2026-10-16

How the cortex supports complex, naturalistic behavior can be revealed only in freely moving animals. Although head-mounted microscopes promise access to the neural dynamics underlying such behavior, fundamental trade-offs among field of view, spatial resolution, device weight, and background contamination have prevented cortex-wide single-neuron recording, leaving distributed cortical coordination largely inaccessible. To meet these challenges, we introduce COMET (Cortex-wide Observational Miniature Epifluorescence Technique), a 3.75-g head-mounted mesoscope that integrates an aberration-controlled wide-field optical design, uniform high-efficiency excitation and single-coaxial power-and-data transmission with an end-to-end denoising and signal-extraction pipeline. This enables cortex-wide calcium imaging at single-cell resolution in freely moving mice. COMET captures activity from >15,000 layer 2/3 neurons per 5-min recording over fields of view up to 10 mm in diameter while preserving natural behavior. Benchmarking against benchtop two-photon microscopy demonstrates high spatial concordance of detected neurons and matched event-level calcium dynamics. We apply COMET to social interaction to quantify region-specific engagement and to an auditory trace fear-conditioning task that requires natural movement and behavioral expression, revealing time-ordered changes in regional firing-rate structure and functional connectivity preceding a global conditioned response. COMET provides an open, lightweight hardware-software framework for linking single-neuron activity to cortex-scale network dynamics during freely expressed behaviors under changing internal or external conditions.

Because of the paucity of pattern-generating recurrent excitation in the CA1 hippocampal region, place field sequences are assumed to be inherited from upstream regions. Alternatively, disinhibition may play a role in shaping pyramidal cell activity. We propose a model of CA1 activity using one layer of excitatory cells and one layer of inhibitory cells, with local excitatory-to-inhibitory connectivity, broad inhibitory-to-excitatory connectivity without recurrent excitatory connections, and broad inhibitory-inhibitory connections. The layers need not follow a topographic organization; instead they can represent sequences of place cells structured by local inhibition. Our mathematical model of CA1 neurons with data-inspired connectivity demonstrates place fields sharpened by disinhibition, mimicking a recently discovered decrease in inhibitory input within place fields and matching in vivo patterns of disinhibition. Mathematical analysis of our model suggests the importance of inhibitory-to-excitatory connections in control of place cell firing rate and sparsity. We also demonstrate that a disinhibition-based mechanism of pattern generation is more flexible without recurrent excitation than the recurrent excitation-rich CA3-like model. Finally, we demonstrate disinhibition as an efficient mechanism for internally-generated sequential activity, where the speed of sequential change depends on both input strength and inhibitory-to-excitatory connection strength. Overall, our model suggests that theta time-scale disinhibition is a foundational mechanism of self-organized sequential activity in the CA1 region, and, possibly, in other networks.