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Targeted effects of ketamine on perceptual expectation during mediated learning in rats

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Abstract

Rationale

While neural correlates of hallucinations are known, the mechanisms have remained elusive. Mechanistic insight is more practicable in animal models, in which causal relationships can be established. Recent work developing animal models of hallucination susceptibility has focused on the genesis of perceptual expectations and perceptual decision-making. Both processes are encompassed within mediated learning, which involves inducing a strong perceptual expectation via associative learning, retrieving that memory representation, and deciding whether this internally generated percept is predictive of an external outcome. Mediated learning in rodents is sensitive to many psychotomimetic manipulations. However, we do not know if these manipulations selectively alter learning of perceptual expectations versus their retrieval because of their presence throughout all task phases.

Objectives

Here, we used mediated learning to study the targeted effect of a psychotomimetic agent on the retrieval of perceptual expectation.

Methods

We administered (R,S)-ketamine to rats selectively during the devaluation phase of a mediated learning task, when the representation of the expected cue is retrieved, to test the hypothesis that internally generated perceptual experiences underlie this altered mediated learning.

Results

We found that ketamine increased only mediated learning at a moderate dose in rats, but impaired direct learning at the high dose.

Conclusions

These results suggest that ketamine can augment retrieval of perceptual expectations and thus this may be how it induces hallucination-like experiences in humans. More broadly, mediated learning may unite the conditioning, perceptual decision-making, and even reality monitoring accounts of psychosis in a manner that translates across species.

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Notes

  1. These differences include the following: (1) In the associative phase of the mediated learning paradigm, the cues are either presented simultaneously or in the opposite order as used in sensory preconditioning paradigms, thus changing their predictive relationship, and, (2) in sensory preconditioning paradigms, the cues used in the associative phase are motivationally neutral and often used to study how neutral associations can form, whereas mediated learning is focused on how this association formed in the associative phase (which may or may not be neutral) can mediate subsequent learning.

References

  • Abdallah CG, Sanacora G, Duman RS, Krystal JH (2015) Ketamine and rapid-acting antidepressants: a window into a new neurobiology for mood disorder therapeutics. Annu Rev Med 66:509–523

    Article  CAS  PubMed  Google Scholar 

  • Aguado L, Antonio AS, Pérez L, Gómez VR, J, (1994) Effects of the NMDA receptor antagonist ketamine on flavor memory: conditioned aversion, latent inhibition, and habituation of neophobia. Behav Neural Biol 61:271–281

    Article  CAS  PubMed  Google Scholar 

  • Bainbridge KE, Byrd-Clark D, Leopold D (2018) Factors associated with phantom odor perception among US adults findings from the National Health and Nutrition Examination Survey. JAMA Otolaryngol head neck Surg 144:807–814

    Article  PubMed  PubMed Central  Google Scholar 

  • Barron HC, Reeve HM, Koolschijn RS, Perestenko PV, Shpektor A, Nili H, Rothaermel R, Campo-Urriza N, O’Reilly JX, Bannerman DM, Behrens TEJ, Dupret D (2020) Neuronal computation underlying inferential reasoning in humans and mice. Cell 183:228-243.e21

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bates D, Mächler M, Bolker B, Walker S (2015) Fitting linear mixed-effects models using lme4. J Stat Softw 67:1–48

    Article  CAS  Google Scholar 

  • Beck K, Borgan HG, Ginestet F, McCutcheon C, Brugger R, Driesen S, Ranganathan N, MD’Souza DC, Taylor M, Krystal JH, Howes OD (2020) Association of ketamine with psychiatric symptoms and implications for its therapeutic use and for understanding schizophrenia: a systematic review and meta-analysis. JAMA Netw Open 3:e204693–e204693

    Article  PubMed  PubMed Central  Google Scholar 

  • Bentall RP, Baker GA, Havers S (1991) Reality monitoring and psychotic hallucinations. Br J Clin Psychol 30:213–222

