CONNECTIVITY AND DYNAMICS ACROSS AN ENTIRE VERTEBRATE BRAIN

A fundamental idea in systems neuroscience is that the functional response properties of neurons depend in large part on their synaptic connections, but testing these hypotheses has been challenging. Ideally, one would want a dataset consisting of both synaptic resolution connectivity, acquired with volumetric electron microscopy (EM), for a circuit, as well as the activity, acquired using functional calcium or voltage imaging, of all its constituent neurons. For much of the history of neuroscience, such an experiment was technically infeasible, as expressed in 1979 by Francis Crick, writing that “It is no use asking for the impossible, such as, say, the exact wiring diagram for a cubic millimetre of brain tissue and the way all its neurons are firing”. Here, we bridge neuronal activity and connectivity in an entire larval zebrafish brain. We first performed whole-brain functional imaging using light-sheet microscopy in a larval zebrafish performing various visuomotor tasks, including the optomotor response, gain adaptation, light- and dark-flash responses, phototaxis, and futility-induced passivity. We then performed whole-brain, serial-section scanning electron microscopy to generate a synaptic resolution dataset of the entire brain. The functional dataset was registered to the anatomical dataset, so for a majority of neurons in the fish brain, we can interrogate functional responses as well as anatomical connectivity. In collaboration with many groups, we are leveraging this dataset to validate and falsity circuit hypotheses for behavior. I will present insights gained on ​circuits for motor control and cerebellar learning in the context of the vestibulo-ocular reflex.