Decoding the complexity of astrocyte reactivity in neurodegenerative diseases – DecodAstro

Astrocytes have long been neglected in the field of Neuroscience. Now that their multiple roles in brain physiology are recognized, the next challenge is to understand their implication in disease. Astrocytes become reactive in virtually all pathological situations affecting the brain. This response is defined by conserved morphological changes but its functional impact on brain homeostasis and neuronal survival remains debated, especially in the context of neurodegenerative diseases. Such conflicting results are classically justified by differences in molecular triggers or experimental conditions, but instead, they reveal that astrocyte reactivity is a much complex response than initially thought.
It is now time to address this complexity and to decipher the molecular mechanisms governing the different states of astrocyte reactivity. If we are able to identify these mechanisms then, we will be able to target them for therapeutic purposes. The DecodAstro project aims at breaking the code of reactivity, thanks to cell-specific, sensitive and novel techniques applied to relevant in vivo models of neurodegenerative diseases.
We recently established the importance of the JAK2/STAT3 pathway for reactivity in neurodegenerative diseases. Here, we will identify additional master regulators of astrocyte reactivity in an unbiased manner, through genome-wide screening in vivo. In addition, we will monitor the heterogeneity of astrocyte reactivity with time-lapse two-photon microscopy in situ and determine how specific signaling networks translate into unique transcriptional programs and functional outcomes.
The paradigm shift is to no longer consider averaged populations of reactive astrocytes with inevitable discrepancy between experimental conditions, but instead reveal and study cellular heterogeneity of reactive astrocytes in situ. DecodAstro will significantly improve our understanding of brain response to disease. By addressing the emerging theme of cell-to-cell variability in biological responses, this project will open new conceptual and technical avenues in Neuroscience and adjacent fields.