Astroglial heterogeneity closely reflects the neuronal-defined anatomy of the adult murine CNS

Abstract

Astroglia comprise an extremely morphologically diverse cell type that have crucial roles in neural development and function. Nonetheless, distinct regions of the CNS have traditionally been defined by the phenotypic characteristics and connectivity of neuros. In a complementary fashion, we present evidence that discrete regions of the adult CNS can be delineated based solely on the morphology, density and proliferation rates of astroglia. We used transgenic hGFAP-GFP mice in which robust expression of GFP in adult astroglia enables detailed morphological characterization of this diversely heterogeneous cell population with 3D confocal microscopy. By using three complementary methods for labeling adult astroglia (hGFAP-GFP expression, and GFAP and S100beta immunostaining), we find that there is a remarkably diverse, regionally stereotypical array of astroglial morphology throughout the CNS, and that discrete anatomical regions can be defined solely on the morphology of astroglia within that region. Second, we find that the density of astroglia varies dramatically across the CNS, and that astroglial density effectively delineates even the sub-regions of complex structures, such as the thalamus. We also find that regional astroglial density varies depending on how astroglia are labeled. To quantify and illustrate these broad differences in astroglial density, we generated an anatomical density atlas of the CNS. Third, the proliferation rate, or mitotic index, of astroglia in the adult CNS also effectively defines anatomical regions. These differences are present regardless of the astroglial-labeling method used. To supplement our atlas of astroglial density we generated an atlas of proliferation density for the adult CNS. Together, these studies demonstrate that the morphology, density and proliferation rate of astroglia can independently define the discrete cytoarchitecture of the adult mammalian CNS, and support the concept that regional astroglial heterogeneity reflects important molecular and functional differences between distinct classes of astroglia, much like the long-accepted heterogeneity of neuronal populations.

The Marginal Zone/Layer I as a Novel Niche for Neurogenesis and Gliogenesis in Developing Cerebral Cortex

“…However, transforming figures with a radial process were never found in the surface of the cortex, and a bistratified organization of astrocytes was seen from early on. This idea is also in line with the progression of GFAP staining during rodent cortical development (Choi, 1988a) and is intriguing in regard to astroglia heterogeneity in the adult brain (Emsley and Macklis, 2006). Furthermore, MZ progenitors could also contribute to the dorsal sources of cortical oligodendrocytes arising at later stages (Kessaris et al, 2006).…”

Phenotypic Polarization of Activated Astrocytes: The Critical Role of Lipocalin-2 in the Classical Inflammatory Activation of Astrocytes

“…Astrocytes exhibited functional heterogeneity with respect to membrane conductance (58,59), expression of transmitter receptors (60), extent of gap junction coupling (61), glutamate transporter expression (62), and Ca 2+ signaling (63). Diverse astrocyte morphologies across various regions of the CNS also were observed, hinting at an extensive reservoir of astrocyte molecular heterogeneity (64). Comparison of gene signature of astrocytes supported astrocyte heterogeneity (65,66).…”

Glucose Regulates Hypothalamic Long-chain Fatty Acid Metabolism via AMP-activated Kinase (AMPK) in Neurons and Astrocytes

“…In line with this finding, we observed a similar difference in palmitate oxidation between MBH and cortical slices obtained from mouse brain (data not shown). Although the reason for this difference is unknown, this could be related to a lower number of astrocytes in cortical versus hypothalamic areas (52) and/or differences in the expression of proteins and enzymes involved in LCFA metabolism (LCFA transporters, acyl-CoA synthase, and CPT-1) that may affect LCFA uptake. Nonetheless, our results are consistent with previous reports showing regional differences in palmitate oxidation and incorporation in rat (51,53) or human brain (54) and high levels of palmitate incorporation in the arcuate nucleus compared with non-hypothalamic areas (53) after systemic administration of radiolabeled palmitate tracers.…”