Single-cell activity tracking reveals that orbitofrontal neurons acquire and maintain a long-term memory to guide behavioral adaptation

Nat Neurosci. 2019 Jul;22(7):1110-1121. doi: 10.1038/s41593-019-0408-1. Epub 2019 Jun 3.


Learning to predict rewards based on environmental cues is essential for survival. The orbitofrontal cortex (OFC) contributes to such learning by conveying reward-related information to brain areas such as the ventral tegmental area (VTA). Despite this, how cue-reward memory representations form in individual OFC neurons and are modified based on new information is unknown. To address this, using in vivo two-photon calcium imaging in mice, we tracked the response evolution of thousands of OFC output neurons, including those projecting to VTA, through multiple days and stages of cue-reward learning. Collectively, we show that OFC contains several functional clusters of neurons distinctly encoding cue-reward memory representations, with only select responses routed downstream to VTA. Unexpectedly, these representations were stably maintained by the same neurons even after extinction of the cue-reward pairing, and supported behavioral learning and memory. Thus, OFC neuronal activity represents a long-term cue-reward associative memory to support behavioral adaptation.

Publication types

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

MeSH terms

  • Acoustic Stimulation
  • Adaptation, Psychological / physiology*
  • Animals
  • Association Learning / physiology*
  • Calcium Signaling*
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / physiology
  • Conditioning, Classical / physiology*
  • Cues
  • Drinking Behavior / physiology
  • Extinction, Psychological
  • Male
  • Memory, Long-Term / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Nerve Tissue Proteins / physiology
  • Neurons / enzymology
  • Neurons / physiology*
  • Optogenetics
  • Patch-Clamp Techniques
  • Prefrontal Cortex / cytology
  • Prefrontal Cortex / physiology*
  • Reward*
  • Single-Cell Analysis
  • Ventral Tegmental Area / physiology


  • Nerve Tissue Proteins
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2