eprintid: 10111479 rev_number: 14 eprint_status: archive userid: 608 dir: disk0/10/11/14/79 datestamp: 2020-10-07 14:12:18 lastmod: 2021-09-20 22:37:25 status_changed: 2020-10-07 14:12:18 type: article metadata_visibility: show creators_name: Cavanagh, SE creators_name: Lam, NH creators_name: Murray, JD creators_name: Hunt, LT creators_name: Kennerley, SW title: A circuit mechanism for decision-making biases and NMDA receptor hypofunction ispublished: pub divisions: UCL divisions: B02 divisions: C07 divisions: D07 divisions: F84 keywords: NMDA receptor, decision-making, ketamine, network model, neuroscience, rhesus macaque, schizophrenia note: © 2020, Cavanagh et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. abstract: Decision-making biases can be features of normal behaviour, or deficits underlying neuropsychiatric symptoms. We used behavioural psychophysics, spiking-circuit modelling and pharmacological manipulations to explore decision-making biases during evidence integration. Monkeys showed a pro-variance bias (PVB): a preference to choose options with more variable evidence. The PVB was also present in a spiking circuit model, revealing a potential neural mechanism for this behaviour. To model possible effects of NMDA receptor (NMDA-R) antagonism on this behaviour, we simulated the effects of NMDA-R hypofunction onto either excitatory or inhibitory neurons in the model. These were then tested experimentally using the NMDA-R antagonist ketamine, a pharmacological model of schizophrenia. Ketamine yielded an increase in subjects' PVB, consistent with lowered cortical excitation/inhibition balance from NMDA-R hypofunction predominantly onto excitatory neurons. These results provide a circuit-level mechanism that bridges across explanatory scales, from the synaptic to the behavioural, in neuropsychiatric disorders where decision-making biases are prominent. date: 2020-09-29 date_type: published official_url: http://dx.doi.org/10.7554/eLife.53664 oa_status: green full_text_type: pub pmcid: PMC7524553 language: eng primo: open primo_central: open_green verified: verified_manual elements_id: 1816985 doi: 10.7554/eLife.53664 pii: 53664 lyricists_name: Kennerley, Steven lyricists_id: SWKEN38 actors_name: Flynn, Bernadette actors_id: BFFLY94 actors_role: owner full_text_status: public publication: eLife volume: 9 article_number: e53664 event_location: England issn: 2050-084X citation: Cavanagh, SE; Lam, NH; Murray, JD; Hunt, LT; Kennerley, SW; (2020) A circuit mechanism for decision-making biases and NMDA receptor hypofunction. eLife , 9 , Article e53664. 10.7554/eLife.53664 <https://doi.org/10.7554/eLife.53664>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/10111479/1/elife-53664-v2.pdf