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Multisensory signal processing: From brain-wide neuronal circuits to behavior

Periodic Reporting for period 2 - MultiSense (Multisensory signal processing: From brain-wide neuronal circuits to behavior)

Reporting period: 2018-09-01 to 2020-02-29

Our brain needs to constantly fuse sensory information detected by our multiple senses in order to produce a seamless coherent representation of the world.  Rather than being the exception, this binding process is ubiquitous to sensory-motor integration and is implicated in most cognitive functions. Its impairment is a cause of various pathologies, such as schizophrenia or autism. Multisensory processing operates on all brain levels from primary cortices over subcortical structures up to higher associative centers, while the smallest operational units are single multisensory neurons. In an interdisciplinary effort, we combine optical developments, genetics and neuro-computation to obtain new insights into the activity of brain-wide neural circuits that process multisensory information. To reduce the complexity, we study the small transparent brain of zebrafish larvae as a model system. We focus on gaze stabilization as an inherently multisensory model task that is conserved among all vertebrates. This reflex uses both vestibular and visual information to drive eye movements in order to compensate for self-motion and maintain clear vision. We will build a novel experimental platform in which a restrained larva will be submitted to vestibular and visual stimuli, as a pilot in a flight simulator. We will optically record the activity of all 100,000 neurons of the animal brain as it performs multisensory integration tasks.  To extract basic principles of how behavior is coded in multisensory neuronal circuits we will interpret the brain-wide activity and the observed behavior with methods from statistical physics. No other system can today provide a similar brain-scale, yet cell-resolved view on the neuronal network dynamics subserving such a complex integration process. Thus, our data will constitute an invaluable arena to test circuit-based models for sensory-motor integration, decision-making and multisensory-motor learning.
First, we developed an ultra-stable rotating one-photon light-sheet microscope that overcame the standing challenge to make functional whole-brain imaging compatible with physiological vestibular stimulation. It is based on a novel miniaturized light-sheet unit that is mounted on a rotating stage—the unit can additionally be mounted as light-sheet module on standard microscopes. Co-rotating the tethered fish and the microscope stimulates the vestibular system while maintaining stable imaging conditions. With the system, we mapped, for the first time, the brain-wide response of larval zebrafish to vestibular rolling stimuli and identified three major functional clusters that exhibit well-defined phasic and tonic response patterns (Migault et al. Current Biology 2018).
Second, we gained high control over the visual environment of the fish by developing a two-photon version of the system based on an infrared light-sheet for which the fish is blind so that the laser light-sheet does not excite the photoreceptors in the fish eye. The challenge was to fiber deliver the femtosecond pulsed laser required for two-photon microscopy onto our rotating light-sheet platform. We achieved broadband and dispersion free laser delivery with a hollow-core negative curvature fiber. This fiber should find additional application in head mounted miniscopes for the excitation of a large spectrum of optogenetic and fluorescent proteins via a single fiber or to share the high cost laser source required for two-photon microscopy between different setups. With our rotatable two-photon system, we succeeded to mapped, for the first time, the pure brain-wide vestibular response of larval zebrafish to dynamic tilt stimuli (Trentesaux et al. manuscript in preparation).
With our rotating one- and two-photon rotating light-sheet microscopy platform, we have developed an unconventional methodology. With the system brain-wide neuronal activity recordings during dynamic vestibular stimulation are now possible. We are the only lab in the world that has such a system at hand and we use this system now to characterize vestibular processing in the brain and to study how this pathway is integrated with visual information when animals interact in a virtual vestibular-visual environment comparable to a flight simulator for pilot training.
Whole-brain calcium imaging during physiological vestibular stimulation in larval zebrafish