitimo. Laikinės integracijos metu padidėja priešmotorinių neuronų aktyvumas ir tai gali lemti informacijos apie somatosensorinį įėjimą saugojimą. Somatosensorinis tylos periodas – tai motorinio aktyvumo slopinimas po skausmingo stimulo. Jis plačiai aprašytas žmonėse, bei taikomas diagnostikoje. Nepaisant plataus taikymo, somatosensorinio tylos periodo mechanizmai nėra ištirti – nebuvo žinoma ar šis motorinio aktyvumo slopinimas vyksta slopinant motorinius neuronus, ar eliminuojant motorinių neuronų žadinimą. Disertacijoje parodoma, kad somatosensorinio tylos periodo metu motoriniai neuronai yra slopinami. Be somatosensorinės informacijos apdorojimo nugaros smegenų neuronų tinklai užtikrina judėjimo ir refleksų valdymą. Yra priimta, kad priekines ir užpakalines galūnes valdantys neuronų tinklai išsidėstę atitinkamai nugaros smegenų kaklinės ir strėnų sričių išplatėjimuose. Disertacijoje parodoma, kad ir krūtininiai nugaros smegenų segmentai prisideda prie užpakalinių galūnių motorinio aktyvumo generavimo. Tai leidžia manyti, kad neuronų tinklas generuojantis judesius yra išplitęs labiau, nei manyta iki šiol.Spinal cord integrates somatosensory information and generates coordinated motor responses. Temporal integration can be used for discrimination of important stimuli from noise. Here it is shown that temporal integration of somatosensory inputs in sub second time scale is possible without changes of intrinsic properties of motoneurons. The activity of premotor neurons increases during temporal integration and can be a mechanism for short term information storage in spinal cord. Suppression of motor activity after painful somatosensory stimulus is called cutaneous silent period. This motor suppression is well described in humans and used for diagnostics. However it is not known if the suppression of motor activity is due to inhibition of motoneurons or reduction of excitatory drive from premotor neurons. Here it is shown that motoneurons are inhibited during cutaneous silent period. Neural networks of spinal cord not only process somatosensory information but generate locomotion and reflexes too. It is accepted that neural networks controlling front and hind limb movements are located in cervical and lumbar enlargements respectfully. Here it is shown that thoracic segments of spinal cord contribute to hind limb movements as well. It means that neural network generating movements is much more widely distributed than previously thought.
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Bouhadfane, Mouloud. "Propriétés électriques bistables des motoneurones de la moelle épinière : Identification des mécanismes ioniques sous-jacents." Thesis, Aix-Marseille, 2014. http://www.theses.fr/2014AIXM5030/document.
Full textAbstract:
La posture, composante statique du contrôle moteur permettant une position érigée du corps, repose sur une décharge tonique des motoneurones innervant nos muscles antigravitaires. La décharge prend la forme de « potentiel de plateau » au niveau de motoneurones matures chez de nombreux vertébrés. Pour déterminer une éventuelle concordance entre l'émergence des propriétés de plateau et le développement postural, notre travail a eu pour but d'étudier la maturation et la nature ionique des potentiels de plateau des motoneurones innervant le muscle triceps surae (extenseur de la cheville) chez le rat nouveau-né.La réalisation de ces travaux de thèse nous a permis de dégager un mécanisme fondamental dans la genèse des propriétés de plateau des motoneurones lombaires. Ce mécanisme dont le fondement repose sur l'activation d'un « ménage à trois » jouerait un rôle majeur dans le développement moteur chez le rat. Dans la mesure où les potentiels de plateau des motoneurones sont fortement perturbés à la suite d'une lésion médullaire, cette avancée scientifique permettra éventuellement de mieux comprendre l'origine de certains déficits sensori-moteurs (spasticité, hyperalgésie...) et le développement de nouvelles stratégies thérapeutiquesPosture allowing an erect posture of the body relies on spiking activity of motoneurons innervating antigravitary muscle. Discharge could take the form of plateau potential on mature motoneurons of numerous vertebrates. To determine a possible concordance between the emergence of plateau potential and postural control development, we studied the maturation and ionic nature of plateau potential of motoneurons innervating triceps surae muscle of neonatal rat.The conclusion of our work allows us to propose a fundamental mechanism in the genesis of plateau potential on lumbar motoneurons. This mechanism based on a "ménage a trois" seems to play an important role in the neonatal motor development. This scientific advance could eventually lead to a better understanding of the origin of some sensori-motor impairments (spasticity, hyperalgesia...) and development of therapeutic strategies
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Martin, Elodie. "Altérations précoces des réseaux moteurs spinaux chez la souris SOD1, modèle de la Sclérose Latérale Amyotrophique." Thesis, Bordeaux 1, 2013. http://www.theses.fr/2013BOR14873/document.
