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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - MITOPLASTICITY (Mitochondrial regulation of structural and functional plasticity within adult neurogenic circuits)

Teaser

Summary

The project mainly aims to investigate the energy constrains that regulate the plasticity of hippocampal circuits, with a particular focus on adult neurogenesis. As mitochondria are the key organelles regulating cellular energy metabolism in neurons, we focus on aspects of mitochondrial positioning and function in order to address this main question in the adult mouse brain. Adult neurogenesis - i.e. the process through which new neurons are produced from resident neural stem cells â€“ is used here as a role model to understand how mitochondrial function may regulate the behaviour of neural stem cells, the genesis of new neurons and their ultimate integration process within the pre-existing hippocampal circuit. The questions addressed in this project are important for several reasons. Firstly, this neurogenesis process is exceptionally rare in the adult mammalian brain, given that virtually no brain region other than the hippocampus and the lateral ventricles experience any substantial degree of postnatal generation of new neurons. Therefore, understanding the principles governing this mechanism may pave the way to regenerative approaches aiming to re-instate neurogenesis in other adult brain areas (like the cerebral cortex), for examples in settings of brain injury or disease. Secondly, by investigating the roles of mitochondria during the lineage progression that brings a neural stem cell to give rise to a fully functional new neuron, we expect to identify new cellular mechanisms of relevance not only for stem cell biology but also for synaptic plasticity. In particular, a main hypothesis is brought forward that the transduction of new individual experiences into changes in synaptic strength and connectivity (experience-dependent plasticity) may necessarily require an adjustment of the mitochondrial network to fuel and stabilize these connectivity changes. Following this hypothesis, I proposed three main objectives: investigating the role of specific mitochondrial-dependent processes in regulating neural stem cell behaviour (i), new neuron development (ii) and plasticity of the newly generated neurons (iii).

Work performed

For this project we have been generating a number of new transgenic mouse lines to allow the investigation of cellular/subcellular compartments and the concurrent manipulation of regulatory genes in specific subsets of brain cells. The same holds true for a number of viral vectors permitting the controlled co-expression of genetically encoded indicators and genes of relevance for this project. Finally, we are optimizing existing imaging approaches to visualize with subcellular resolution mitochondrial structures in brain tissue. Once published, these tools and approaches will be made available to the scientific community.

Besides collecting, generating and optimizing the tools and approaches required for the successful realization of this project, we have intensively worked to first validate our initial hypotheses in each aim. For at least the first two aims, this led to a significant amount of new data which we are currently analysing. The results obtained so far were disseminated via participation to several international scientific meetings, and led to the initial publication of 2 reviews and 2 co-authored articles.

Final results

This is a project that focuses on brain plasticity mechanisms taking place in vivo. The work done so far already allows us to reach a certain number of conclusions on several aspects of the biology of neural stem cells and new neurons which appear to be regulated by mitochondria. On the one side this nicely complement with existing recent literature on the two main topics touched by this project (brain plasticity and mitochondrial biology), while on the other it reveals new layers of control over complex processes (adult neurogenesis and hippocampal circuit function) that are central in neuroscience. For example, in Aim I we have identified a key regulator of neural stem cell proliferation which resides in mitochondria, and that modulates mitochondrial metabolism thereby affecting the behaviour of these unique stem/progenitor cells in vivo. Likewise, in Aim II we are revealing how quality control mechanisms in mitochondria contribute to the connectivity establishment of new neurons. I am convinced that this is a clear step beyond the current state of the art in understanding the mechanisms at the core of stem cell renewal, proliferation and differentiation into functional new neurons.

We expect several publications of relevance in the coming 1-2 years. For Aim I, we are currently finalizing two studies (the first focused on the role of mitochondrial in neural stem cell function and neurogenic potential, and the second study essentially arising from milestone 4, which is focused on a directed differentiation approach of neural stem cells towards fates distinct from granule cells). For Aim II, we are well advanced in revealing one important aspect of mitochondrial function in determining the structural development of newborn neurons and their synaptic plasticity. We expect these data to be ready for publication next year. For the last Aim (III), we expect a final manuscript towards the end of the project, given the technological challenges of the proposed approaches.