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                             Hidenori Aizawa、MD、PhD


Since trained as a psychiatrist, I have been trying to unravel the basic feature of neural function underlying mental disorders. We do not always fall into the mental illness like depression or schizophrenia when we encounter a stressful situation in daily life. How we overcome the life event? I suppose that this stability should not be derived from one gene or a specific part of the brain but the adaptive behavior should be generated from the coordication of multiple neural circuitries. To understand the neural function as a system for the adaptive behavior, I focus on extracting an essence of evolutionary conserved circuit that governs the regulation of monoaminergic system such as serotonin and dopamine. Zebrafish, tiny tropical fish, has a transparent brain during development and minimal version of vertebrate brain in it. By examining this from the molecular perspective, I begin to elucidate the way how we cope with the social stress or environmental change.

Left-right asymmetry in neural connectivity of zebrafish brain

Functional asymmetries within the brain are not unique to humans and indeed may be a universal feature of teh nervous systems. Previous studies imply that specializations in information processing on the left and right sides of the brain are evolutionarily conserved. Although functional asymmetry is a conserved feature of teh vertebrate brain, surprisingly little is known about the patterns of neuronal connectivity that account for it. For instance, it is completely unknown how left-right (LR) information is converyed from sensory processing structures towards the motor regions of the brain. As the motor outputs elicited by lateralized brain activity involve both sides of the body, then one might predict the existence of circuitry that converys information from left or right-sided neural structures to nuclei on both sides of the brain. However, it is totally unknown if, how and where such conversion takes place.

We have unraveled a novel aspect of neural circuitry that provides a mechanism by which information from left and right sides of the brain is transmitted to different dorso-ventral (DV) regions of a bilaterally positioned target nucleus. This issue was addressed by analysis of the output circuitry of the lateralized habenular nuclei in the zebrafish. The habenulae are part of an evolutionarily highly conserved conduction pathway within the limbic system that connects telencephalic nuclei to the interpreduncular nucleus (IPN) of the midbrain (Figure 1A) and are implicated in the regulation of dopaminergic and serotonergic neuronal activities. We show the asymmetric connectivity in the habenulo-interpreduncular projection in zebrafish, i.e. the stereotypic, topographic projection of left-sided habenular axons to the dorsal region of the IPN and right-sided habenular axons to the ventral IPN (Figures 1B-1F). This asymmetric projection is accounted for by a prominet LR difference in the size ratio of the medical and lateral sub-nuclei of the habenulae, each of which specifically projects either to ventral or dorsal IPN targets (Figure 1B and 1C).

It is known that the Nodal signaling pathway regulates laterality decisions in the viscera and, in zebrafish, unilateral activation of the Nodal signaling pathway in the left brain specifies the laterality of the asymmetry of habenular size (Figure 2A-2D). Asymmetric Nodal signaling specifies the DV polarity of innervation of the IPN by left and right habenular axons (Figure 2E and 2F), which is consistent with a role for the Nodal pathway in ensuring coordinated laterality of circuitry between all individuals at the population level.

Our results reveal a mechanism by which information distributed between left and right sides of the brain can be transmitted bilaterally without loss of LR coding and they begin to elucidate the signaling pathways that direct the establishment of lateralized circuitry.

Figure Legends

Figure 1. Asymmetric projections from the habenular nuclei to the IPN.
(A) Schematic illustration of a lateral view of an adult zebrafish brain. (B), (C) Transverse sections at the level of the habenulae (B) and the IPN (C). Medial sub-nuclei, green; lateral sub-nuclei, red. (D) Parasagittal section showing axonal projections from the right (green) and left (red) habenula to the IPN. (E), (F) Horizontal sections showing the spiraling of left (E, red) and right (F, green) habenular axons in the IPN at the midline. In both cases, the labeled axons surround the cell bodies (blue) at the center of the nucleus. Abbreviations: Cbll, cerebellum; d, dorsal; Hb, habenula; Hy, hypothalamus; IPN, interpeduncular nucleus; l, left; OB, olfactory bulb; r, right; Tel, telencephalon; TeO, optic tectum; v, ventral.

Figure 2. Reversal of Nodal activation correlates with reversal of habenular laterality and inversion of projections in about face mutant fish.
(A, B) Dorsal views of wild-type (A) and heart-reversed about face mutant (B) embryos showing the direction of Nadal signal in the habenular primordium by green fluorescent protein in the left (A) and in the right (B). (C, D) Dorsal views of the habenulae of a wild-type (C) and a heart-reversed about face mutant (D) larvae showing prominent leftover expression (marker for the left-sided lateral sub-nuculeus). (G, H) Dorsal views of habenular projections in the IPN of a wild-type (G) and an about face larvae with reversed Nodal activation (H). Axons from the left habenula have been labeled green and axons from the right habenula labeled red.

Figure 1