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

arXiv: https://arxiv.org/abs/2610.09643 · HTML: https://mlsanity.com/paper/2610.09643/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Placed in Clinical and biomedical applications, one of 17 directions in LLM reasoning.
- Builds on 7 of its 50 references that are in the map.
- First posted on arXiv 7 Oct 2026.

## Placed in

- LLM reasoning / [Clinical and biomedical applications](https://mlsanity.com/lr/clinical-and-biomedical-applications/)
- LLM agents and tool use / [Medical and scientific domain agents](https://mlsanity.com/agents/medical-and-scientific-domain-agents/)

## Builds on (most cited first, 7 of 7)

- [Retrieval-Augmented Generation for Knowledge-Intensive NLP Tasks](https://mlsanity.com/paper/2005.11401/) (2020)
- [Shortcut Learning in Deep Neural Networks](https://mlsanity.com/paper/2004.07780/) (2020)
- [Markerless tracking of user-defined features with deep learning](https://mlsanity.com/paper/1804.03142/) (2018)
- [Language agents achieve superhuman synthesis of scientific knowledge](https://mlsanity.com/paper/2409.13740/) (2024)
- [Autonomous LLM-driven research from data to human-verifiable research papers](https://mlsanity.com/paper/2404.17605/) (2024)
- [PubTator 3.0: an AI-powered Literature Resource for Unlocking Biomedical Knowledge](https://mlsanity.com/paper/2401.11048/) (2024)
- [Graph AI generates neurological hypotheses validated in molecular, organoid, and clinical systems](https://mlsanity.com/paper/2512.13724/) (2025)

## Abstract (arXiv)

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 introduce a human-governed in vivo lab-in-the-loop linking hypothesis generation to experimental iteration. Within this framework an agent nominated ATP1A3, the neuronal alpha3 Na+/K+-ATPase, as a control point on cortical excitability; interneuron-restricted expression of ATP1A3 abolished the beta- and gamma-band response to a focal 4-aminopyridine challenge in vivo, and the validated target was then carried into a structure-guided small-molecule campaign terminating in a defined assay to resolve the direction of modulation. CircuitATLAS thus provides a framework for discovering therapeutics based not only on what is molecularly disrupted in disease, but on what can be controlled to restore circuit function.