Astrocytes—the brain’s most abundant cell type—are widely assumed to do the same job everywhere in the brain, but this project will test whether they actually come in many specialised varieties. Neurons are known to have thousands of subtypes, each with distinct roles. Astrocytes, which outnumber neurons in the human brain, have largely been treated as a uniform support cell. Yet recent work from the applicant’s lab shows that spinal cord astrocytes can be molecularly specialised—for example, one subtype produces a protein essential for sensorimotor circuit integrity. If astrocyte diversity proves to be a general principle, it would overturn a long-standing assumption in neuroscience. This is fundamental science: the project will map astrocyte molecular and functional heterogeneity across the vertebrate brain and investigate whether similar diversity exists in fruit flies. Success would force a reassessment of how local neural circuits are regulated, potentially reshaping our understanding of brain development and the regional vulnerability seen in disorders such as multiple sclerosis or motor neuron disease. No immediate clinical application is expected, but past discoveries about cell-type diversity—such as the identification of distinct neuron subtypes—have repeatedly opened new avenues for treating neurological conditions.
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The mammalian central nervous system (CNS) shows remarkable regional specialization. This organization, reflected in local and long-range neuronal circuit signaling, underlies both functional complexity of the human brain and vulnerability in certain neurological disorders. It is well recognized that neurons are a diversified population with thousands of sub-types to carry out many specialized functions. In contrast, astrocytes, the most prevalent cell type in the brain, are generally assumed to have homogenous functions across brain regions. However, since astrocytes comprise over 50% of total cells in the brain (Nedergaard et al., 2003, Azevedo et al.,2009), they can be considered as major environmental determinants for local/regional circuits and white matter (Corty & Freeman, 2013, Zhang & Barres, 2010, Han et al., 2013). As such, it is timely and important to challenge the conventional paradigm of astrocyte homogeneity. I propose that astrocyte regional and functional diversity regulates the local in mammals and perhaps invertebrates (Freeman & Rowitch, 2013). Prior work from my lab has-specific shown that astrocytes are allocated according to a spatial-segmental template (Tsai et al.,uit function 2012; Fig. 1). But, a critical unanswered question is whether astrocytes are functionally diversified? We recently reported initial evidence for such heterogeneous function at the single gene level; namely, that ventral spinal cord astrocytes are specialized to encode Sema3a, which is required for sensorimotor circuit integrity (Molofsky et al., 2014). Proving generalized astrocyte regional and functional diversification would defy conventional views and provoke a pervasive reassessment of the roles for astrocytes as key regulators of local neural circuit activity. The proposal will feature interactions between a mammalian and fly lab to: (i) comprehensively determine astrocyte molecular and functional heterogeneity in the vertebrate brain and (ii) investigate evolutionarily conserved astroglial functions in Drosophila. We will develop new transgenic tools and reporters for manipulation of genes required for heterogeneous astrocyte functions during CNS development. The studies are intended to establish whether astrocyte regional and functional diversity is valid as a general neurobiological principle.
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