The conserved dopaminergic diencephalospinal tract mediates vertebrate locomotor development in zebrafish larvae

Lambert, A.M., Bonkowsky, J.L., and Masino, M.A.
The Journal of neuroscience : the official journal of the Society for Neuroscience   32(39): 13488-13500 (Journal)
Registered Authors
Bonkowsky, Joshua
MeSH Terms
  • Analysis of Variance
  • Animals
  • Animals, Genetically Modified
  • Diencephalon/cytology
  • Diencephalon/growth & development*
  • Dopamine/metabolism*
  • Dopamine Agents/pharmacology
  • Dose-Response Relationship, Drug
  • Electrophysiology
  • Excitatory Amino Acid Agonists/pharmacology
  • Green Fluorescent Proteins/genetics
  • In Situ Nick-End Labeling
  • Larva
  • Locomotion/drug effects
  • Locomotion/physiology*
  • Metronidazole/pharmacology
  • N-Methylaspartate/pharmacology
  • Neural Pathways/growth & development
  • Neural Pathways/injuries
  • Neurons/drug effects
  • Neurons/metabolism
  • Nitroreductases/genetics
  • Peripheral Nerves/physiology
  • Peripheral Nervous System Diseases/physiopathology
  • Receptors, Dopamine D4/metabolism
  • Signal Transduction/drug effects
  • Signal Transduction/genetics
  • Spinal Cord/growth & development*
  • Transcription Factors/genetics
  • Video Recording
  • Zebrafish
  • Zebrafish Proteins/genetics
23015438 Full text @ J. Neurosci.

The most conserved part of the vertebrate dopaminergic system is the orthopedia (otp)-expressing diencephalic neuronal population that constitutes the dopaminergic diencephalospinal tract (DDT). Although studies in the neonatal murine spinal cord in vitro suggest an early locomotor role of the DDT, the function of the DDT in developing vertebrates in vivo remains unknown. Here, we investigated the role of the DDT in the locomotor development of zebrafish larvae. To assess the development of the behavioral and neural locomotor pattern, we used high-throughput video tracking in combination with peripheral nerve recordings. We found a behavioral and neural correspondence in the developmental switch from an immature to mature locomotor pattern. Blocking endogenous dopamine receptor 4 (D4R) signaling in vivo either before or after the developmental switch prevented or reversed the switch, respectively. Spinal transections of post-switch larvae reestablished the immature locomotor pattern, which was rescued to a mature-like pattern via spinal D4R agonism. Selective chemogenetic ablation of otp b (otpb) neurons that contribute to the DDT perpetuated the immature locomotor pattern in vivo. This phenotype was recapitulated by diencephalic transections that removed the dopaminergic otpb population and was rescued to a mature-like locomotor pattern by D4R agonism. We conclude that the dopaminergic otpb population, via the DDT, is responsible for spinal D4R signaling to mediate the developmental switch to the mature locomotor pattern of zebrafish. These results, integrated with the mammalian literature, suggest that the DDT represents an evolutionarily conserved neuromodulatory system that is necessary for normal vertebrate locomotor development.

Genes / Markers
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes