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Emerging strategies for the genetic dissection of gene functions, cell types, and neural circuits in the mammalian brain

Abstract

The mammalian brain is composed of a large number of highly diverse cell types with different molecular, anatomical, and functional features. Distinct cellular identities are generated during development under the regulation of intricate genetic programs and manifested through unique combinations of gene expression. Recent advancements in our understanding of the molecular and cellular mechanisms underlying the assembly, function, and pathology of the brain circuitry depend on the invention and application of genetic strategies that engage intrinsic gene regulatory mechanisms. Here we review the strategies for gene regulation on DNA, RNA, and protein levels and their applications in cell type targeting and neural circuit dissection. We highlight newly emerged strategies and emphasize the importance of combinatorial approaches. We also discuss the potential caveats and pitfalls in current methods and suggest future prospects to improve their comprehensiveness and versatility.

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Fig. 1: Regulation strategies at the DNA, RNA, and protein levels.
Fig. 2: Genetic approaches for cell type targeting, conditional gene regulation, and lineage tracing.
Fig. 3: Genetic approaches for circuit mapping and functional interrogations.

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Acknowledgements

This study was supported by funds from the National Key R&D Program of China 2018YFA0108000, National Natural Science Foundation of China (31970971, 31771196, 32000729), Shanghai Rising-Star Program (18QA1400600), Shanghai Municipal Science and Technology Major Project (No.2018SHZDZX01), and ZJLab.

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Conceptualization: MH. Writing—original draft: LG, XL, JW, and MH. Writing—review and editing: MH, LG, and XL. All authors reviewed and approved the final version.

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Correspondence to Miao He.

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Gong, L., Liu, X., Wu, J. et al. Emerging strategies for the genetic dissection of gene functions, cell types, and neural circuits in the mammalian brain. Mol Psychiatry (2021). https://doi.org/10.1038/s41380-021-01292-x

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