Full textAbstract:
Les études basées sur l’utilisation de modèles murins de la Sclérose Latérale Amyotrophique (SLA) portent très souvent sur des stades symptomatiques ou pré-symptomatiques. Des données existent cependant montrant que des altérations morphologiques des motoneurones existent aux stades post-nataux, suggérant que la SLA pourrait être une maladie neurodéveloppementale. Dans ce travail de thèse basé sur l’utilisation du modèle murin SOD1G93A de la SLA, nous avons cherché à savoir si dès le développement des réseaux moteurs, des perturbations existaient notamment au niveau de la mise en place des inhibitions, c'est-à-dire au niveau de l’homéostasie chlorure. En effet, nous pensons qu’une mauvaise construction du réseau pendant la vie embryonnaire serait la cause des dysfonctionnements observés lors de la survenue de la SLA. Nos données mettent en évidence que la morphologie des motoneurones est modifiée chez les embryons SOD1G93A au stade de développement E17,5 par rapport aux embryons WT et que cette modification de morphologie induit une hyperexcitabilité. De plus, nous montrons une altération du potentiel d’équilibre des ions chlorure (ECl) due à une modification de l’équilibre de la balance des co-transporteurs NKCC1/KCC2. Enfin, nous avons cherché à savoir si une modification du ECl avait une conséquence fonctionnelle au niveau de la mise en place de l’activité locomotrice exprimée par le réseau spinal lombaire. En conclusion, les travaux de cette thèse démontrent pour la première fois un déficit développemental au niveau du modèle murin SOD1G93A et ouvre des perspectives sur la recherche des mécanismes de compensations opérant jusqu’à la survenue du phénotype de la maladieMost studies based on the use of Amyotrophic Lateral Sclerosis (ALS) mouse models focus on symptomatic or presymptomatic periods. However, morphological alterations of ALS motoneurons have been described in post-natal stages, suggesting that ALS could be a neurodevelopmental disease. In this PhD Thesis, based on the use of the SOD1G93A mouse model of ALS, we tried to know if during the embryonic development of the spinal motoneuronal networks, alterations occur particularly at the level of the maturation of GABA/Glycine inhibition, driven by the chloride homeostasis. Indeed, we believe that a wrong construction of the motor network during the embryonic life may be the cause of the troubles observed at the onset of ALS. Our data show that the morphology of motoneurons is altered in E17,5 SOD1G93A embryos compared to WT embryos and that this changes in morphology induced hyperexcitability. In addition, we show an alteration of the equilibrium potential of chloride ions (ECl) due to a modification of the balance of NKCC1/KCC2 chloride co-transporters. Finally, we tried to know if a modification of the ECl had functional consequences in the development of locomotor activity expressed by the lumbar spinal network. In conclusion, the work of this PhD Thesis demonstrates, for the first time, a developmental deficit in the SOD1G93A mouse model and opens new perspectives based on understanding compensatory mechanisms occuring until the appearance of the disease
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Buišas, Rokas. "The gain of spinal cord motoneurons and its modification." Doctoral thesis, Lithuanian Academic Libraries Network (LABT), 2012. http://vddb.laba.lt/obj/LT-eLABa-0001:E.02~2012~D_20121001_093711-87354.
Full textAbstract:
Motoneurons are the spinal neurons that directly control the muscle contraction. The gain characterizes how the synaptic input to motoneuron is converted in to action potential firing and subsequent muscle contraction. The high gain allows a high force and fast contraction, while the low gain is essential for a fine control of movements. The gain of motoneurons is mainly determined by a set of ion channels in membrane and therefore is a subject for modification. It is known, that the gain decreases during adaptation of action potential firing. Moreover, the neurotransmitters released during spinal network activity may modify the ion channel activity and therefore adjust the gain to the functional needs. The aim of this study was to evaluate the gain of spinal cord motoneurons and investigate mechanisms of its modification. Spinal motoneurons from adult turtle were used. We found that the gain of motoneurons estimated from triangular current ramps is the same as steady one obtained from square current steps. Pharmacologically increased conductance of motoneuron membrane does not change the gain. Finally, we demonstrated that persistent inward Na+ current increases excitability and reduces the transient and early gain of spinal motoneurons.Motoneuronai – tai nervinės ląstelės tiesiogiai valdančios raumenis. Motoneuronuose, kaip ir kitose neuronuose, įėjimo transformacija į išėjimą charakterizuojama perdavimo funkcija, kuri dažniausiai aprašoma tam tikro statumo tiesine priklausomybe. Didelis perdavimo funkcijos statumas leidžia išvystyti didelę raumens susitraukimo jėgą, o mažas – įgalina tikslų raumenų valdymą. Perdavimo funkcijos charakteristikas apsprendžia neurono membranoje esantys joniniai kanalai. Pavyzdžiui, veikimo potencialų adaptaciją sukeliantys joniniai kanalai perdavimo funkcijos statumą mažina. Be to, neuroninio tinklo veikimo metu išskirti neurotransmiteriai gali veikti joninius kanalus ir pritaikyti perdavimo funkciją konkretaus judesio vykdymui. Šio darbo tikslas buvo įvertinti nugaros smegenų motoneuronų perdavimo funkcijos ypatybes ir ištirti jos galimus modifikavimo mechanizmus. Tyrimams naudoti vėžlio nugaros smegenų motoneuronai. Disertacijoje parodėme, kad perdavimo funkcijos statumas įvertintas trikampiais srovės impulsais sutampa su stacionariu perdavimo funkcijos statumu, įvertintu stimuliuojant motoneuronus stačiakampiais srovės impulsais. Nustatėme, kad farmakologiškai padidintas motoneuronų membranos laidumas neįtakoja perdavimo funkcijos statumo. Taip pat parodėme, kad nuolatinė Na+ srovė sumažina pradinį ir ankstyvąjį perdavimo funkcijų statumus.
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Leroy, Félix. "Atteinte différentielle de deux populations de motoneurones spinaux chez le souriceau SOD1 G93A (modèle de la maladie de Charcot)." Thesis, Paris 5, 2013. http://www.theses.fr/2013PA05T063/document.
