TY - JOUR T1 - Loss of the Habenula Intrinsic Neuromodulator Kisspeptin1 Affects Learning in Larval Zebrafish JF - eneuro JO - eNeuro DO - 10.1523/ENEURO.0326-16.2017 SP - ENEURO.0326-16.2017 AU - Charlotte Lupton AU - Mohini Sengupta AU - Ruey-Kuang Cheng AU - Joanne Chia AU - Vatsala Thirumalai AU - Suresh Jesuthasan Y1 - 2017/05/08 UR - http://www.eneuro.org/content/early/2017/05/08/ENEURO.0326-16.2017.abstract N2 - Learning how to actively avoid a predictable threat involves two steps: recognizing the cue that predicts upcoming punishment, and learning a behavioral response that will lead to avoidance. In zebrafish, ventral habenula (vHb) neurons have been proposed to participate in both steps by encoding the expected aversiveness of a stimulus. vHb neurons increase their firing rate as expectation of punishment grows, but reduce their activity as avoidance learning occurs. This leads to changes in the activity of raphe neurons, which are downstream of the vHb, during learning. How vHb activity is regulated is not known. Here, we ask whether the neuromodulator kisspeptin1, which is expressed in the ventral habenula together with its receptor, could be involved. Kiss1 mutants were generated with Cas9 using guide RNAs targeted to the signal sequence. Mutants, which have a stop codon upstream of the active kisspeptin1 peptide, have a deficiency in learning to avoid a shock that is predicted by light. Electrophysiology indicates that kisspeptin1 has a concentration-dependent effect on vHb neurons: depolarizing at low concentrations and hyperpolarizing at high concentrations. Two-photon calcium imaging shows that mutants have reduced raphe response to shock. These data are consistent with the hypothesis that kisspeptin1 modulates habenula neurons as the fish learns to cope with a threat. Learning a behavioral strategy to overcome a stressor may thus be accompanied by physiological change in the habenula, mediated by intrinsic neuromodulation.Significance Statement Learning to deal with adversity can positively affect one’s ability to cope with challenges in the immediate future. Control thus causes short-term change in the brain. Here, we show that the neuromodulator kisspeptin1 is involved in learning to avoid a punishment. The expression pattern of this gene and electrophysiological recordings suggest that this molecule may function by modulating the ventral habenula, a region of the brain that mediates fear by regulating serotonin release. Kisspeptin1 could thus be a potential player in resilience developed as a result of control, extending previous findings that it can reduce fear. ER -