    Article  CAS  PubMed  Google Scholar 

  • Busquets-Garcia A, Soria-Gómez E, Redon B, Mackenbach Y, Vallée M, Chaouloff F, Varilh M, Ferreira G, Piazza PV, Marsicano G (2017) Pregnenolone blocks cannabinoid-induced acute psychotic-like states in mice. Mol Psychiatry 22:1594–1603

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Canetta S, Kellendonk C (2018) Can we use mice to study schizophrenia? Philos Trans R Soc Lond B Biol Sci 373:20170032

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Cannon DS, Berman RF, Baker TB, Atkins CA (1975) Effect of preconditioning unconditioned stimulus experience on learned taste aversions. J Exp Psychol Anim Behav Process 1:270–284

    Article  CAS  PubMed  Google Scholar 

  • Corlett PR, Cambridge V, Gardner JM, Piggot JS, Turner DC, Everitt JC, Arana FS, Morgan HL, Milton AL, Lee JL, Aitken MR, Dickinson A, Everitt BJ, Absalom AR, Adapa R, Subramanian N, Taylor JR, Krystal JH, Fletcher PC (2013) Ketamine effects on memory reconsolidation favor a learning model of delusions. PLoS One 8:e65088

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Corlett PR, Horga G, Fletcher PC, Alderson-Day B, Schmack K, Powers AR (2019) Hallucinations and strong priors. Trends Cogn Sci 23:114–127

    Article  PubMed  Google Scholar 

  • Cribari-Neto F, Zeileis A (2010) Beta regression in R. J Stat Softw 34:1–24

    Article  Google Scholar 

  • Domjan M, Best MR (1977) Paradoxical effects of proximal unconditioned stimulus preexposure: interference with and conditioning of a taste aversion. J Exp Psychol Anim Behav Process 3:310–321

    Article  CAS  PubMed  Google Scholar 

  • Duncan GE, Leipzig JN, Mailman RB, Lieberman JA (1998) Differential effects of clozapine and haloperidol on ketamine-induced brain metabolic activation. Brain Res 812:65–75

    Article  CAS  PubMed  Google Scholar 

  • Dwyer DM (2018) Associations and hallucinations in mice and men. Learn Behav 46:223–224

    Article  PubMed  Google Scholar 

  • Ferrari S, Cribari-Neto F (2004) Beta regression for modelling rates and proportions. J Appl Stat 31:799–815

    Article  Google Scholar 

  • Fleming LM, Javitt DC, Carter CS, Kantrowitz JT, Girgis RR, Kegeles LS, Ragland JD, Maddock RJ, Lesh TA, Tanase C, Robinson J, Potter WZ, Carlson M, Wall MM, Choo TH, Grinband J, Lieberman J, Krystal JH, Corlett PR (2019) A multicenter study of ketamine effects on functional connectivity: large scale network relationships, hubs and symptom mechanisms. Neuroimage Clin 22:101739

    Article  PubMed  PubMed Central  Google Scholar 

  • Fry BR, Russell N, Gifford R, Robles CF, Manning CE, Sawa A, Niwa M, Johnson AW (2020) Assessing reality testing in mice through dopamine-dependent associatively evoked processing of absent gustatory stimuli. Schizophr Bull 46:54–67

    Article  PubMed  Google Scholar 

  • Halberstadt AL, Geyer MA (2018) Effect of hallucinogens on unconditioned behavior. Curr Top Behav Neurosci 36:159–199

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Holland P (1998) Amount of training affects associatively-activated event representation. Neuropharmacology 37:461–469

    Article  CAS  PubMed  Google Scholar 

  • Holland PC (1981) Acquisition of representation-mediated conditioned food aversions. Learn Motiv 12:1–18

    Article  Google Scholar 

  • Holmes NM Wong FS Bouchekioua Y Westbrook RF 2021 Not “either-or” but “which-when”: a review of the evidence for integration in sensory preconditioning. Neurosci Biobehav Rev