Full textAbstract:
La deuxième semaine qui suit la naissance est critique pour le développement du système locomoteur de la souris. C’est pendant cette semaine que les souriceaux acquièrent leur posture et commencent à marcher. Cette transformation implique une réorganisation en profondeur des éléments composant les unités motrices. Cependant, nous ne savons encore que peu de choses sur la différenciation des propriétés intrinsèques des motoneurones innervant les fibres musculaires. Contrairement à l’adulte, où la décharge démarre au début de la stimulation, les motoneurones de souriceaux déchargent de façon hétérogène. En effet, une stimulation au seuil induit chez certains motoneurones une décharge commençant au début du créneau alors que la décharge est retardée dans d’autres motoneurones. Par des enregistrements de motoneurones sur des tranches de moelle épinière à P6-P10, j’ai dans un premier temps caractérisé les courants sous‐tendant la décharge retardée et j’ai constaté que deux conductances potassiques (l’une ressemblant au courant de type A et l’autre très lente) étaient activées autour du seuil de décharge. Lorsqu’elles s’activent, ces conductances sont capables d’hyperpolariser le potentiel de membrane et d’empêcher le motoneurone de décharger. Puis, en s’inactivant, la membrane se dépolarise et le neurone commence à décharger avec un retard pouvant aller jusqu’à plusieurs secondes après le début du créneau. En outre, les deux populations de motoneurones présentent des propriétés électro-physiologiques et morphologiques différentes. Les motoneurones à décharge retardée possèdent un arbre dendritique plus ramifié que ceux à décharge immédiate. En conséquence, les motoneurones à décharge retardée possèdent une conductance d’entrée et un seuil de recrutement plus faible. De plus le temps de relaxation de l’hyperpolarisation suivant chaque potentiel d’action (AHP) est plus long dans les motoneurones à décharge immédiate. Enfin, une partie des motoneurones à décharge retardée exprime la protéine chondrolectine récemment décrite comme un marqueur moléculaire des motoneurones de type rapide. L’ensemble de nos résultats nous permet de faire l’hypothèse que les motoneurones à décharge retardée sont des motoneurones innervant les unités motrices de type rapide alors que ceux à décharge immédiate innervent les unités motrices de type lent. Dans un second temps, j’ai étudié l’effet de la mutation SOD1 G93A, un modèle murin de la sclérose latérale amyotrophique, sur les motoneurones spinaux à P6‐P10. Sachant que cette maladie affecte les motoneurones de façon différente à l’âge adulte, j’ai cherché à savoir si, chez les souriceaux SOD1 G93A, les motoneurones à décharge retardée et immédiate étaient affectés de la même façon. Mes résultats montrent que seuls les motoneurones à décharge immédiate sont hyperexcitables. Pour ces motoneurones, le seuil de décharge est plus hyperpolarisé et leurs dendrites sont plus courtes de 35%. Ces résultats amènent à reconsidérer le lien supposé entre hyperexcitabilité et dégénérescence des motoneuronesIn the second postnatal week, the locomotor behavior of mice changes from crawling to walking. This is made possible by profound changes in motor units. Yet, how the discharge properties of spinal motoneurons evolve during post-‐natal maturation and whether they have an effect on the motor unit maturation remains an open question. In neonates, the spinal motoneurons display two modes of discharge. For threshold pulses, 33% of the motoneurons have a discharge that start at the current onset and adapts during the pulse (“immediate firing motoneurons”). The remaining 66% motoneurons fire with a large delay and the discharge then accelerates throughout the pulse (“delayed firing motoneurons”). Though the delayed firing pattern is quite common in spinal motoneurons of neonates, the ionic mechanisms that elicit this mode of discharge have received little attention. Using the patch-clamp technique to record P6‐P10 mouse motoneurons in a spinal cord slice preparation, I characterized the ionic currents that underlie the delayed firing pattern. This is caused by a combination of an A-like potassium current that acts on a short time scale and a slow‐inactivating potassium current that delays the discharge on a much longer time scale. I then investigated how these two potassium currents contribute to the recruitment threshold and how they shape the F-I function of delayed motoneurons in neonatal mice. The slow inactivating potassium current induces memory effects that have a strong impact on motoneuron excitability and on its discharge. Building on these results, I tried to correlate the discharge pattern to known physiological sub‐types. The delayed firing motoneurons have a larger input conductance, a higher rheobase, a narrower action potential, a shorter AHP and a more complex dendritic arbor than the immediate firing motoneurons. Additionally, only a sub-‐population of the delayed firing motoneurons expressed the chondrolectin protein, a fast motoneuron marker. Based on this body of corroborating evidence, the immediate firing motoneurons would be slow type motoneurons whereas the delayed firing motoneurons would be fast type motoneurons. Finally, numerous electrical and geometrical abnormalities have been observed in spinal motoneurons of SOD1 G934 mice (model of the amyotrophic lateral sclerosis) during the second post-natal week but the results were somehow contradictory. In relation to the known differential sensitivity to the disease exhibited by slow and fast motoneurons, I investigated whether the immediate and delayed firing motoneurons are equally affected by the SOD1 mutation. This is not the case. I found that the SOD1 mutation induced a decrease in the rheobase and a hyperpolarization of the voltage threshold only in the immediate firing motoneurons, thereby making them more excitable than in WT mice. Furthermore, the dendrites of the immediate firing motoneurons are substantially shorter (about 35%) in the mutant than in the WT. In sharp contrast, the excitability of the delayed firing motoneurons is unchanged and the dendritic tree is nearly unaffected (the dendrites only undergo a 10% elongation). These results allow for reconsidering the link between hyperexcitability and degenerescence of the motoneurons
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Cisi, Rogério Rodrigues Lima. "Sistema de simulação de circuitos neuronais da medula espinhal desenvolvido em arquitetura web." Universidade de São Paulo, 2007. http://www.teses.usp.br/teses/disponiveis/3/3142/tde-31032008-173530/.
