No description available.

No description available.

No description available.

Although the management of Motor Neuron Disease (MND) remains devoid of a cure, persons affected by this devastating condition are nonetheless entitled to the best quality care that is available. A paucity of information exists documenting the perceptions of healthcare consumers regarding the management that is provided. In addition optimal healthcare comprises an intricate interaction of patient-centred care, patient-centred communication, and bioethical practice, and when these three dimensions are implemented according to acceptable standards, high-quality healthcare is perceived by the healthcare consumer. Given however the socio-political challenges that face healthcare systems, the management of MND needs to be considered against current trends in service delivery and the need for evidence-based medicine. An exploratory study was therefore conducted to investigate the perceptions of persons with MND and their family members regarding current medical and rehabilitative management. The sample comprised six persons with MND who presented with a communication impairment, as well as six family members. Participants’ perceptions were elicited through the use of a semi-structured interview schedule, and questions focused on healthcare professionals’ behaviours during healthcare encounters. In addition emphasis was placed on the potential of the communication impairment to influence management. A standardised dysarthria assessment was conducted to characterise the nature of the speech impairment in each person with MND. Qualitative responses obtained from the interviews were analysed in accordance with a matrix-based approach, while quantitative data from the dysarthria assessment were analysed using descriptive statistics. Despite individual variability, perceptions of both persons with MND and their family members revealed general dissatisfaction with regard to medical and rehabilitative management. The majority of persons with MND were not referred for intervention following diagnosis, and the recommended team approach for the management of MND was absent. In addition the bioethical practice of many healthcare professionals was deemed questionable, and the communication impairment was perceived to impose a significant burden on the healthcare encounter. Furthermore all participants perceived a lack of available support systems for persons with MND, and it was thus not uncommon for individuals to pursue complementary and alternative medicine. South Africa’s current healthcare climate also appeared to further limit healthcare for this clinical population. In an attempt to improve the management of MND, implications are provided in terms of health communication, intervention, bioethical practice, and support systems. A proposed new framework of ideal service delivery for healthcare consumers of MND management is also presented. Further implications are outlined with regard to the need for innovative models of service delivery in South Africa’s healthcare context, as well as the role of speech-language pathologists, other healthcare professionals, policy makers, and educators in the improvement of the medical and rehabilitative management of MND. Finally theoretical implications and implications for future research are also documented.

Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 5 uppsatser.

Locomotion is controlled in large part by neural circuits (CPGs) that generate rhythmic stereotyped outputs in the absence of descending or sensory inputs. The output of a neural circuit is determined by the configuration of the circuit, synapse properties, and the intrinsic properties of component neurons. In order to understand how a neural circuit functions component neurons, their connections, and their intrinsic properties must be characterized. Motoneurons are a useful cell in which to begin investigation of CPG function because they are accessible and provide a measure of the cumulative activity of the circuit. Drosophila is a potentially useful model system for the study of motoneuron intrinsic properties, their contribution to locomotion, and of locomotor CPGs because the genetic and molecular techniques available in Drosophila are surpassed in no other organism and because the Drosophila nervous system is small in comparison to vertebrate nervous systems. Further, whole-cell in situ patch clamp recordings from adult and larval motoneurons in relatively intact preparations are possible. Therefore, the first goal of this work was to investigate whether the firing behavior and recruitment of identified Drosophila 1b and 1s motoneurons is analogous to the recruitment of high-threshold, phasic and low-threshold, tonic motoneurons in other organisms. The second goal was to determine whether active conductances influence motoneuron recruitment in response to synaptic input. The final aim was to investigate how these factors influence CPG output to muscles. Findings from current clamp studies indicate that1b motoneurons are more easily recruited than 1s motoneurons, in agreement with the hypothesis that 1b motoneurons are analogous to low-threshold motoneurons described in other organisms. Further, orderly recruitment of Drosophila 1b motoneurons before 1s motoneurons is not a result of passive properties. Instead, the Shal channel that encodes a large portion of IA in motoneuron somatodendritic regions is a critical determinant of delay-to-spike in larval Drosophila motoneurons. These findings are behaviorally-relevant because the same recruitment order is seen in simultaneous recordings from motoneuron pairs recruited by synaptic input.

No description available.

No description available.

