Challenges and opportunities in adapting high-throughput functional assays for in vivo neuroscience.

🤖 Plain-English Summary

High-throughput functional assays, including CRISPR perturbations with single-cell readouts and massively parallel reporter assays, are redefining studies of gene regulation and function. We outline advances, obstacles, and a framework organized around two central challenges: (1) library delivery and signal recovery, and (2) cellular complexity.

🔑 Key Findings

• These assays are effective in homogeneous cultured cells, where libraries can be efficiently scaled, delivered, and recovered.
• The brain, however, imposes steeper barriers.
• Viral packaging limits, sparse recovery, and restricted expression constrain throughput, while cellular heterogeneity, spatial architecture, and activity-dependent dynamics demand greater resolution.

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