The Cholinergic Basal Forebrain Links Auditory Stimuli with Delayed Reinforcement to Support Learning

Neuron. 2019 Sep 25;103(6):1164-1177.e6. doi: 10.1016/j.neuron.2019.06.024. Epub 2019 Jul 24.


Animals learn to fear conditioned sound stimuli (CSs) that accompany aversive unconditioned stimuli (USs). Auditory cortex (ACx) circuits reorganize to support auditory fear learning when CS-evoked activity temporally overlaps with US-evoked acetylcholine release from the basal forebrain. Here we describe robust fear learning and acetylcholine-dependent ACx plasticity even when the US is delayed by several seconds following CS offset. A 5-s CS-US gap was not bridged by persistent CS-evoked spiking throughout the trace period. Instead, within minutes following the start of conditioning, optogenetically identified basal forebrain neurons that encode the aversive US scaled up responses to the CS and increased functional coupling with the ACx. Over several days of conditioning, bulk imaging of cholinergic basal forebrain neurons revealed sustained sound-evoked activity that filled in the 5-s silent gap preceding the US. These findings identify a plasticity in the basal forebrain that supports learned associations between sensory stimuli and delayed reinforcement.

Keywords: acetylcholine; auditory cortex; basal forebrain; classical conditioning; credit assignment problem; fear conditioning; globus pallidus; nucleus basalis; substantia innominata; trace conditioning.

Publication types

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

MeSH terms

  • Acetylcholine / metabolism*
  • Acoustic Stimulation
  • Animals
  • Auditory Cortex / physiology*
  • Basal Forebrain / cytology
  • Basal Forebrain / metabolism
  • Basal Forebrain / physiology*
  • Cholinergic Neurons / metabolism
  • Cholinergic Neurons / physiology*
  • Conditioning, Classical / physiology*
  • Fear*
  • Mice
  • Neuronal Plasticity
  • Optogenetics
  • Reinforcement, Psychology*
  • Time Factors


  • Acetylcholine