Periodic Reporting for period 4 - MITOPLASTICITY (Mitochondrial regulation of structural and functional plasticity within adult neurogenic circuits)
Reporting period: 2021-02-01 to 2021-11-30
The adult hippocampus is a brain region fundamental in regulating key aspects of cognition and emotional behavior. It is also a region endowed with prominent forms of plasticity throughout life. One such example involves the hosting of stem cells which are capable to generate life-long new neurons that incorporate into and modify the pre-existing circuitry. However, the mechanisms underlying this extended form of plasticity, in particular in response to injury or to individuals experiences, remain unclear. This project aimed at developing innovative approaches to investigate the energy constrains that regulate the plasticity of adult neurogenic circuits. For this purpose, we focused on how certain structural and functional aspects of mitochondria – key organelles controlling cellular energy metabolism – may regulate the process of adult neurogenesis and the plasticity of associated circuits. For this, we investigated the role played by the mitochondrial network in driving significant changes along the lineage that bring a neural stem cell to become a fully-functional new neuron, that is, in modulating the extent of neurogenesis in relation to certain experiences. As neurogenesis is an exceptionally rare event in the adult mammalian brain, addressing this main objective may pave the way to regenerative approaches following brain injury or disease. During our investigations we revealed that mitochondria execute important forms of plasticity underling the activity of neural stem cells and their neuronal progeny, with key implications for approaches meant to ameliorate brain repair following brain damage.
A major finding linked to this project has been the identification of a novel layer of regulation of neural stem cell activity, namely an acute rewiring of their mitochondrial proteome which underlies the acquisition of specific metabolic states. By introducing genetic manipulations meant to alter this rewiring process, we showed direct consequences for the proliferative and neurogenic potential of neural stem cells, demonstrating that compartmentalized changes in protein networks can have an instructive role in driving neural stem cell fate. Importantly, by applying this knowledge to mature glial cells in non-neurogenic brain areas exposed to injury settings, we revealed that a dynamic remodelling of the mitochondrial network is essential in promoting brain tissue repair. Lastly, by extending our investigations to neurons newly-generated from adult neural stem cells, we were able to reveal that mitochondrial dynamics and positioning contribute to important aspects during the incorporation of these neurons into the pre-existing network. These findings disclose an important role played by mitochondria in regulating the plasticity of adult brain cells and therefore have key implications for understanding how to improve tissue repair during injury and disease.
The work performed in this project revealed several novel aspects concerning the biology of neural stem cells, glial cells and new neurons that are controlled by mitochondria. Specifically, our work reveals that the regulated activity of these organelles critically contributes to complex processes (adult neurogenesis and hippocampal circuit function) that are central for cognition. This also creates the basis for devising approaches to manipulate mitochondrial function within adult brain circuits, in an effort to enhance cellular resilience and improve tissue plasticity in disease settings.