Dissecting asymmetric habenular neural circuit formation and function in vivo

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Neural network formation needs to be tightly controlled to avoid devastating consequences for the organism ranging from mental illnesses to motoric diseases. Neurons are specialized cells, which during network development extend protrusions (axons) over various distances through the body of all animals. On their way, the axons are influenced by extrinsic signals to find and eventually precisely innervate their targets. We study the zebrafish habenular circuitry as an in vivo model for neural network formation and function. The conserved bilaterally formed habenulae consist of distinct groups of neurons named dorsal and ventral habenulae (dHb and vHb). Intriguingly, the dHb are established asymmetrically across the midline in many vertebrates regarding for instance the cell number of neuronal subpopulations. dHb neurons develop from pools of precursor cells in the forebrain. Our recent work has uncovered a fundamental mechanism by which Wnt signaling influences this developmental program within precursor cells important for the establishment of brain asymmetry. We can also show that the same pathway is essential for the formation of the vHb and we aim to address the underlying mechanism.Habenular neurons send out longitudinal projections, which elongate seemingly coordinated on either side of the brain and eventually innervate their targets in about 300 µm distance. We apply 2-photon microscopy long-term imaging and computational depth colour coding to follow habenular neural network formation on a single axon level in the 3-D volume. We combine this versatile system with laser ablations of neurons elucidating the key-events during network formation over 4 days and to study the functional relevance of its components. This allowed us to uncover an intriguing mechanism by which habenular axons use a second network connecting the two sides of the brain to coordinate their elongation. The inevitable goal now is to find the molecules important for the interhemispheric exchange of information.The habenular network integrates cognitive input such as olfactory and visual information and is involved in various behaviors ranging from fear to reward responses. Functional impairment causes pathophysiological syndromes. We now know how the habenular neural circuit develops in the living embryo and we have the tools and resources to manipulate its asymmetry and laterality genetically and physically. This puts us in a headstart position to elucidate the axonal pathways used to integrate cognitive stimuli. Habenular axons transfer these from the forebrain into the mid- and hindbrain. By establishing a functional projection map of these connections, we can analyse the functional consequences of precise network manipulations. These studies will substantially contribute to our understanding of neural network function and functional lateralization of the brain.