CircuitATLAS: Agentic reasoning over a systems neuroscience knowledge graph for target discovery in circuitopathies

Gabriel Ocana-Santero, Marko Tvrdic

Drug discovery for neurological disease has traditionally centered on the molecules altered by disease. But the molecules that cause pathology are not necessarily the best points from which to reverse it. Here, we ask which otherwise unaltered molecular control points can be engaged to restore pathological neural circuits toward functional states. We present CircuitATLAS, a provenance-grounded systems-neuroscience knowledge graph and agentic framework for target discovery in circuitopathies. It structures literature-derived relationships across diseases, phenotypes, electrophysiology, circuits, brain regions, cell types and molecular effectors, while deliberately excluding direct disease-gene and disease-protein edges to reduce shortcut reasoning. The graph contains 3.83 million nodes and 7.66 million edges, including 5.31 million LLM-extracted relations, and incorporates structured datasets such as the Human Cell Atlas and new multimodal in vivo measurements. We then introduce an agentic workflow that reasons from measurable disease phenotypes through their circuit and cellular substrates to molecular interventions, therapeutic feasibility and clinical constraints. Finally, we…