Optogenetic Editing Reveals the Hierarchical Organization of Learned Action Sequences

Cell. 2018 Jun 28;174(1):32-43.e15. doi: 10.1016/j.cell.2018.06.012.


The organization of action into sequences underlies complex behaviors that are essential for organismal survival and reproduction. Despite extensive studies of innate sequences in relation to central pattern generators, how learned action sequences are controlled and whether they are organized as a chain or a hierarchy remain largely unknown. By training mice to perform heterogeneous action sequences, we demonstrate that striatal direct and indirect pathways preferentially encode different behavioral levels of sequence structure. State-dependent closed-loop optogenetic stimulation of the striatal direct pathway can selectively insert a single action element into the sequence without disrupting the overall sequence length. Optogenetic manipulation of the striatal indirect pathway completely removes the ongoing subsequence while leaving the following subsequence to be executed with the appropriate timing and length. These results suggest that learned action sequences are not organized in a serial but rather a hierarchical structure that is distinctly controlled by basal ganglia pathways.

Keywords: action sequence; basal ganglia; direct pathway; electrophysiology; indirect pathway; optogenetics; striatum.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal / drug effects
  • Behavior, Animal / radiation effects
  • Diphtheria Toxin / pharmacology
  • Electrodes, Implanted
  • Evoked Potentials, Visual
  • Female
  • Lasers
  • Learning*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muscimol / pharmacology
  • Nerve Tissue Proteins / deficiency
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neurons / drug effects
  • Neurons / metabolism*
  • Optogenetics*
  • RGS Proteins / genetics
  • Receptors, N-Methyl-D-Aspartate / deficiency
  • Receptors, N-Methyl-D-Aspartate / genetics
  • Receptors, N-Methyl-D-Aspartate / metabolism


  • Diphtheria Toxin
  • Gprin1 protein, mouse
  • Nerve Tissue Proteins
  • RGS Proteins
  • Receptors, N-Methyl-D-Aspartate
  • regulator of g-protein signaling 9
  • Muscimol