Functional connectivity constrained simulations of visuomotor circuits in zebrafish

Visual motion processing in the brain is critical for generating movements with appropriate speed and vigor. However, single-cell mechanistic characterizations in vertebrates remain challenging due to the complexity of mammalian brains. The translucent larval zebrafish provides an important model for studying brain-wide visual computations at the cellular level. A key visuomotor transformation in zebrafish is the optomotor response (OMR), where fish stabilize their body position in response to optic flow. The underlying neural circuits involve the retinorecipient pretectum (Pt) and descending motor command neurons in the midbrain nucleus of the medial longitudinal fasciculus (nMLF). By modeling these circuits in a physics-based neuromechanical simulation, we show that the functional connections between these populations are critical for accurate speed adaptation in the simulation. To causally map how neurons interact and compute visual motion information, we integrated volumetric two-photon microscopy with simultaneous 3D holographic optogenetic photostimulation during visual stimulation and tail tracking. Using these all-optical methods, we uncovered the cellular level Pt-nMLF functional connectivity, defined as a neuron’s functional identity or ‘receptive field’ and its functional role in the circuit’s computation or ‘projective field’. Our findings reveal that specific visually responsive Pt subtypes differentially modulate specific nMLF neural activity, forming correlation-based functional connectomes that guide motor output. We applied these experimentally derived functional connectivity weights to update our model, improving its behavioral response to variable-speed visual stimuli. These results highlight how all-optical methods can map functional connections to provide new insight into brain-scale sensorimotor transformations in vertebrates.