Pharmacological Fingerprints of Contextual Uncertainty

• DOI: 10.1371/journal.pbio.1002575
• Publication Date: 2016-11-15T18:59:41Z
• Authors: Louise Marshall; Christoph Mathys; Diane Ruge; Archy O. de Berker; Peter Dayan; Klaas E. Stephan; Sven Bestmann
• Keywords: Adult; 0301 basic medicine; QH301-705.5; Cholinergics; 610 Medicine & health; 1100 General Agricultural and Biological Sciences; Sensory perception; Drug interactions; 170 Ethics; 03 medical and health sciences; Neuropharmacology; 0302 clinical medicine; 1300 General Biochemistry, Genetics and Molecular Biology; 2400 General Immunology and Microbiology; Cholinergics ; Learning ; Body weight ; Drug interactions ; Dopaminergics ; Behavioral pharmacology ; Neuropharmacology ; Sensory perception; Learning; Humans; 10237 Institute of Biomedical Engineering; Biogenic Monoamines; Biology (General); BAYESIAN MODEL SELECTION; LOCUS-COERULEUS NEURONS; MEDIAL FRONTAL-CORTEX; HUMAN MOTOR CORTEX; PARKINSONS-DISEASE; SPATIAL ATTENTION; NORADRENERGIC SYSTEM; BASAL FOREBRAIN; CHOLINERGIC MODULATION; VISUOSPATIAL ATTENTION; Likelihood Functions; Neuromodulation; Uncertainty; 2800 General Neuroscience; Brain; Body weight; Models, Theoretical; Dopaminergics; Research Article

ISSN:1545-7885<br/>PLoS Biology, 14 (11)<br/>Successful interaction with the environment requires flexible updating of our beliefs about the world. By estimating the likelihood of future events, it is possible to prepare appropriate actions in advance and execute fast, accurate motor responses. According to theoretical proposals, agents track the variability arising from changing environments by computing various forms of uncertainty. Several neuromodulators have been linked to uncertainty signalling, but comprehensive empirical characterisation of their relative contributions to perceptual belief updating, and to the selection of motor responses, is lacking. Here we assess the roles of noradrenaline, acetylcholine, and dopamine within a single, unified computational framework of uncertainty. Using pharmacological interventions in a sample of 128 healthy human volunteers and a hierarchical Bayesian learning model, we characterise the influences of noradrenergic, cholinergic, and dopaminergic receptor antagonism on individual computations of uncertainty during a probabilistic serial reaction time task. We propose that noradrenaline influences learning of uncertain events arising from unexpected changes in the environment. In contrast, acetylcholine balances attribution of uncertainty to chance fluctuations within an environmental context, defined by a stable set of probabilistic associations, or to gross environmental violations following a contextual switch. Dopamine supports the use of uncertainty representations to engender fast, adaptive responses.<br/>ISSN:1544-9173<br/>