Regional characterization of astrocytes in the human brain

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Introduction: Until the 1990s, astrocytes were largely considered to be passive components of the central nervous system, providing mainly structural support for neurons. It is now clear that astrocytes are highly dynamic cells that play a variety of roles that are essential for the proper function of cerebral networks. However, our current knowledge on the morpho-functional properties of these cells comes essentially from studies conducted with animal models, rodents in particular. Despite the many similarities in the basic organization of rodent and human brains, significant differences can exist at the cellular level. Our work as well as that of other groups has recently shown that human cortical astrocytes are much more complex and diverse than their rodent counterparts. Despite these recent findings, much remains to be discovered regarding the cellular and subcellular organization and molecular properties of astrocytes in the human brain. In particular, virtually nothing is known about the morphometric and molecular features of astrocytes in other, non-cortical, brain regions.Main and specific objectives: The main objective of this research program is to characterize the distributional, morphometric and transcriptomic profiles of astrocytic subtypes found in different regions of the human brain. More specifically, we will use fine neuroanatomical and molecular approaches to describe, qualitatively and quantitatively, the distribution and cellular/subcellular properties of astrocytes in various cortical and subcortical brain regions, and characterize in a cell population-specific manner the regional astrocytic gene expression profiles.Methods: Well-characterized fixed and frozen postmortem brain samples will be obtained from the Douglas-Bell Canada Brain Bank. These samples will come from healthy 35-40 year-old male and female donors with no history of psychiatric, neurological, or chronic inflammatory conditions. State-of-the-art approaches routinely used in my laboratory will be employed to quantify regional astrocytic densities and morphological features. These include stereological quantifications of immunostained cells and 3D cell reconstructions. In each region, astrocytes will be extracted by laser-capture microdissection, and their transcriptomic profiles determined following ultra-low input RNA sequencing.Significance: It is expected that this research will lead to the identification of new astrocytic subtypes, and that distinct regional properties of astrocytic networks will emerge. This will allow us to better understand the fine structural and functional organization of the human brain.