Habenula and the asymmetric development of the vertebrate brain

Habenula is a relay nucleus connecting the forebrain with the brain stem and plays a pivotal role in cognitive behaviors by regulating serotonergic and dopaminergic activities. The mammalian habenula is divided into the medial and lateral habenulae, each of which consists of a heterogeneous population of neurons. Recent comparative analyses of zebrafish and rodent habenulae have provided molecular insights into the developmental mechanism of the habenula. Hodological and gene expression analyses revealed that these two habenular pathways are conserved phylogenetically between fish and mammals. The anatomical information make the zebrafish and rodent model animals amenable to the genetic analysis of the development and physiological role of the vertebrate habenula. Intriguingly, habenula has also attracted interest as a model for brain asymmetry, since many vertebrates show left-right differences in habenular size and neural circuitry. Left-right asymmetry is a common feature of the central nervous system in vertebrates. Despite its prevalence and functional importance, few studies have addressed the molecular mechanism for generation of the asymmetric brain structure, probably due to the absence of genetically accessible model animals showing obvious asymmetry. The results from recent studies on zebrafish habenula suggest that development of habenular asymmetry is mediated by differential regulation of the neurogenetic period for generating specific neuronal subtypes. Since the orientation and size ratio of the medial and lateral habenulae differs across species, evolution of those subregions within the habenula may also reflect changes in neurogenesis duration for each habenular subdivision according to the evolutionary process.