Activity-dependent mechanisms of axonal growth

dc.contributor
Universitat de Barcelona. Departament de Biologia Cel·lular, Fisiologia i Immunologia
dc.contributor.author
Mesquida Veny, Francina
dc.date.accessioned
2022-06-09T05:44:23Z
dc.date.available
2022-09-28T02:00:16Z
dc.date.issued
2022-04-01
dc.identifier.uri
http://hdl.handle.net/10803/674471
dc.description
Programa de Doctorat en Biomedicina / Tesi realitzada a l'Institut de Bioenginyeria de Catalunya (IBEC)
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dc.description.abstract
Spinal cord injuries (SCI) are a major cause of paralysis in young adults. In this type of injuries recovery is impaired as adult central nervous system (CNS) axons fail to regenerate. This results from both a loss of intrinsic growing capacities in developmental axons when they mature, together with the presence of extrinsic factors hampering this regeneration, including a glial scar together with the production of growth-inhibitory molecules, as well as a lack of injury resolution leading to a chronic inflammation. Unfortunately, despite research efforts, current therapies for this type of injuries only lead to mild improvements and among them, activity-based therapies seem to raise above the others. Activity- based therapies try to induce recovery by increasing neuronal activity, however, a proper physiological and molecular characterization of the rationale behind their success is still missing. Neuronal activity has been described to regulate transcriptional and epigenetic mechanisms; moreover, it also alters neuronal secretion with an impact on cellular dialogues. These characteristics indicate neuronal activity may be modulating both of the CNS barriers for regeneration. During this doctoral thesis we aimed to explore the influence of neuronal activity on SCIs, hypothesizing specific neuronal activations were the principal responsible for success in activity-based therapies. Particularly, we studied the role of precise manipulations of neuronal activity, using optogenetic and chemogenetic tools, in axonal growth of stimulated neurons as well as the impact these activations could have on neuronal extrinsic signalling. Our results show that optogenetic and chemogenetic stimulations of neuronal activity enhanced growth in both regenerating and refractory to regenerate neurons. However, this growth was hampered by the inhibitory molecules present in the injured CNS and did not result in functional recovery in rodent models of SCI. Our data indicated that the growth induction in specifically stimulated neurons resulted from local adjustments rather than inducing a pro-regenerative transcriptional state, as seen by our gene expression analysis of regeneration-associated genes (RAGs). Altogether, our results suggest recovery in activity-based therapies derives from the summation of various forms of plasticity, induced by their simultaneous recruitment of several circuits. In parallel, we observed that these precise modulations of neuronal activity, while unable to alter the predominant environment after SCI, could initiate previously undescribed intricate cellular dialogues. Specifically, we found an increase in the chemokine CCL21 upon nociceptor activation which triggered the response of several cell types in the injury. In proprioceptors, this CCL21 was responsible for a growth induction after CCR7 activation, which required the MEK-ERK pathway as well as the modulation of the actin cytoskeleton. Meanwhile, the CCL21 interaction with CXCR3 in other cells effectively aborted this regeneration. All in all, our work reveals the existence of a complex plethora of synergic mechanisms, far from understood, contributing to the outcome of activity-based therapies and reinforces the need for further mechanistic studies which would allow the optimization of their success.
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dc.format.extent
181 p.
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application/pdf
dc.language.iso
eng
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dc.publisher
Universitat de Barcelona
dc.rights.license
L'accés als continguts d'aquesta tesi queda condicionat a l'acceptació de les condicions d'ús establertes per la següent llicència Creative Commons: http://creativecommons.org/licenses/by-nc-sa/4.0/
dc.rights.uri
http://creativecommons.org/licenses/by-nc-sa/4.0/
*
dc.source
TDX (Tesis Doctorals en Xarxa)
dc.subject
Neurones
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dc.subject
Neuronas
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Neurons
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dc.subject
Regeneració del sistema nerviós
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dc.subject
Regeneración del sistema nervioso
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dc.subject
Nervous system regeneration
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dc.subject
Axons
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dc.subject
Axones
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Interacció cel·lular
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Interacción celular
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dc.subject
Cell interaction
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Lesions medul·lars
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Lesiones medulares
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dc.subject
Spinal cord injuries
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dc.subject.other
Ciències Experimentals i Matemàtiques
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dc.title
Activity-dependent mechanisms of axonal growth
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dc.type
info:eu-repo/semantics/doctoralThesis
dc.type
info:eu-repo/semantics/publishedVersion
dc.subject.udc
616.8
en_US
dc.contributor.director
Hervera Abad, Arnau
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Río Fernández, José Antonio del
dc.contributor.tutor
Río Fernández, José Antonio del
dc.embargo.terms
6 mesos
en_US
dc.rights.accessLevel
info:eu-repo/semantics/openAccess


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