Loss of the Habenula Intrinsic Neuromodulator Kisspeptin1 Affects Learning in Larval Zebrafish

Lupton, C., Sengupta, M., Cheng, R.K., Chia, J., Thirumalai, V., Jesuthasan, S.
eNeuro   4(3): (Journal)
Registered Authors
Jesuthasan, Suresh, Sengupta, Mohini, Thirumalai, Vatsala
Calcium imaging, electrophysiology, habenula, intrinsic neuromodulation, mutant, operant learning
MeSH Terms
  • Animals
  • Animals, Genetically Modified
  • Avoidance Learning/physiology*
  • CRISPR-Cas Systems
  • Calcium/metabolism
  • Conditioning, Operant/physiology
  • Dorsal Raphe Nucleus/metabolism
  • Electroshock
  • Habenula/metabolism*
  • Kisspeptins/deficiency*
  • Kisspeptins/genetics
  • Larva
  • Membrane Potentials/physiology
  • Neurons/metabolism*
  • Patch-Clamp Techniques
  • Photic Stimulation
  • Voltage-Sensitive Dye Imaging
  • Zebrafish
  • Zebrafish Proteins/deficiency*
  • Zebrafish Proteins/genetics
28534042 Full text @ eNeuro
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 CRISPR/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.
Genes / Markers
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Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes