Introducing the brain: astrocyte diversity (Introduction)

by David Turell , Friday, November 04, 2022, 20:44 (533 days ago) @ David Turell

Review article:

https://www.sciencemagazinedigital.org/sciencemagazine/library/item/04_november_2022/40...

"Astrocytes are morphologically complex glial cells that regulate essential aspects of central nervous system (CNS) function, including synapse formation, ion homeostasis, and neurovascular coupling. Once viewed as a homogeneous population of cells, astrocytes are now known to exhibit molecular and functional heterogeneity at the regional and cellular level. How this diversity arises is unclear. On page 514 of this issue, Endo et al. investigate the molecular basis of astrocyte heterogeneity in mice, uncovering shared core features and identifying key differences that are specific to CNS regions. Their findings suggest that astrocyte diversity arises primarily from differences in the tissue microenvironment and highlight a key role for astrocyte morphological complexity in brain health and disease.

"Astrocytes are ubiquitous throughout the CNS. During development, astrocytes arise from neural progenitors in the ventricular zone (VZ) and migrate to different CNS regions, where they undergo local clonal expansion and morphogenesis (5). Morphological complexity is a hallmark feature of astrocytes. All astrocytes possess densely branched arbors that directly contact neighboring cells and structures to actively control the formation and function of neuronal circuits and execute a diverse array of homeostatic functions. Overall, the morphological complexity of astrocytes is a prerequisite for their functional complexity.

"Astrocytes in different regions of the mouse CNS show variations in gene expression, morphology, and function. Heterogeneity is also observed among astrocytes within the same CNS region. What is the source of astrocyte diversity? Some aspects of heterogeneity are developmentally encoded. In the spinal cord, for example, astrocyte location and gene expression are determined by the site of origin of progenitor cells in the VZ. Heterogeneity may also arise locally, although the extent to which differences in the tissue microenvironment influence regional astrocyte diversity is largely unexplored. Questions also remain regarding the relationship between molecular diversity and morphological and functional complexity, as well as the relevance of these features to disease.

"To address these knowledge gaps, Endo et al. analyzed anatomical, molecular, and morphological features of astrocytes across 13 different CNS regions from mice. Although neuronal density differed substantially between regions, astrocyte density was relatively constant, underscoring their importance for brain homeostasis. Accordingly, astrocytes from all brain regions shared expression of genes related to core astrocyte functions, including neurotransmitter homeostasis, cholesterol biosynthesis, and glucose metabolism. The expression of many transcriptional regulators and ligand-dependent nuclear receptors was also shared among astrocytes across regions, suggesting that common mechanisms of upstream regulation may control core functional properties.

"To investigate the extent of astrocyte diversity across CNS regions, Endo et al. focused on astrocyte-enriched differentially expressed genes (DEGs) that were distinct to a particular region or shared by a subset of regions. DEGs from the 13 CNS regions clustered into three broad regions based on anatomical proximity: cerebrum, brain stem–spinal cord, and cerebellum. Furthermore, astrocyte region-enriched DEGs correlated with region-enriched DEGs from bulk tissue, indicating that the identity of astrocytes reflects the tissue microenvironment. Singlecell sequencing analysis of a subset of brain regions identified seven astrocyte subclusters that were present at different proportions in each brain region. Several extracellular signaling molecules were identified as upstream regulators of each cluster, suggesting that local cues may shape the identify of these subclusters. Collectively, these findings provide strong evidence that astrocyte regional heterogeneity is shaped by the tissue microenvironment.

"In addition to molecular heterogeneity, Endo et al. characterized the morphological features of astrocytes from the same 13 CNS regions and found considerable regional differences in territory size, sphericity, and branching complexity. For example, astrocytes in the motor cortex displayed the largest territory size of all CNS regions, whereas striatal astrocytes were among the smallest. Both motor cortex and striatal astrocytes had a relatively round shape, whereas astrocytes in the cerebellum had the lowest degree of circularity and the longest length (see the figure). Intriguingly, astrocyte morphological diversity correlated strongly with two gene modules from the region-specific DEGs. The authors selected top morphologylinked genes from these modules for further investigation. Deletion of morphology-linked genes from astrocytes in mice resulted in morphological and synaptic deficits and impaired spatial memory. Together, these findings establish a functional link between gene expression, astrocyte morphology, and functional output."

Comment: astrocytes add an additional complexity to the functionality of the brain. It is not just the neuron contingent doing all the work. This degree of complexity cannot appear by chance, and strongly implies a designer at work.