The Medial Orbitofrontal Cortex-Basolateral Amygdala Circuit Regulates the Influence of Reward Cues on Adaptive Behavior and Choice

J Neurosci. 2021 Aug 25;41(34):7267-7277. doi: 10.1523/JNEUROSCI.0901-21.2021. Epub 2021 Jul 16.


Adaptive reward-related decision making requires accurate prospective consideration of the specific outcome of each option and its current desirability. Often this information must be inferred based on the presence of predictive environmental events. The basolateral amygdala (BLA) and medial orbitofrontal cortex (mOFC) are two key nodes in the circuitry supporting such outcome expectations, but very little is known about the function of direct connections between these regions. Here, in male rats, we first anatomically confirmed the existence of bidirectional, direct projections between the mOFC and BLA and found that BLA projections to mOFC are largely distinct from those to lateral OFC (lOFC). Next, using pathway-specific chemogenetic inhibition and the outcome-selective Pavlovian-to-instrumental transfer and devaluation tests, we interrogated the function of the bidirectional mOFC-BLA connections in reward-directed behavior. We found evidence that the mOFC→BLA pathway mediates the use of environmental cues to understand which specific reward is predicted, information needed to infer which action to choose, and how desirable that reward is to ensure adaptive responses to the cue. By contrast, the BLA→mOFC pathway is not needed to use the identity of an expected reward to guide choice but does mediate adaptive responses to cues based on the current desirability of the reward they predict. These functions differ from those we previously identified for the lOFC-BLA circuit. Collectively, the data reveal the mOFC-BLA circuit as critical for the cue-dependent reward outcome expectations that influence adaptive behavior and decision making.SIGNIFICANCE STATEMENT To make good decisions we evaluate how advantageous a particular course of action would be. This requires understanding what rewarding outcomes can be expected and how desirable they currently are. Such prospective considerations are critical for adaptive decision making but disrupted in many psychiatric diseases. Here, we reveal that direct connections between the medial orbitofrontal cortex and basolateral amygdala mediate these functions. These findings are especially important in light of evidence of dysfunction in this circuit in substance use disorder and mental illnesses marked by poor decision making.

Keywords: Pavlovian conditioning; Pavlovian-to-instrumental transfer; appetitive behavior; decision making; devalaution; memory.

Publication types

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

MeSH terms

  • Acoustic Stimulation
  • Adaptation, Psychological / physiology*
  • Animals
  • Axonal Transport
  • Basolateral Nuclear Complex / physiology*
  • Choice Behavior / physiology*
  • Conditioning, Classical / drug effects
  • Cues*
  • Decision Making / physiology*
  • Dependovirus / genetics
  • Extinction, Psychological
  • Fluorescent Dyes / analysis
  • Genetic Vectors / administration & dosage
  • Genetic Vectors / genetics
  • Humans
  • Image Processing, Computer-Assisted
  • Male
  • Neural Pathways / physiology*
  • Prefrontal Cortex / physiology*
  • Rats
  • Rats, Long-Evans
  • Receptor, Muscarinic M4 / genetics
  • Receptor, Muscarinic M4 / physiology
  • Recombinant Proteins / metabolism
  • Reward*


  • Fluorescent Dyes
  • Receptor, Muscarinic M4
  • Recombinant Proteins