Uncertainty, neuromodulation, and attention

Neuron. 2005 May 19;46(4):681-92. doi: 10.1016/j.neuron.2005.04.026.


Uncertainty in various forms plagues our interactions with the environment. In a Bayesian statistical framework, optimal inference and prediction, based on unreliable observations in changing contexts, require the representation and manipulation of different forms of uncertainty. We propose that the neuromodulators acetylcholine and norepinephrine play a major role in the brain's implementation of these uncertainty computations. Acetylcholine signals expected uncertainty, coming from known unreliability of predictive cues within a context. Norepinephrine signals unexpected uncertainty, as when unsignaled context switches produce strongly unexpected observations. These uncertainty signals interact to enable optimal inference and learning in noisy and changeable environments. This formulation is consistent with a wealth of physiological, pharmacological, and behavioral data implicating acetylcholine and norepinephrine in specific aspects of a range of cognitive processes. Moreover, the model suggests a class of attentional cueing tasks that involve both neuromodulators and shows how their interactions may be part-antagonistic, part-synergistic.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acetylcholine / metabolism
  • Acetylcholine / pharmacology
  • Algorithms
  • Animals
  • Attention / drug effects
  • Attention / physiology*
  • Bayes Theorem
  • Computer Simulation
  • Dose-Response Relationship, Drug
  • Generalization, Psychological / drug effects
  • Generalization, Psychological / physiology
  • Humans
  • Learning / drug effects
  • Learning / physiology
  • Likelihood Functions*
  • Maze Learning / drug effects
  • Maze Learning / physiology
  • Models, Neurological*
  • Muscarinic Antagonists / pharmacology
  • Nicotine / pharmacology
  • Nicotinic Agonists / pharmacology
  • Norepinephrine / metabolism
  • Norepinephrine / pharmacology
  • Rats
  • Scopolamine / pharmacology
  • Signal Detection, Psychological*
  • Time Factors
  • Uncertainty*


  • Muscarinic Antagonists
  • Nicotinic Agonists
  • Nicotine
  • Scopolamine
  • Acetylcholine
  • Norepinephrine