The cellular processes that translate a genetic mutation into neurodegeneration are often poorly understood, in part because it has been difficult to link the functional activity of a neuron to its underlying transcriptional and genetic state. To close this gap, we are developing a new technology that enables functional readout of neural activity in the same cells used for other genomic profiling. By combining this technology with genetic perturbation, we can run functional genomics screens that directly link specific genes and pathways to neural activity phenotypes, rather than relying on more indirect measures of cell state. We are deploying this technology across cell culture models, including patient- and disease-model-derived iPSC-derived neurons, as well as more intact systems, including ex vivo organotypic brain slice cultures and in vivo models, to uncover new biology by coupling neural activity with cell identity through transcriptomics, and to reveal both disease-specific and shared mechanisms of neurodegeneration, and IDDs that point toward new therapeutic targets.