Full textAbstract:
Este trabalho descreve o desenvolvimento de um sistema de simulação de circuitos neuronais, com interface de utilização amigável e arquitetura baseada em web. O sistema é direcionado ao estudo de redes de neurônios da medula espinhal, responsáveis pelo controle motor, sujeitas à ativação por vias superiores e periféricas ou por estímulos elétricos. Sua utilidade está relacionada à criação de hipóteses ou teorias sobre o processamento neuronal realizado no caso são ou patológico, a atividades como a interpretação de resultados de experimentos eletrofisiológicos realizados em humanos e no direcionamento e validação de procedimentos experimentais. Para os propósitos deste projeto, a simulação computacional é o recurso mais indicado a se utilizar, considerando o grande número de variáveis envolvidas e o caráter não-linear dos elementos constituintes. As simulações devem retratar de maneira fidedigna as principais propriedades que caracterizam os núcleos neuronais a se estudar. Essas propriedades estão associadas ao recrutamento de unidades motoras, às relações de entrada-saída dos conjuntos neuronais, à influência das vias aferentes sobre os motoneurônios, ao papel da inibição recorrente e da inibição recíproca, à geração de força e do sinal eletromiográfico, entre outros. A simulação do reflexo H, que é uma técnica muito importante utilizada em estudos neurofisiológicos, está presente neste trabalho. Pretende-se que o sistema de simulação aqui proposto seja uma ferramenta útil para pesquisa e ensino da neurofisiologia do controle motor, provendo subsídios que levem a um melhor entendimento dos circuitos neuronais modelados.This work describes the development of a simulation system of neuronal circuitry, having a user-friendly interface and based on web architecture. The system is intended for studying spinal cord neuronal networks responsible for muscle control, subjected to descending drive or electrical stimulation. It is potentially useful in many activities, such as the interpretation of electrophysiological experiments conducted with humans, the proposition of hypotheses or theories on neuronal processing. Computer simulation is the most indicated approach to attain the objectives of this project because of the huge number of variables and the non-linear characteristics of the constituting elements. The simulations should mimic in a faithful way the main properties related to the modeled neuronal nuclei. These properties are associated with: i) motor-unit recruitment, ii) neuronal nuclei input-output relations, iii) afferent tract influence on motoneurons, iv) effects of recurrent inhibition and reciprocal inhibition, v) generation of force and electromyogram, and others. The generation of the H-reflex by the Ia-motoneuron pool system, which is an important tool in human neurophysiology, is included in the simulation system. The biological reality obtained with the present simulator and its web-based implementation make it a powerful tool for researchers in neurophysiology.
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Benito, González Ana. "V1-DERIVED RENSHAW CELLS AND IA INHIBITORY INTERNEURONS DIFFERENTIATE EARLY DURING DEVELOPMENT." Wright State University / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=wright1310071181.
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Buišas, Rokas. "Nugaros smegenų motoneuronų perdavimo funkcija ir jos modifikavimas." Doctoral thesis, Lithuanian Academic Libraries Network (LABT), 2012. http://vddb.laba.lt/obj/LT-eLABa-0001:E.02~2012~D_20121001_093702-49526.
Full textAbstract:
Motoneuronai – tai nervinės ląstelės tiesiogiai valdančios raumenis. Motoneuronuose, kaip ir kitose neuronuose, įėjimo transformacija į išėjimą charakterizuojama perdavimo funkcija, kuri dažniausiai aprašoma tam tikro statumo tiesine priklausomybe. Didelis perdavimo funkcijos statumas leidžia išvystyti didelę raumens susitraukimo jėgą, o mažas – įgalina tikslų raumenų valdymą. Perdavimo funkcijos charakteristikas apsprendžia neurono membranoje esantys joniniai kanalai. Pavyzdžiui, veikimo potencialų adaptaciją sukeliantys joniniai kanalai perdavimo funkcijos statumą mažina. Be to, neuroninio tinklo veikimo metu išskirti neurotransmiteriai gali veikti joninius kanalus ir pritaikyti perdavimo funkciją konkretaus judesio vykdymui. Šio darbo tikslas buvo įvertinti nugaros smegenų motoneuronų perdavimo funkcijos ypatybes ir ištirti jos galimus modifikavimo mechanizmus. Tyrimams naudoti vėžlio nugaros smegenų motoneuronai. Disertacijoje parodėme, kad perdavimo funkcijos statumas įvertintas trikampiais srovės impulsais sutampa su stacionariu perdavimo funkcijos statumu, įvertintu stimuliuojant motoneuronus stačiakampiais srovės impulsais. Nustatėme, kad farmakologiškai padidintas motoneuronų membranos laidumas neįtakoja perdavimo funkcijos statumo. Taip pat parodėme, kad nuolatinė Na+ srovė sumažina pradinį ir ankstyvąjį perdavimo funkcijų statumus.Motoneurons are the spinal neurons that directly control the muscle contraction. The gain characterizes how the synaptic input to motoneuron is converted in to action potential firing and subsequent muscle contraction. The high gain allows a high force and fast contraction, while the low gain is essential for a fine control of movements. The gain of motoneurons is mainly determined by a set of ion channels in membrane and therefore is a subject for modification. It is known, that the gain decreases during adaptation of action potential firing. Moreover, the neurotransmitters released during spinal network activity may modify the ion channel activity and therefore adjust the gain to the functional needs. The aim of this study was to evaluate the gain of spinal cord motoneurons and investigate mechanisms of its modification. Spinal motoneurons from adult turtle were used. We found that the gain of motoneurons estimated from triangular current ramps is the same as steady one obtained from square current steps. Pharmacologically increased conductance of motoneuron membrane does not change the gain. Finally, we demonstrated that persistent inward Na+ current increases excitability and reduces the transient and early gain of spinal motoneurons.
