2-1. Research on the role of habenula in emotional behaviors using zebrafish
The homology of the habenula in fish and mammals
The habenula, located in the dorsal diencephalon, conveys information from the telencephalon to the midbrain dopaminergic neurons or hindbrain serotonergic neurons. The structure and connectivity of the habenula is well conserved from the fish to the mammals. In fish, the habenula is consisted of the dorsal and ventral habenula. Recently, we have revealed that the dorsal and vetral habenula of fish correspond to the medial and lateral habenula in mammals (Figure 6, Amo et al., 2010, J Neurosci, 30).
The dorsal habenula of zebrafish is further divided into two subnulei: lateral subnucleus and medial subnucles. We have found that the lateral and medial subnucleus exclusively project to the dorsal half and ventral half of the interpeduncular nucleus (IPN), respectively (Aizawa et al., 2005, Curr Biol, 15). Interestingly, in zebrafish, the lateral subnucleus is significantly larger than the medial subnucleus in the left dorsal habenula (and vice versa in the right dorsal habenula), showing the laterality. We also have revealed that the different birth timing of neurons in the lateral and medial subnucleus during the development causes this laterality ( Aizawa et al., 2007, Dev Cell, 12).
It has been reported that zebrafish uses their right eye when they are detecting a novel object (Miklósi A et al., 1997, Physiol Behav, 63). Mutants that have a inversed laterality of the central nervous system including the habenula shows inversed eye use for novel object detection (Barth et al., 2005, Curr Biol, 15). These results raise the possibility that emotional behaviors may be controlled by two distinct pathways via lateral and media subnucleus of the dorsal habenula in fish.
Choice of behaviors in coping the fear
The lateral and medial subnucleus of the dorsal habenula in fish exclusively project to the dorsal half and ventral half of the interpeduncular nucleus (IPN), respectively (Figure 7). We further showed that the dorsal IPN projects to the central grey (mammalian periaquedactal gray: PAG), a center for the escaping or aggressive behaviors, whereas the ventral IPN projects to Raphé, which is known to play an important role in coping the stress as well as in establishing the strategic behavioral programs through serotonerginc neurons’ activity (Figure7).
We selectively silenced the transmission of information from the medial subnucleus of the dorsal habenula to the ventral IPN using a transgenic zebrafish and examined how the emotional behavior of these fish were modified in the cued-fear conditioning (Agetsuma et al., 2010, Nat Neurosci, 13). In the cued-fear conditioning, fish is put in a square chamber (10 cm X 10 cm) and given 10-second presentation of red LED lamp during which an aversive mild electric shock of 0.5-second duration is overlapped at the end. By repeating trials, fish learns the association between the red lamp and the electric shock and shows escaping behaviors upon the presentation of the red lamp. However, medial subnucleus-silenced fish showed an excessively prolonged freezing behavior instead of escaping behaviors (Figure 7).
Thus, we have shown that the medial subnucleus of the dorsal habenula conveys an experience-dependent update information to control emotional behaviors.
2-2 Research on the role of habenula in emotional behaviors using mice and rats