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A circuit mechanism for irrationalities in decision-making and NMDA receptor hypofunction: behaviour, computational modelling, and pharmacology

View ORCID ProfileSean E. Cavanagh, Norman H. Lam, View ORCID ProfileJohn D. Murray, View ORCID ProfileLaurence T. Hunt, View ORCID ProfileSteven W. Kennerley
doi: https://doi.org/10.1101/826214
Sean E. Cavanagh
Department of Clinical and Movement Neurosciences, University College London, London, WC1N 3BG, UK
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Norman H. Lam
Department of Physics, Yale University, New Haven, CT 06510, USA
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John D. Murray
Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06510, USA
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  • For correspondence: john.murray@yale.edu laurence.hunt@psych.ox.ac.uk s.kennerley@ucl.ac.uk
Laurence T. Hunt
Department of Clinical and Movement Neurosciences, University College London, London, WC1N 3BG, UKWellcome Trust Centre for Neuroimaging, University College London, London, WC1N 3BG, UKMax Planck-UCL Centre for Computational Psychiatry and Aging, University College London, London, UKWellcome Centre for Integrative Neuroimaging, Department of Psychiatry, University of Oxford, Oxford, UK
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  • For correspondence: john.murray@yale.edu laurence.hunt@psych.ox.ac.uk s.kennerley@ucl.ac.uk
Steven W. Kennerley
Department of Clinical and Movement Neurosciences, University College London, London, WC1N 3BG, UK
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  • For correspondence: john.murray@yale.edu laurence.hunt@psych.ox.ac.uk s.kennerley@ucl.ac.uk
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Abstract

Decision-making biases can be systematic features of normal behaviour, or deficits underlying neuropsychiatric symptoms. We used behavioural psychophysics, spiking-circuit modelling and pharmacological manipulations to explore decision-making biases in health and disease. Monkeys performed an evidence integration task in which they 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 neural mechanism for this behaviour. Because NMDA receptor (NMDA-R) hypofunction is a leading hypothesis for neuropathology in schizophrenia, we simulated behavioural effects of NMDA-R hypofunction onto either excitatory or inhibitory neurons in the model. These were tested experimentally using the NMDA-R antagonist ketamine, yielding changes in decision-making consistent with lowered cortical excitation/inhibition balance from NMDA-R hypofunction 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.

Significance People can make apparently irrational decisions because of underlying features in their decision circuitry. Deficits in the same neural circuits may also underlie debilitating cognitive symptoms of neuropsychiatric patients. Here, we reveal a neural circuit mechanism explaining an irrationality frequently observed in healthy humans making binary choices – the pro-variance bias. Our circuit model could be perturbed by introducing deficits in either excitatory or inhibitory neuron function. These two perturbations made specific, dissociable predictions for the types of irrational decisionmaking behaviour produced. We used the NMDA-R antagonist ketamine, an experimental model for schizophrenia, to test if these predictions were relevant to neuropsychiatric pathophysiology. The results were consistent with impaired excitatory neuron function, providing important new insights into the pathophysiology of schizophrenia.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted October 31, 2019.
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A circuit mechanism for irrationalities in decision-making and NMDA receptor hypofunction: behaviour, computational modelling, and pharmacology
Sean E. Cavanagh, Norman H. Lam, John D. Murray, Laurence T. Hunt, Steven W. Kennerley
bioRxiv 826214; doi: https://doi.org/10.1101/826214
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A circuit mechanism for irrationalities in decision-making and NMDA receptor hypofunction: behaviour, computational modelling, and pharmacology
Sean E. Cavanagh, Norman H. Lam, John D. Murray, Laurence T. Hunt, Steven W. Kennerley
bioRxiv 826214; doi: https://doi.org/10.1101/826214

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