TY - JOUR
T1 - Serotonin depletion impairs both Pavlovian and instrumental reversal learning in healthy humans
AU - Kanen, Jonathan W.
AU - Apergis-Schoute, Annemieke M.
AU - Yellowlees, Robyn
AU - Arntz, Fréderique E.
AU - van der Flier, Febe E.
AU - Price, Annabel
AU - Cardinal, Rudolf N.
AU - Christmas, David M.
AU - Clark, Luke
AU - Sahakian, Barbara J.
AU - Crockett, Molly J.
AU - Robbins, Trevor W.
N1 - Funding Information:
TWR discloses consultancy with Cambridge Cognition, Greenfield Bioventures and Unilever; he receives research grants from Shionogi & Co and GlaxoSmithKline and royalties for CANTAB from Cambridge Cognition and editorial honoraria from Springer Verlag and Elsevier. BJS discloses consultancy with Cambridge Cognition, and Greenfield BioVentures, and receives royalties for CANTAB from Cambridge Cognition. RNC consults for Campden Instruments and receives royalties from Cambridge Enterprise, Routledge, and Cambridge University Press. LC is the Director of the Centre for Gambling Research at UBC, which is supported by funding from the Province of British Columbia and the British Columbia Lottery Corporation (BCLC), a Canadian Crown Corporation. JWK, MJC, FEA, RY, DMC, AMAS, and AP declare no competing interests.
Funding Information:
This research was funded in whole, or in part, by a Wellcome Trust Senior Investigator Award (Grant 104631/Z/14/Z) to TWR. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted paper version arising from this submission. BJS receives funding from the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (Mental Health Theme); the views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. RNC’s research is supported by the UK Medical Research Council (MC_PC_17213). JWK and MJC were supported by Gates Cambridge Scholarships. We would like to thank the staff at the NIHR/ Wellcome Trust Clinical Research Facility at Addenbrooke’s Hospital and at the Wolfson Brain Imaging Centre where the experiments were conducted, and Rachel Kyd of the Cambridge University Hospital Research & Development Office for assistance with study approval.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - Serotonin is involved in updating responses to changing environmental circumstances. Optimising behaviour to maximise reward and minimise punishment may require shifting strategies upon encountering new situations. Likewise, autonomic responses to threats are critical for survival yet must be modified as danger shifts from one source to another. Whilst numerous psychiatric disorders are characterised by behavioural and autonomic inflexibility, few studies have examined the contribution of serotonin in humans. We modelled both processes, respectively, in two independent experiments (N = 97). Experiment 1 assessed instrumental (stimulus-response-outcome) reversal learning whereby individuals learned through trial and error which action was most optimal for obtaining reward or avoiding punishment initially, and the contingencies subsequently reversed serially. Experiment 2 examined Pavlovian (stimulus-outcome) reversal learning assessed by the skin conductance response: one innately threatening stimulus predicted receipt of an uncomfortable electric shock and another did not; these contingencies swapped in a reversal phase. Upon depleting the serotonin precursor tryptophan—in a double-blind randomised placebo-controlled design—healthy volunteers showed impairments in updating both actions and autonomic responses to reflect changing contingencies. Reversal deficits in each domain, furthermore, were correlated with the extent of tryptophan depletion. Initial Pavlovian conditioning, moreover, which involved innately threatening stimuli, was potentiated by depletion. These results translate findings in experimental animals to humans and have implications for the neurochemical basis of cognitive inflexibility.
AB - Serotonin is involved in updating responses to changing environmental circumstances. Optimising behaviour to maximise reward and minimise punishment may require shifting strategies upon encountering new situations. Likewise, autonomic responses to threats are critical for survival yet must be modified as danger shifts from one source to another. Whilst numerous psychiatric disorders are characterised by behavioural and autonomic inflexibility, few studies have examined the contribution of serotonin in humans. We modelled both processes, respectively, in two independent experiments (N = 97). Experiment 1 assessed instrumental (stimulus-response-outcome) reversal learning whereby individuals learned through trial and error which action was most optimal for obtaining reward or avoiding punishment initially, and the contingencies subsequently reversed serially. Experiment 2 examined Pavlovian (stimulus-outcome) reversal learning assessed by the skin conductance response: one innately threatening stimulus predicted receipt of an uncomfortable electric shock and another did not; these contingencies swapped in a reversal phase. Upon depleting the serotonin precursor tryptophan—in a double-blind randomised placebo-controlled design—healthy volunteers showed impairments in updating both actions and autonomic responses to reflect changing contingencies. Reversal deficits in each domain, furthermore, were correlated with the extent of tryptophan depletion. Initial Pavlovian conditioning, moreover, which involved innately threatening stimuli, was potentiated by depletion. These results translate findings in experimental animals to humans and have implications for the neurochemical basis of cognitive inflexibility.
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U2 - 10.1038/s41380-021-01240-9
DO - 10.1038/s41380-021-01240-9
M3 - Article
C2 - 34429517
AN - SCOPUS:85113411388
SN - 1359-4184
VL - 26
SP - 7200
EP - 7210
JO - Molecular Psychiatry
JF - Molecular Psychiatry
IS - 12
ER -