Molecular and cellular mechanisms of cortical functional regeneration through diterpenoid-induced neurogenesis

The discovery of adult neural stem cells (NSCs) has revealed the potential of endogenous neurogenesis as a therapeutic mechanism for brain repair. Among the neurogenic niches of the adult brain, the subventricular zone (SVZ) responds to cortical injury by generating neuroblasts that attempt to migrate toward the damaged area. However, most fail to reach or integrate into the lesion unless stimulated by signals or chemical compounds like diterpene EOF2. This thesis investigates the cellular and molecular mechanisms regulating the migration, differentiation and functional maturation of SVZ derived progenitors in models of cortical injury. We first characterized the temporal dynamics of electrophysiological maturation of layer V pyramidal neurons during postnatal development, establishing a baseline to interpret neuronal differentiation after injury. We then analysed the long term effect of the diterpenoid compound EOF2, a PKC activator known to promote cell migration and differentiation. EOF2 treatment enhanced the recruitment of SVZ derived neuroblasts toward the lesion. Newly generated neurons exhibited progressive electrophysiological maturation, and by four weeks after injury about half displayed spontaneous synaptic activity, compatible with their incorporation into existing circuits. EOF2 also elevated NRG1 expression in the cortex and SVZ in vivo and stimulated its release from neural precursors in vitro, supporting a model in which EOF2 modulates NRG1 availability to favour SVZdriven neurogenesis and neuronal maturation in the injured brain. We next examined the role of NRG1 in cortical repair. Cortical injury increased NRG1 immunoreactivity in activated microglia and reduced homeostatic markers, indicating a transition toward reactive states. Local delivery of recombinant NRG1 promoted the recruitment of lineage traced SVZ derived cells and increased both immature and mature neuronal phenotypes in the ipsilateral cortex, indicating neuronal differentiation and incorporation within the lesion. These findings identify NRG1 as a mediator linking microglial activation with neuroblast migration and cortical neurogenesis. Additionally, a comprehensive review of the role of ErbB receptors in neurogenesis and cortical repair was conducted, integrating the experimental results of this thesis within the current framework of NRG1 dependent regenerative signalling. Finally, our data identify EOF2 as a pharmacological modulator of NRG1 mediated signalling that enhances endogenous neurogenesis, neuronal differentiation and integration within the damaged cortex, offering new insights for regenerative strategies in the adult brain. Overall, this thesis highlights the capacity of EOF2 and NRG1 to modulate endogenous neurogenesis and identifies diterpenes as promising candidates for therapeutic strategies aimed at promoting neuronal regeneration and functional recovery after cortical injury.

Author dc:creator

• Pérez García, Patricia

Advisors dc:contributor.advisor

• Castro González, Carmen
• Pardillo Díaz, Ricardo

Statement dc:rights

• Attribution-NonCommercial-NoDerivatives 4.0 Internacional

Licence dc:rights.uri

• http://creativecommons.org/licenses/by-nc-nd/4.0/

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/10498/39518

OAI identifier oai:identifier

oai:rodin.uca.es:10498/39518