Quantitative approaches to decipher neuronal network function in situ

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For a long time, the extracellular matrix (ECM) was considered a supportive structure solely dedicated to maintaining neuronal tissue architecture. Yet, it is now clear that the ECM regulates many cellular processes in partnership with several actors. Among those, glia cells can modulate tissue organization and membrane receptors can regulate ions and water movements between the intracellular and extracellular spaces thus modifying cell volume, the ECM dimensions and ultimately their respective functioning. Still, little is known about the interplay between function and organization of the extracellular matrix at the nanoscale level in living tissue. ******The lack of understanding of this discipline has been due to the absence of tools allowing precise examination in intact samples. However, we recently developed an approach using near-infrared microscopy based on nanoprobes tracking. We highlighted that the extracellular space (ECS) viscoelastic properties vary in space and that these changes are dependent on the ECM composition. In turn, the ECM organization and function rely on the ion homeostasis and neuronal activity. To understand these interplays, it is imperative to monitor the ECS concurrently (composition of the ECM, ion concentrations and receptors distributions). For this, we established an approach to monitor activity and receptor distribution in intact tissue. Together these approaches allow the monitoring of the structural evolution of the network. My research program will investigate the role of the brain structure and the ECM on the extracellular fluidity. I divided it into 3 aims: ******1: Study the interrelated roles of the extracellular space organization and neuronal activity***2: Investigate the role of the extracellular matrix on extracellular dimensions, free-ion concentrations and ion homeostasis***3: Investigate the role of the extracellular matrix in neurotransmitter/ion clearance capacity of tissue. ******This program will address important inquiries associated with acute or chronic alterations of the ECM organization. This reinforces the notion that the ECS organization is associated with changes in the ion homeostasis. The study of the biophysical properties of the ECS paves a new way of probing intact nervous system. Monitoring changes in the ECM organization and how it influences cellular homeostasis will offer new investigations of intact tissue and my research program will contribute to study important but still neglected mechanisms due to lack of tools. The long-term plan will link the extracellular organization to cellular homeostasis while mapping alterations to the ECM and intracellular mechanisms (e.g., receptor distribution, activity and trafficking). By studying water movements in the intact live brain, I predict that a better understanding of the diffusive properties of the extracellular matrix at the nanoscale level will open the door to the elaboration of new models of water transport in tissue.