  • Homayoun H, Stefani MR, Adams BW, Tamagan GD, Moghaddam B (2004) Functional interaction between NMDA and mGlu5 receptors: effects on working memory, Instrumental learning, motor behaviors, and dopamine release. Neuropsychopharmacology 29:1259–1269

    Article  CAS  PubMed  Google Scholar 

  • Honsberger MJ, Taylor JR, Corlett PR (2015) Memories reactivated under ketamine are subsequently stronger: a potential pre-clinical behavioral model of psychosis. Schizophr Res 164:227–233

    Article  PubMed  PubMed Central  Google Scholar 

  • Ionescu DF, Felicione JM, Gosai A, Cusin C, Shin P, Shapero BG, Deckersbach T (2018) Ketamine-associated brain changes: a review of the neuroimaging literature. Harv Rev Psychiatry 26:320–339

    Article  PubMed  PubMed Central  Google Scholar 

  • Jardri R, Pouchet A, Pins D, Thomas P (2011) Cortical activations during auditory verbal hallucinations in schizophrenia: a coordinate-based meta-analysis. Am J Psychiatry 168:73–81

    Article  PubMed  Google Scholar 

  • Javitt DC 2007 Glutamate and schizophrenia: phencyclidine N‐Methyl‐d‐aspartate receptors, and dopamine–glutamate interactions international review of neurobiology. Academic Press, pp 69–108

  • Kafadar E, Mittal VA, Strauss GP, Chapman HC, Ellman LM, Bansal S, Gold JM, Alderson-Day B, Evans S, Moffatt J, Silverstein SM, Walker EF, Woods SW, Corlett PR, Powers AR (2020) Modeling perception and behavior in individuals at clinical high risk for psychosis: support for the predictive processing framework. Schizophr Res 226:167–175

    Article  PubMed  PubMed Central  Google Scholar 

  • Kerfoot EC, Agarwal I, Lee HJ, Holland PC (2007) Control of appetitive and aversive taste-reactivity responses by an auditory conditioned stimulus in a devaluation task: a FOS and behavioral analysis. Learn Mem 14:581–589

    Article  PubMed  PubMed Central  Google Scholar 

  • Kim HJ, Koh HY (2016) Impaired reality testing in mice lacking phospholipase Cβ1 observed by persistent representation-mediated taste aversion. PLoS One 11:e0146376

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Koh MT, Ahrens PS, Gallagher M (2018) A greater tendency for representation mediated learning in a ketamine mouse model of schizophrenia. Behav Neurosci 132:106–113

    Article  PubMed  PubMed Central  Google Scholar 

  • Koh MT, Gallagher M (2020) Using internal memory representations in associative learning to study hallucination-like phenomenon. Neurobiol learning memory 175:107319

    Article  CAS  Google Scholar 

  • Kopala L, Good K, Honer W (1994) Olfactory hallucinations and olfactory identification ability in patients with schizophrenia and other psychiatric disorders. Schizophr Res 12:205–211

    Article  CAS  PubMed  Google Scholar 

  • Lahti AC, Weiler MA, Tamara M, Parwani A, Tamminga CA (2001) Effects of ketamine in normal and schizophrenic volunteers. Neuropsychopharmacology 25:455–467

    Article  CAS  PubMed  Google Scholar 

  • Lee G, Zhou Y (2019) NMDAR hypofunction animal models of schizophrenia. Front Mol Neurosci 12:185–185

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Leptourgos P, Bansal S, Dutterer J, Culbreth A, Powers A, Suthaharan P, Kenney J, Erickson M, Waltz J, Wijtenburg SA, Gaston F, Rowland LM, Gold J, Corlett P (2022) Relating glutamate, conditioned, and clinical hallucinations via 1H-MR spectroscopy. Schizophr Bull.