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Moran, Linda Bridget. "Synaptic connectivity of normal and axotomised developing rat motoneurons." Thesis, Imperial College London, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.251825.
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Bair, Woei-Nan. "The convergence of descending motor volleys onto human spinal motoneurons." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp04/mq22271.pdf.
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Deng, Zhihui. "SMALL CONDUCTANCE CALCIUM-ACTIVATED POTASSIUM (SK) CHANNELS IN MAMMALIAN SPINAL MOTONEURONS." Wright State University / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=wright1237821684.
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Lawson, Simon John. "A morphological study of naturally occuring and induced neuronal death in the developing spinal cord of the rat." Thesis, Imperial College London, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.265974.
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Welin, Dag. "Neuroprotection and axonal regeneration after peripheral nerve injury." Doctoral thesis, Umeå : Umeå university, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-32819.
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Gou, Fàbregas Myriam. "Spinal cord motoneurons,morphological and molecular study during development and pathology." Doctoral thesis, Universitat de Lleida, 2010. http://hdl.handle.net/10803/8105.
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La identificació dels mecanismes moleculars que regulen la supervivència i mort de les motoneurones representa una informació important per a la comprensió funcional i l'establiment de potencials dianes terapèutiques per a les malalties que cursen amb degeneració i mort d'aquestes neurones. Per aquest motiu hem dedicat aquest treball a:a) L'estudi dels mecanismes intracel·lulars dependents de calci que modulen la supervivència de les motoneurones durant el desenvolupament.
Com a efecte inductor de supervivència hem analitzat la participació de la proteïna quinasa dependent de Ca2+/Calmodulina IV (CaMKIV) en motoneurones embrionàries de pollastre, i demostrem que la seva activació calci dependent indueix la fosforilació d'Akt i la supervivència d'aquestes neurones. Per altra banda, com a efecte inductor de mort demostrem que els increments excessius de la concentració del calci intracel·lular induïts per la despolarització de la membrana, són responsables de l'activació de la proteasa Calpaïna i la conseqüent degeneració de les motoneurones de ratolí. Proposem la inhibició de Calpaïna com a mecanisme neuroprotector.
b) La generació d'un model in vitro per a l'estudi dels mecanismes patològics que causen la degeneració específica de les motoneurones en Atròfia Muscular Espinal.
En aquesta segona part del treball, amb la finalitat de contribuir a la comprensió de la fisiopatologia d'aquesta malaltia hem desenvolupat un model in vitro utilitzant tècniques d'interferència d'RNA. Reduïm l'expressió de la proteïna Survival Motoneuron (SMN) en les motoneurones fins a nivells representatius de la forma severa de la malaltia. L'estudi morfològic i de viabilitat en aquestes cèl·lules ens facilitarà la identificació dels mecanismes moleculars implicats en la malaltia.
Els resultats presentats en aquesta tesi impliquen l'activació de CaMKIV en la regulació de la supervivència de les motoneurones; proporcionen nous coneixements sobre les vies de regulació que en provoquen la seva degeneració (nivells de potassi elevats al medi extracel·lular i Calpaïna), i demostren alteracions d'aquestes neurones en un models d'Atròfia Muscular Espinal (degeneració neurítica i mort).
La identificación de los mecanismos moleculares que regulan la supervivencia y muerte de las motoneuronas representa una información importante de conocimiento básico y para el establecimiento de potenciales dianas terapéuticas para las enfermedades que cursan con degeneración y muerte de estas neuronas. Por este motivo hemos dedicado este trabajo al estudio de:
a) Mecanismos intracelulares básicos dependientes de calcio que modulan la supervivencia de las motoneuronas durante el desarrollo.
Como efecto inductor de supervivencia hemos analizado la participación de la proteína quinasa dependiente de Ca2+/Calmodulina IV (CaMKIV) en motoneuronas embrionarias de pollo, y demostramos que su activación calcio dependiente, induce la fosforilación de Akt y supervivencia de estas neuronas. Por otro lado, como a efecto inductor de muerte demostramos que incrementos de la concentración del calcio intracelular inducidos por la despolarización de la membrana, son responsables de la activación de la proteasa Calpaína y la degeneración de las motoneuronas de ratón. Nuestros resultados apoyan el uso de inhibidores de Calpaína como estrategia neuroprotectora.
b) Mecanismos patológicos que causan la degeneración específica de las motoneuronas en Atrofia Muscular Espinal.
En esta segunda parte del trabajo, con la finalidad de contribuir a la comprensión de la fisiopatología de esta enfermedad hemos desarrollado un modelo in Vitro utilizando técnicas de interferencia de RNA. Reducimos la expresión de la proteína Survival Motoneuron (SMN) en las motoneuronas hasta niveles representativos de la forma severa de la enfermedad. El estudio morfológico y de viabilidad en estas células nos facilitará la identificación de los mecanismos moleculares implicados en la enfermedad.
Los resultados que presentamos en esta tesis implican la activación de CaMKIV en la regulación de la supervivencia de las motoneuronas; proporcionan nuevos conocimientos sobre las vías de regulación que provocan su degeneración (niveles de potasio elevados al medio extracelular y Calpaína), así como alteraciones específicas de estas neuronas en modelos de Atrofia Muscular Espinal (degeneración neurítica y muerte).