Injury and degenerative disease of the central nervous system (CNS) are among the major causes for disabilities in humans. They result in permanent damage that is not repaired by regenerative processes. In contrast, anamniotes like fish and amphibia display a striking potential for successful regeneration in the CNS. The zebrafish (Danio rerio) has been established as a model for successful regeneration after spinal cord injury. However, it is yet unknown which factors are involved in regeneration after spinal lesions and other insults to the CNS. Focusing on motor neurons, I asked whether regeneration can also be observed in larval zebrafish. This would allow to take advantage of their accessibility to live imaging, pharmacological and genetic manipulation. It is unknown, whether the loss of a specific cell type in the absence of injury, which is reminiscent of the pathological change observed in neurodegenerative diseases, would be sufficient to induce regeneration. Comparing the regenerative response after spinal lesion to that after selective neuronal cell loss would allow to identify factors that act as a trigger for regeneration, e.g. mechanical injury signals, the extent of cell death or microglia activation. To address these questions, an experimental paradigm in which motor neurons can be selectively ablated without the need to inflict tissue damage would prove useful. Key findings of this work are: · Motor neuron generation ceases during early larval developmental stages. · The Nitroreductase system can be used for successful ablation of motor neurons in the larval spinal cord. · New motor neurons are generated in a regenerative response to both targeted ablation of motor neurons and spinal lesion in larval zebrafish after cessation of developmental generation of MNs. To test whether larval zebrafish can be used to analyse motor neuron regeneration, I carried out a birthdating study to establish a developmental time line for motor neuron generation in the spinal cord. The end of developmental motor neuron generation at an early time point, at around 54 hours post fertilisation, allows for the use of larval zebrafish to assess the regenerative response after insults to the spinal cord. In addition, I could show a time dependent role for Hedgehog signalling during the generation of a motor neuron subpopulation. The influence of Hedgehog is diminished before the end of motor neurogenesis. Utilizing the Gal4/UAS system to combine the Nitroreductase‐mCherry fusion protein expressing Tg(UAS:nfsB‐mCherry) with the motor neuron specific driver Tg(hb9:Gal4), I generated a new transgenic zebrafish line for the genetically targeted ablation of motor neurons. In the resulting transgenic fish, the administration of the prodrug Metronidazole induces apoptotic cell death in ~25% of spinal motor neurons leading to impaired motor performance and increased numbers of microglia in the spinal cord. My work shows that larval animals subjected to motor neuron ablation or spinal lesion display a regenerative response detected by increased numbers of newborn motor neurons. Importantly, this happens after developmental production of motor neurons has ceased, suggesting that progenitor cells are reverting to the generation of motor neurons. The data presented shows that in larval zebrafish, the selective loss of motor neurons is sufficient to induce a regenerative response in the spinal cord. The increased numbers of microglial profiles in the spinal cord after both spinal lesion and targeted cell ablation indicates a role for the immune system in mediating a regenerative response. This new targeted cell ablation paradigm in larval zebrafish will allow to identify and characterize the progenitor cell population forming new motor neurons. One can then further investigate how specific loss of motor neurons is sensed and which factors contribute to the activation of the endogenous stem cell populations. Using larval zebrafish has many benefits, as they are accessible to pharmacological testing with small molecules and live imaging. Moreover, the combination of additional transgenic reporter lines will allow for the investigation of single cell behaviour during regeneration.

The hallmark of an adult mammalian central nervous system is the inability to regenerate after an injury. Zebrafish, on the other hand, have an astounding regenerative capacity. After a spinal cord lesion, zebrafish can re-establish the damaged neuronal network and regain their swimming ability within weeks. This is partly due to the presence of the ependymal radial glia (ERGs), which line the wall of the central canal and act as the stem/progenitor cells of the spinal cord. Under homeostatic conditions the ERGs are largely quiescent, however, the lesion triggers them to proliferate and replace cells that have been lost due to the damage. Previous studies have shown that the regeneration of the motor neurons is affected by the signalling pathways similar to those governing the first development of these cells during embryogenesis, such as Sonic hedgehog, Notch and dopamine signalling. Serotonin (5-HT), similar to dopamine, is a monoaminergic neurotransmitter with a wide range of physiological and behavioural functions. It has also been shown to play a role during development of the nervous system. In this doctoral thesis I address the hypothesis that 5-HT has a positive effect on the development and adult regeneration of motor neurons. In addition, I expand on the previously discovered augmenting effect of dopamine on motor neuron development, by analysing the downstream pathways of its action. I show that during the development, incubating embryos in 5-HT increases the proliferation of the motor neuron progenitor (pMN) cells, which leads to augmented motor neuron production. RT-PCR on FAC sorted pMN cells highlights a number of serotonergic receptors that might be responsible for this effect. Although the downstream pathways are still unknown, 5-HT appears not to act on the sonic hedgehog canonical pathway, as shown by the unchanged expression of the hedgehog effector gene, patched2 after 5-HT treatment. I show that 5-HT does not affect the generation of vsx1+ or pax2a+ interneurons, suggesting that it has a predominant effect on motor neuron production. In the intact spinal cord of an adult zebrafish, the pMN-like ERGs express serotonergic receptors, indicating they are responsive to 5-HT stimulation. After a lesion, 5-HT administration enhances the proliferation of the pMN-like ERGs caudal to the lesion site resulting in an increase in the number of newborn motor neurons. Rostral to the lesion site, administration of exogenous 5-HT does not have an effect on the ERG proliferation, possibly due to the fact that the endogenous source of 5-HT, in the form of the descending axons, is still present and might already elicit a maximal response of the progenitor cells. 5-HT does not have an effect on the proliferation of the progenitor cells dorsal or ventral to the pMNlike domain, nor does it affect the regeneration of the serotonergic interneurons. These results suggest that 5-HT from the brain preferentially contributes to the regeneration of the motor neurons. Dopamine is another monoamine shown to enhance motor neuron production during the development and regeneration. To investigate the downstream pathways of dopamine signalling on motor neuron production during embryogenesis, RNA-sequencing was performed on FAC sorted pMN cells after a treatment with a dopamine agonist, pergolide. The results yielded 14 differentially expressed genes (FDR < 0.05) with diverse functions in the cell, indicating that dopamine might act on multiple targets to promote motor neuron production. Taken together, these results demonstrate the positive effect of monoaminergic stimulation on motor neuron development and regeneration. They provide an insight into the pathways that govern the proliferation of stem/progenitor cells in the embryonic and adult spinal cord, which might contribute to the research working on enhancing adult neurogenesis in mammals.