Language as the Interface: Foundation-Model Contrastive Learning Links Transcriptomes and Electrophysiology

Abstract

Integrating transcriptomic and electrophysiological data is essential for building multimodal foundation models for neuroscience. Patch-seq provides paired measurements of gene expression and intrinsic electrophysiology from the same neuron, establishing a basis for training cross-modal models. Here we introduce LangPatch, a foundation-model-based contrastive learning framework that uses paired Patch-seq data to align pretrained GenePT representations with electrophysiological phenotypes through a language-based interface. Gene descriptions and verbalized electrophysiological profiles are embedded by the same frozen text encoder. A context adapter and projection modules connect the modalities through paired contrastive learning. Across mouse visual, mouse motor, and human cortical cohorts, LangPatch achieves the highest mean transcriptome-to-electrophysiology prediction correlation among the evaluated foundation-model and representation-learning methods. It also improves held-out cross-modal alignment in the two mouse cohorts (FOSCTTM 0.107/0.135 vs. 0.208/0.222 for JAMIE, an existing cross-modal Patch-seq imputation method). It predicts transcriptomic family, type, cortical layer, and marker-gene expression from electrophysiology, exceeding other baselines on most endpoints. More importantly, the method transfers across brain areas and species: a model trained on mouse visual cortex predicts electrophysiology in motor cortex with approximately 70% correlation retention and in human cortex with 47% (58% on acute-slice recordings). Together, these results demonstrate alignment between molecular and functional representations of neurons, providing a building block for multimodal foundation models in neuroscience.