Identification of molecular mechanisms that regulate motoneuron survival and death represent valuable basic knowledge to elucidate potential therapeutic targets for those diseases that imply motoneuron degeneration and death. For this reason in the present work we studied:
a) Basic calcium-dependent intracellular mechanisms which modulate motoneuron survival during development.
As a pro-survival effect we analysed the role of the calcium/calmodulin dependent protein kinase IV (CaMKIV) in cultured chicken motoneurons. Results demonstrated that CaMKIV activation induces Akt phosphorylation and motoneuron survival. On the other hand, as a prodegenerative effect we demonstrate that in mouse motoneurons depolarization induced excessive calcium influx activates the protease Calpain and causes motoneurons death. Our results suggest that Calpain inhibitors may induce neuroprotective effects.
b) Intrinsic motoneuron pathological mechanisms underlying Spinal Muscular Atrophy.
In this second part, with the aim to facilitate the understanding of the physiopathology of SMA we developed an in vitro model using RNA interference techniques. We reduce Survival Motoneuron (SMN) protein expression in motoneurons to representative levels from severe Spinal Muscular Atrophy mouse models. Morphologic and survival analysis of these cultured neurons may contribute to the identification of pathologic molecular mechanisms implicated in the disease.
Reported results, obtained from the morphological and molecular analysis of primary motoneuron cultures, provide new knowledge on motoneuron development and survival regulating pathways (implication of CaMKIV activation in motoneuron survival regulation), about regulation pathways involved in motoneuron degeneration (high potassium extracellular levels and Calpain activation), as well as motoneuron alterations in a severe SMA culture model (neurite degeneration and death).
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Hammarberg, Henrik. "Spinal motoneurons and molecules related to neurotrophic function after axon injury /." Stockholm, 2000. http://diss.kib.ki.se/2000/91-628-3976-4/.
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Thams, Sebastian. "Immune recognition molecules in synaptic plasticity and regeneration of spinal motoneurons." Stockholm, 2009. http://diss.kib.ki.se/2009/978-91-7409-721-4/.
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Nascimento, Filipe. "Cholinergic modulation of spinal motoneurons and locomotor control networks in mice." Thesis, University of St Andrews, 2018. http://hdl.handle.net/10023/16141.
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Locomotion is an innate behaviour that is controlled by different areas of the central nervous system, which allow for effectiveness of movement. The spinal cord is an important centre involved in the generation and maintenance of rhythmic patterns of locomotor activity such as walking and running. Interneurons throughout the ventral horn of the spinal cord form the locomotor central pattern generator (CPG) circuit, which produces rhythmic activity responsible for hindlimb movement. Motoneurons within the lumbar region of the spinal cord innervate the leg muscles to convey rhythmic CPG output to drive appropriate muscle contractions. Intrinsic modulators, such as acetylcholine acting via M2 and M3 muscarinic receptors, regulate CPG circuitry to allow for flexibility of motor output. Using electrophysiology and genetic techniques, this work characterized the receptors involved in cholinergic modulation of locomotor networks and the role and mechanism of action of a subpopulation of genetically identified cholinergic interneurons in the lumbar region of the neonatal mouse spinal cord. Firstly, the effects of M2 and M3 muscarinic receptors on the output of the lumbar locomotor network were characterised. Experiments in which fictive locomotor output was recorded from the ventral roots of isolated spinal cord preparations revealed that M3 muscarinic receptors are important in stabilizing the locomotor rhythm while M2 muscarinic receptor activation seems to increase the irregularity of the locomotor frequency whilst increasing the strength of the motor output. This work then explored the cellular mechanisms through which M2 and M3 muscarinic receptors modulate motoneuron output. M2 and M3 receptor activation exhibited contrasting effects on motoneuron function suggesting that there is a fine balance between the activation of these two receptor subtypes. M2 receptor activation induces an outward current and decreases synaptic drive to motoneurons while M3 receptors are responsible for an inward current and increase in synaptic inputs to motoneurons. Despite the different effects of M2 and M3 receptor activation on synaptic drive and subthreshold properties of MNs, both M2 and M3 receptors are required for muscarine-induced increase in motoneuron output. CPG networks therefore appear to be subject to balanced cholinergic modulation mediated by M2 and M3 receptors, with the M2 subtype also being important for regulating the intensity of motor output. Next, using Designer Receptor Exclusively Activated by Designer Drug (DREADD) technology, the impact of the activation or inhibition of a genetically identified group of cholinergic spinal interneurons that express the Paired-like homeodomain 2 (Pitx2) transcription factor was explored. Stimulation of these interneurons increased motoneuron output through the activation of M2 muscarinic receptors and subsequent modulation of Kv2.1 channels. Inhibition of Pitx2+ interneurons during fictive locomotion decreased the amplitude of locomotor bursting. Genetic ablation of these cells confirmed that Pitx2+ interneurons increase the strength of locomotor output by activating M2 muscarinic receptors. Overall, this work provides new insights into the receptors and mechanisms involved in intraspinal cholinergic modulation. Furthermore, this study provides direct evidence of the mechanism through which Pitx2+ interneurons regulate motor output. This work is not only important for advancing understanding of locomotor networks that control hindlimb locomotion, but also for dysfunction and diseases where the cholinergic system is impaired such as Spinal Cord Injury and Amyotrophic Lateral Sclerosis.
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Duclos, Yann. "Etude des processus spinaux qui préparent à la réalisation d'un mouvement volontaire chez l'homme : implication précoce des motoneurones dans la préparation motrice." Thesis, Aix-Marseille 2, 2011. http://www.theses.fr/2011AIX20683.
