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Brain-wide recordings of large-scale networks of neurons now provide an unprecedented view into how the brain drives behavior. However, brain activity contains both information directly related to behavior as well as the potential for many internal computations. Moreover, observable behavior is executed not only by the brain, but also by the spinal cord and peripheral nervous system. Behavior is a coarse-grained product of neural activity, and we thus take the view that it can be best represented by lower-dimensional latent neural dynamics. Capturing this indirect relationship while disambiguating behavior-generating networks from internal computations running in parallel requires new modeling approaches that can embody the parallel and distributed nature of large-scale neural populations. We thus present behavior-decomposed linear dynamical systems (b-dLDS) to disentangle simultaneously recorded subsystems and identify how the latent neural subsystems relate to behavior. We demonstrate the ability of b-dLDS to decouple behavioral vs. internal computations on controlled, simulated data, showing improvements over a state-of-the-art model that uses behavior to supervise all dynamics based on behavior. We also demonstrate b-dLDS's interpretability benefits on a task-driven RNN dataset featuring a nonlinear relationship between behavior and activations. We then show that b-dLDS can further scale up to tens of thousands of neurons by applying our model to a large-scale recording of a zebrafish hindbrain during the complex positional homeostasis behavior, wherein b-dLDS highlights asymmetry in behavior-related dynamic connectivity networks. 

Abstract Internal signals from the body and external signals from the environment are processed by brain-wide circuits to guide behavior. However, the complete brain-wide circuit activity underlying interoception—the perception of bodily signals—and its interactions with sensorimotor circuits remain unclear due to technical barriers to accessing whole-brain activity at the cellular level during organ physiology perturbations. We developed an all-optical system for whole-brain neuronal imaging in behaving larval zebrafish during optical uncaging of gut-targeted nutrients and visuo-motor stimulation. Widespread neural activity throughout the brain encoded nutrient delivery, unfolding on multiple timescales across many specific peripheral and central regions. Evoked activity depended on delivery location and occurred with amino acids and D-glucose, but not L-glucose. Many gut-sensitive neurons also responded to swimming and visual stimuli, with brainstem areas primarily integrating gut and motor signals and midbrain regions integrating gut and visual signals. This platform links body-brain communication studies to brain-wide neural computation in awake, behaving vertebrates. 

Genetically encoded voltage indicators (GEVIs) enable monitoring of neuronal activity at high spatial and temporal resolution. However, the utility of existing GEVIs has been limited by the brightness and photostability of fluorescent proteins and rhodopsins. We engineered a GEVI, called Voltron, that uses bright and photostable synthetic dyes instead of protein-based fluorophores, thereby extending the number of neurons imaged simultaneously in vivo by a factor of 10 and enabling imaging for significantly longer durations relative to existing GEVIs. We used Voltron for in vivo voltage imaging in mice, zebrafish, and fruit flies. In the mouse cortex, Voltron allowed single-trial recording of spikes and subthreshold voltage signals from dozens of neurons simultaneously over a 15-minute period of continuous imaging. In larval zebrafish, Voltron enabled the precise correlation of spike timing with behavior.