Selective asymmetry in a conserved forebrain to midbrain projection

How the left and right sides of the brain acquire anatomical and functional specializations is not well understood. The zebrafish has proven to be a useful model to explore the genetic basis of neuroanatomical asymmetry in the developing forebrain. The dorsal diencephalon or epithalamus consists of the asymmetric pineal complex and adjacent paired nuclei, the left and right medial habenulae, which in zebrafish larvae, exhibit differences in their size, neuropil density and patterns of gene expression. In all vertebrates, axons from the medial habenular nuclei project within a prominent fiber bundle, the fasciculus retroflexus, to a shared midbrain target, the interpeduncular nucleus of the ventral tegmentum. However, in zebrafish, projections from the left habenula innervate the dorsal and ventral regions of the target nucleus, whereas right habenular efferents project only to the ventral region. A similar dorsoventral difference in habenular connectivity is found in another teleost species, the highly derived southern flounder, Paralichthys lethostima. In this flatfish, directional asymmetry of the habenular projection appears to be independent of the left-right morphology and orientation that an individual adopts post-metamorphosis. Comparative anterograde labeling of the brains of salamanders, frogs and mice reveals that axons emanating from the left and right medial habenulae do not project to different domains, but rather, they traverse the target nucleus in a complementary mirror image pattern. Thus, although the habenulo-interpeduncular conduction system is highly conserved in the vertebrate brain, the stereotypic dorsoventral topography of left-right connections appears to be a feature that is specific to teleosts.