Facchin, L., Duboué, E.R., Halpern, M.E. (2015) Disruption of Epithalamic Left-Right Asymmetry Increases Anxiety in Zebrafish. The Journal of neuroscience : the official journal of the Society for Neuroscience. 35:15847-59.
Differences between the left and right sides of the brain are found throughout the animal kingdom, but the consequences of altered neural asymmetry are not well understood. In the zebrafish epithalamus, the parapineal is located on the left side of the brain where it influences development of the adjacent dorsal habenular (dHb) nucleus, causing the left and right dHb to differ in their organization, gene expression, and connectivity. Left-right (L-R) reversal of parapineal position and dHb asymmetry occurs spontaneously in a small percentage of the population, whereas the dHb develop symmetrically following experimental ablation of the parapineal. The habenular region was previously implicated in modulating fear in both mice and zebrafish, but the relevance of its L-R asymmetry is unclear. We now demonstrate that disrupting directionality of the zebrafish epithalamus causes reduced exploratory behavior and increased cortisol levels, indicative of enhanced anxiety. Accordingly, exposure to buspirone, an anxiolytic agent, significantly suppresses atypical behavior. Axonal projections from the parapineal to the dHb are more variable when it is located on the right side of the brain, revealing that L-R reversals do not necessarily represent a neuroanatomical mirror image. The results highlight the importance of directional asymmetry of the epithalamus in the regulation of stress responses in zebrafish.
Significance statement The asymmetric epithalamus of zebrafish has emerged as a valuable model to explore the formation and function of left-right differences in the brain. To probe the relationship between brain laterality and behavior, we examined the effects of left-right reversal of epithalamic asymmetry or symmetric development on behavior. In both cases, zebrafish showed increased measures of fear/anxiety, including reduced exploratory behavior and delayed exit from a confined space. Adults with reversed L-R asymmetry also have elevated cortisol levels relative to controls. The results reveal the importance of directional asymmetry of the dorsal diencephalon in the modulation of anxiety.