Cross-species representation learning aligns mouse and human neural dynamics and tracks clinical drug efficacy

Abstract

Preclinical models poorly predict human drug efficacy, particularly in neurological disorders. Neural activity offers a uniquely rich source of translational information because it captures high-dimensional variation in nervous-system function that can be measured in both animals and humans. However, its high dimensionality makes it difficult to distinguish conserved disease-related features from variation arising from species, recording modality and experimental context. Here, we test whether shared neural dynamics can be identified directly from electrophysiology data by learning representations organized by biological state rather than species. We develop a dual-rule contrastive learning framework that aligns corresponding mouse and human states while preserving separation between distinct phenotypes. This framework recovered conserved sensory-response structure across species and, in epilepsy, resolved distinct relationships between three mouse models and heterogeneous human patient populations. When treated animals were projected into a frozen cross-species representation, drug-induced movement towards the human-aligned healthy state retrospectively tracked known clinical efficacy across ten model-drug combinations including a disease-specific detrimental effect. The framework also identified shared disease-associated neural dynamics between Fmr1-knockout mice and human 16p11.2 copy-number variant carriers despite differences in genetic aetiology and recording modality. Together, these findings show the potential of cross-species neural representation learning to map heterogeneous human disease onto experimentally tractable preclinical states and assess whether interventions restore human-relevant circuit function.