Neural Circuit Function Inference with LLMs

The success of connectome mapping now shifts the challenge of understanding the nervous system to the interpretation of neural circuits. Here, we devise a new automated method, LLantia (LLM automated neural circuit inference and analysis), to systematically infer neural circuit function and the role of its component neural cell types. Our approach distills descriptions of cell type function from the literature and, in combination with the connectome, then infers the function for all other cell types, which serves as a basis for subsequent neural circuit function inference. Results are structured hierarchically, with different possible circuit functions organised under multiple possible behavioural and physiological contexts, and each circuit function composed of subcircuit descriptions alongside relevant cell types to facilitate both backtracking to known, published information and support further experimental research. We illustrate our method by inferring cell type function for all cell types of the adult fruit fly brain and for select broader circuits within, and validate our findings, including by cross-checking with literature published after the release date of our analysis.

Probe-EM: Targeted Neuron Tracing via Training-Free Semantic Verification

Establishing large-scale, high-resolution neural connectivity maps is fundamental to elucidating the structural basis of brain function. However, when processing terabyte- or petabyte-scale electron microscopy data, over-segmentation inherent in automated reconstruction algorithms remains a critical bottleneck, requiring extensive manual proofreading spanning person-years. To alleviate the heavy reliance on annotated data and the limited flexibility of conventional tracing methods, we propose a training-free, targeted neuron tracing framework. Specifically, we introduce a skeleton-guided Heuristic Spatial Search paradigm that leverages geometric priors to iteratively reconstruct neuronal morphologies through a probing-verification cycle. To achieve robust zero-shot semantic verification, we further develop a Dimension-Aware Semantic Verification strategy built upon the foundation model NeuroSAM 2. This strategy resolves intra-slice splits via Planar Ensemble Consensus and inter-slice splits via Axial Spatio-Temporal Propagation. Notably, we integrate the proposed workflow into the Neuroglancer visualization platform, enabling an interactive human-in-the-loop proofreading system. Experimental results demonstrate that the proposed method outperforms supervised baselines and reduces manual proofreading time by 33.4%. The source code is publicly available at https://github.com/HeadLiuYun/Probe-EM.

DevoTG: Temporal Graph Neural Networks for Modeling C. elegans Developmental Connectomics

Understanding how a nervous system wires itself from birth to adulthood is a fundamental challenge in developmental neuroscience. We present DevoTG, a temporal graph framework that applies Temporal Graph Neural Networks (TGNs) to two complementary representations of C. elegans neural development: a Continuous-Time Dynamic Graph (CTDG) of cell division events derived from cell lineage data, and a Discrete-Time Dynamic Graph (DTDG) of the developing synaptic connectome spanning eight reconstructed electron-microscopy datasets. On the lineage prediction task, our TGN achieves a mean test AUC of 0.839 +/- 0.007 (5 seeds; validation AUC 0.937 +/- 0.001), outperforming a static GNN with the identical architecture by 26 AUC points (0.577 +/- 0.080), demonstrating that temporal memory is the decisive factor. Applied to the connectome DTDG, DevoTG identifies three connection stability classes (stable, developmental, and variable) across 225 neurons and 858 to 2,496 connections over development (L1 birth to adult), providing a temporal-graph-theoretic complement to the individual-variability classification of Witvliet et al. Analysis of hub command interneurons AVA, AVB, and AVE reveals their persistent centrality and how their integration roles are progressively reinforced across larval stages. Accompanying interactive visualizations (3D animated networks, centrality heatmaps, and a spatiotemporal lineage graph) make developmental dynamics accessible for biological hypothesis generation. DevoTG is open-source and designed for extension to other developing nervous systems. Code is publicly available at https://github.com/DevoLearn/DevoGraph/tree/main/DevoTG.

ConnectomeBench2: A Unified Benchmark for Automated Connectomic Proofreading

Proofreading--correcting segmentation errors in 3D brain reconstructions--is the rate-limiting step in synapse-resolution connectomics. We release ConnectomeBench2, a unified multi-species dataset of over 716,485 expert-labeled proofreading decisions with >4,500,000 associated images spanning four major open connectomes (mouse, human, zebrafish, fly), spanning both split and merge error correction. Trained on this dataset, a single Vision Transformer with shared encoders for mesh geometry and electron microscopy reaches human-level accuracy across species for split error correction and merge error identification, with performance scaling with data size and modality. Beyond accuracy, we show that the model is well-calibrated within distribution, that measures of distribution distance predict where calibration and accuracy will degrade on unseen data, and that connectomics-specific pretraining and active learning-based sample selection show potential to substantially reduce the labeling effort needed to extend to new species and brain regions. The benchmark provides the infrastructure to train and evaluate increasingly capable vision models for connectomic proofreading. Data and code availability. The ConnectomeBench2 dataset is released on Hugging Face at https://huggingface.co/datasets/jeffbbrown2/ConnectomeBench2. The accompanying codebase is available on GitHub at https://github.com/timfarkas/ConnectomeBench2.

Sex-based Network-Specific Differences in Connectomes: A Krakencoder-Based Analysis

This study examines how deficiencies in one brain connectome modality propagate to the other, using the Krakencoder as a simulation framework. Structural and functional connectomes from 702 healthy participants in the Human Connectome Project were analyzed, with the impact of each of the Yeo-7 functional networks assessed separately. Seven scenarios were considered, each involving the removal of a single network while the remaining networks were preserved. The resulting perturbations in cross-modal predictions were quantified using three complementary metrics: KL divergence on eigenvalue spectra, Frobenius norm, and Wasserstein distance. In addition, the persistence of sex-specific information within the predicted connectomes was evaluated. Across all metrics and both prediction directions, the Default Mode Network produced the largest perturbations, whereas the Somatomotor network yielded the smallest. Sex differences in network-level perturbation signatures were subtle, with the best result being an accuracy of 66.09% from connectomes predicted under network-removal conditions. In contrast, connectomes predicted from intact inputs achieved substantially higher sex classification accuracy, reaching up to 84.76%. These findings confirm that full predicted connectomes retain considerably more sex-discriminative information than perturbation-derived signatures alone.

Harnessing cortical geometry, wiring, and function as inductive biases for recurrent neural networks

How the wiring and functional organization of cortex shape recurrent computation remains a central question in both neuroscience and machine learning. Here, we leverage data released through the Machine Intelligence from Cortical Networks (MICrONS) program--a functional connectomics resource spanning multiple areas of mouse visual cortex, in which dense calcium imaging is co-registered with high-resolution electron microscopy reconstruction from the same animal--to build biologically grounded recurrent neural networks. Using neuronal spatial coordinates, anatomical connectivity, and function-derived relationships from nearly 12,000 coregistered excitatory neurons, we initialize recurrent weights and impose communication-aware spatial constraints during learning. Across three cognitive decision-making tasks, networks constrained by cortical structure and function consistently outperform baseline and partially constrained models. Functional weight initialization provides the largest gain, while real spatial embedding yields robust additional improvements across conditions. These biologically grounded networks also develop low-entropy, modular, and small-world organization, and retain strong performance even when recurrence is restricted to positive weights. Together, our results show that the machinery of cortex--its geometry, wiring, and functional structure--can be harnessed as a powerful inductive basis for building recurrent networks that learn more effectively while converging toward key organizational principles of biological computation.