Bianco, I.H.; (2008) Development of lateralised circuitry in the zebrafish brain. Doctoral thesis , University of London.

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Abstract

Left-right asymmetry is a highly conserved feature of the nervous system. However, it is not known how functional lateralisation is represented at the level of lateral differences in circuit microarchitecture. In this study, I identify asymmetric neuronal connectivity in the larval zebrafish brain, resolve L-R differences in the morphology and connectivity of individual projection neurons and investigate the molecular and cellular mechanisms by which lateralisation develops. The habenular nuclei form part of the highly conserved dorsal dien cephalic conduction system. I find that the habenulae display laterotopic ef ferent connectivity, wherein left and right-sided axons are segregated along the dorso-ventral axis of their target, the interpeduncular nucleus (IPN). Habenular neurons elaborate remarkable "spiralling" terminal arbors within the IPN. I have identified two sub-types of habenular neuron, defined by ax onal arbors with distinct morphology and targeting. Both sub-types are found in both the left and right habenula, but in substantially different ratios. Thus, the vast majority of left habenular neurons elaborate tall, crown-shaped arbors localised to the dorsal IPN, whereas almost all right- sided cells form flattened arbors restricted to the ventral IPN. This left- right asymmetry in cell-type composition, combined with the differential targeting of neuronal sub-types, underlies the laterotopic connectivity of the habenulae. This reveals a fundamental strategy that serves to differentiate functional circuitry on the two sides of the CNS: equivalent components are specified on both sides and lateralisation results from differences in the ratios of neuronal sub-types on the left and right. Left-sided Nodal signalling is essential for controlling the orientation, or laterality, of laterotopic connectivity, but is not required for asymmetry per se. The left-sided parapineal nucleus is required for the development of normal asymmetric phenotypes, including the development of both left and right-sided axon arbors with appropriate morphology and targeting. How ever, following laser-ablation of the parapineal, left and right-sided neurons continue to elaborate arbors with distinct lateralised morphologies, indicating that additional developmental mechanisms act to convey left-right identity information to this highly conserved circuit.

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