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L’objectif de ce travail a été d’analyser les effets d’une préparation motrice sur l’activité des motoneurones (MN). Pour cela, des protocoles expérimentaux combinant l’enregistrement unitaire de l’activité des unités motrices des muscles extenseurs du poignet avec des paradigmes de préparation motrice de nature temporelle ont été utilisés chez l’Homme. L’analyse des caractéristiques de la décharge tonique des MN montre un allongement des intervalles inter-potentiels associé à une diminution de leur variabilité durant la période préparatoire, bien avant que la réponse motrice ne soit déclenchée. Ces changements démontrent clairement l’implication de mécanismes inhibiteurs spinaux au cours de la préparation motrice pouvant s’exercer au travers d’interneurones prémotoneuronaux. Il est montré que les modulations d’activité motoneuronales induites par la préparation motrice ne sont ni spécifiques au muscle effecteur de la réponse motrice ni prédictifs de la performance. Il est proposé que l’inhibition exercée sur les MN pendant la préparation motrice constitue un mécanisme généralisé de frein pour retenir le déclenchement prématuré de la réponse motrice, tandis que la diminution de variabilité dans la décharge serait un phénomène de compensation, permettant de produire des forces stables malgré la désactivation motoneuronale. L’implication du niveau motoneuronal dans la préparation motrice montre qu’une information au préalable influence l’état du système moteur jusqu’à son élément le plus périphérique, supportant ainsi le caractère hautement distribué des processus préparatoires. Ce travail a également conduit à proposer l’utilisation de l’entropie approximative pour l’analyse de l’activité motoneuronale, permettant d’éviter les écueils liés aux méthodes classiques d’analyse tout en respectant l’hypothèse d’un codage neuronal temporelThe aim of this work was to analyze the effects of motor preparation on motoneuron (MN) activity. For this purpose, recordings of wrist extensor muscles motor unit activity were combined with time motor preparation paradigms in Human. Changes in the MN tonic discharge were found to occur during preparatory period, i.e. well before it is time to act. These changes were a lengthening of the mean inter-spike interval associated with a decrease of its variability. These data clearly demonstrate that spinal inhibitory mechanisms are activated during motor preparation and suggest the involvement of premotoneuronal interneurons. The modulations of motoneuronal activity induced by the motor preparation are neither specific to the agonist muscle involved in the motor response nor predictive of the performance. It is assumed that the inhibition acting on the MN during the motor preparation constitutes a general braking mechanism serving to prevent premature motor response, whereas the decrease of discharge variability would be a compensatory phenomenon, allowing to produce an efficient steady force in spite of lower motoneuronal activation. The involvement of the motoneuronal level in motor preparation demonstrates that advance information may influence the state of the motor system, including even the most peripheral motor neurons in the spinal cord, which supports the idea that motor preparation involves highly distributed functional processes. In addition, this work led us to argue in favor of the approximate entropy analysis as a suitable method for analyzing spike trains, allowing to detect changes in the regularity of the time-ordered inter-spikes intervals
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Müller, Katja. "Untersuchung der Erregbarkeit spinaler Motoneurone während Propofolmononarkosen." Doctoral thesis, Humboldt-Universität zu Berlin, Medizinische Fakultät - Universitätsklinikum Charité, 2006. http://dx.doi.org/10.18452/15423.
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Einleitung: Zur Messung der Narkosetiefe standen bisher vor allem aus dem EEG abgeleitete Parameter im Mittelpunkt der Forschung, die sehr gut geeignet sind, die hypnotische Komponente der Anästhesie abzubilden. Eine Vorhersage auf motorische Reaktionen lassen sie jedoch nicht zu. Eine vorausgehende Studie hat gezeigt, dass unter Sevofluran der spinale H-Reflex mit der chirurgischen Immobilität korreliert. Die vorliegende Studie untersucht, ob motorische Reaktionen während Propofolmononarkosen mittels H-Reflex besser vorausgesagt werden können als mit den EEG-Parametern Bispektraler Index (BIS), spektrale Entropie (SE) und response Entropie (RE). Außerdem wurde der Einfluss von Propofol auf die Erholungskurve des H-Reflexes unter Doppelstimulation untersucht. Methodik: Nach Zustimmung der Ethikkommission und schriftlicher Einwilligung wurden 17 Patienten in die Studie eingeschlossen und ausgewertet. Nach der „up-and-down“-Methode von Dixon wurde die Konzentration von Propofol auf einen Wert eingestellt, bei dem die Hälfte der Patienten auf einen am Unterarm ausgelösten elektrischen Tetanus-Reiz (60 mA) mit einer gezielten motorischen Reaktion reagierten. Nach einer Kontrollmessung wurde die Konzentration von Propofol 15 min konstant gehalten. Danach wurde von einem „steady state“ ausgegangen und der Tetanusreiz wurde ausgelöst. Die Vorhersagefähigkeit der möglichen Narkosetiefe-parameter auf eine Bewegung wurde mit der „Prediction Probability“ (PK-Wert) ermittelt. Im zweiten Teil wurde der H-Reflex anhand der Doppelstimulation mit größer werdenden Interstimulusintervallen (50-8000 ms) untersucht. Ergebnisse: Die Wachwerte für die H-Reflexamplitude liegen bei 5,9 (± 3,8 SD) mV. Der von uns berechnete C50-Tetanus-Wert beträgt 4,5 ± 0,45 mg/l. Die PK-Werte 0,47 für den H-Reflex und 0,45 für die Herzfrequenz lassen nur zufällige Aussagen auf motorische Reaktionen zu. Die EEG-Parameter zeigen höhere PK-Werte: