Functional properties of habenular neurons are determined by developmental stage and sequential neurogenesis

Abstract

SUMMARYNeural development is not just a linear expansion of the brain. Instead, the structure and function of developing brain circuits undergo drastic alterations that have a direct impact on the animals’ expanding behavioural repertoire. Here we investigated the developmental changes in the habenula, a brain region that mediates behavioural flexibility during learning, social interactions and aversive experiences. We showed that developing habenular circuits exhibit multiple alterations, which increase the structural and functional diversity of cell types, inputs and functional modules within habenula. As the neural architecture of habenula develops, it sequentially transforms into a multi-sensory brain region that can process visual and olfactory information. Moreover, we also observed that already at early developmental stages, the habenula exhibits spatio-temporally structured spontaneous neural activity that shows prominent alterations and refinement with age. Interestingly, these alterations in spontaneous activity are accompanied by sequential neurogenesis and integration of distinct neural clusters across development. Finally, by combining an in vivo neuronal birthdating method with functional imaging, we revealed that clusters of habenular neurons with distinct functional properties are born sequentially at distinct developmental time windows. Our results highlight a strong link between the function of habenular neurons and their precise birthdate during development, which supports the idea that sequential neurogenesis leads to an expansion of neural clusters that correspond to distinct functional modules in the brain.