BIS (0,74), SE (0,73), RE (0,71). In diesem Bereich liegt auch der PK-Wert der Propofolzielkonzentration (0,76). Der Schmerzreiz beeinflusste weder die H-Reflexamplitude noch die EEG-Parameter. Bei der Doppelstimulation zeigte sich eine verzögerte Erholung des H-Reflexes unter Doppelstimulation, die am stärksten im Bereich der interkurrenten Fazilitation unter den Interstimulusabständen von 150 und 200 ms. Schlussfolgerung: Für die Vorhersage motorischer Reaktionen während Propofolmono-narkosen sind EEG-Parameter wie BIS, SE und RE etwas besser geeignet als der spinale H-Reflex. Dies steht im Gegensatz zu einer Untersuchung mit Sevofluran und wird auf die unterschiedlichen Wirkmechanismen von volatilen und intravenösen Anästhetika zurückgeführt. Die Unterdrückung der Erholungskurve des H-Reflexes unter Doppelstimula-tion, die vor allem im Bereich der interkurrenten Fazilitation stattfindet, ist möglicherweise durch eine Reduktion supraspinaler exzitatorischer Einflüsse zu erklären.Introduction: The measurement of „depth of anaesthesia“ is mostly done by parameters of the electroencephalogram (EEG) which can predict hypnosis whereas the prediction of immobility is not possible with those parameters. A previous study has shown that the H-reflex amplitude can be used for monitoring of immobility during sevoflurane anaesthesia. This study examined whether the prediction of movement to painful stimulation is also possible during propofol anaesthesia on the basis of the H-reflex-amplitude compared with the EEG-parameters bispectral index (BIS), spectral entropy (SE) and response entropy (RE). Furthermore the influence of propofol on the H-reflex-recovery under double pulse stimulation was tested. Methods: After approval of the institutional review board and informed consent were obtained, 17 patients were included into this study. Using the “up-and down”-method the concentration of propofol was adjusted to the level where half of the patients do not move to painful stimulation (C50-tetanus-value). Propofol was administered after a baseline measurement. After at least 15 minutes of constant propofol concentration a "steady-state" was assumed and a painful electrical stimulation (tetanic stimulus of 60mA) was applied. To estimate and compare the predictive value of the parameters, prediction probability Pk was calculated. The H-reflex during double pulse stimulation was examined with interstimulus intervals ranging from 50 to 8000 ms. Results: At awake level, H-reflexes had a mean amplitude of 5.9 (+/- 3.8 SD) mV. The calculated C50-tetanus-value was 4.5 (+/- 0.45 SD) mg/l. With Pk-values of 0.47 for the H-reflex amplitude and 0.45 for the heart rate the prediction of movements is just by chance. The Pk-values of the EEG-parameters were higher: BIS (0.74), SE (0.73), RE (0.71). At this level was also the Pk-value of the propofol concentration (0.76). The painful stimulation influenced neither the H-reflex amplitude nor the EEG-parameters. The double pulse stimulation showed a delay in the H-reflex-recovery at interstimulus intervals of 150 and 200 ms. Conclusion: The prediction of movement during propofol anaesthesia is better using the EEG-parameters BIS, SE and RE compared to the H-reflex-amplitude. These results are in contrast to a previous study with sevoflurane which can be explained by the different molecular mechanisms of action of volatile and intravenous anaesthetics. The depression of the recovery-curve of the H-reflex under double pulse stimulation is possibly due to the reduction of supraspinal excitatory influences.
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Flaith, Leonie. "Klinik, elektrophysiologische und kernspintomographische Untersuchungen bei adulten Vorderhornerkrankungen." [S.l. : s.n.], 2007. http://nbn-resolving.de/urn:nbn:de:bsz:289-vts-60073.
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Lenz, Kathryn M. "Mechanisms mediating the effects of maternal care on the masculinization of spinal motoneurons." [Bloomington, Ind.] : Indiana University, 2009. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3380150.
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Thesis (Ph.D.)--Indiana University, Dept. of Psychological and Brain Sciences and the Program in Neuroscience, 2009.Title from PDF t.p. (viewed on Jul 20, 2010). Source: Dissertation Abstracts International, Volume: 70-12, Section: B, page: 7839. Advisers: Dale R. Sengelaub; Gregory E. Demas.
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Gibbons, Andrew Stuart. "The effects of supplying spinal motoneurons with a constant source of exogenous neurotrophins." Monash University, School of Biological Sciences, 2004. http://arrow.monash.edu.au/hdl/1959.1/9621.
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Johnson, Hans. "Spinal motoneurons and the bulbospinal serotoninergic system in aged rats with behavioral deficits /." Stockholm, 1998. http://diss.kib.ki.se/1998/91-628-3277-8/.
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Chan, Yuen-man, and 陳婉文. "Effect of caspase inhibitors on the survival and regeneration of injured spinal motoneurons." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2001. http://hub.hku.hk/bib/B31242893.
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Widmann, Alexandra. "Quantitative Auswertung spinaler Motoneurone nach intracisternaler Transplantation von Stammzellen in ein Mausmodell der amyotrophen Lateralsklerose." [S.l. : s.n.], 2008. http://nbn-resolving.de/urn:nbn:de:bsz:289-vts-63892.
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MacDonald, Stephen Christopher. "Oligodendrocytes and motoneurons, two cholinergic cell types derived from multipotent spinal neuroepithelial precursor cells." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape2/PQDD_0016/NQ53066.pdf.
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