  • Leptourgos P, Fortier-Davy M, Carhart-Harris R, Corlett PR, Dupuis D, Halberstadt AL, Kometer M, Kozakova E, LarØi F, Noorani TN, Preller KH, Waters F, Zaytseva Y, Jardri R (2020) Hallucinations under psychedelics and in the schizophrenia spectrum: an interdisciplinary and multiscale comparison. Schizophr Bull 46:1396–1408

    Article  PubMed  PubMed Central  Google Scholar 

  • McDannald M, Schoenbaum G (2009) Toward a model of impaired reality testing in rats. Schizophr Bull 35:664–667

    Article  PubMed  PubMed Central  Google Scholar 

  • McDannald MA, Whitt JP, Calhoon GG, Piantadosi PT, Karlsson R-M, O’Donnell P, Schoenbaum G (2011) Impaired reality testing in an animal model of schizophrenia. Biol Psychiatry 70:1122–1126

    Article  PubMed  PubMed Central  Google Scholar 

  • Moghaddam B, Adams B, Verma A, Daly D (1997) Activation of glutamatergic neurotransmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex. J Neurosci 17:2921–2927

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moghaddam B, Krystal JH (2012) Capturing the angel in “angel dust”: twenty years of translational neuroscience studies of NMDA receptor antagonists in animals and humans. Schizophr Bull 38:942–949

    Article  PubMed  PubMed Central  Google Scholar 

  • Oberling P, Di Scala G, Sandner G (1996) Ketamine acts as an internal contextual stimulus that facilitates the retrieval of weak associations in conditioned taste aversion. Psychobiology 24:300–305

    Article  CAS  Google Scholar 

  • Powers AR 3rd, Gancsos MG, Finn ES, Morgan PT, Corlett PR (2015) Ketamine-induced hallucinations. Psychopathology 48:376–385

    Article  PubMed  Google Scholar 

  • Powers AR, Mathys C, Corlett PR (2017) Pavlovian conditioning-induced hallucinations result from overweighting of perceptual priors. Science 357:596–600

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Razoux F, Garcia R, Léna I (2007) Ketamine, at a dose that disrupts motor behavior and latent inhibition, enhances prefrontal cortex synaptic efficacy and glutamate release in the nucleus accumbens. Neuropsychopharmacology 32:719–727

    Article  CAS  PubMed  Google Scholar 

  • Robbins TW (2017) Animal models of hallucinations observed through the modern lens. Schizophr Bull 43:24–26

    Article  CAS  PubMed  Google Scholar 

  • Saddoris MP, Holland PC, Gallagher M (2009) Associatively learned representations of taste outcomes activate taste-encoding neural ensembles in gustatory cortex. J Neurosci 29:15386–15396

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schmack K, Bosc M, Ott T, Sturgill JF, Kepecs A 2021 Striatal dopamine mediates hallucination-like perception in mice. Science 372

  • Slotnick BM, Westbrook F, Darling FMC (1997) What the rat’s nose tells the rat’s mouth: long delay aversion conditioning with aqueous odors and potentiation of taste by odors. Anim Learn Behav 25:357–369

    Article  Google Scholar 

  • Smithson M, Verkuilen J (2006) A better lemon squeezer? Maximum-likelihood regression with beta-distributed dependent variables. Psychol Methods 11(1):54–71

    Article  PubMed  Google Scholar 

  • Team R (2016) RStudio: integrated development for R. RStudio Inc, Boston, MA

    Google Scholar 

  • Valle AL, Rd Pérez L (1997) The NMDA-receptor antagonist ketamine as an unconditioned stimulus in taste aversion learning. Neurobiol Learn Mem 68:189–196

    Article  PubMed  Google Scholar 

  • van den Buuse M (2010) Modeling the positive symptoms of schizophrenia in genetically modified mice: pharmacology and methodology aspects. Schizophr Bull 36:246–270

    Article  PubMed  Google Scholar 

  • Wang F, Howard JD, Voss JL, Schoenbaum G, Kahnt T (2020) Targeted stimulation of an orbitofrontal network disrupts decisions based on inferred, not experienced outcomes. J Neurosci 40:8726–8733

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ward-Robinson G, Hall J (1998) Backward sensory preconditioning when reinforcement is delayed. Q J Exp Psychol Section B 51:349–362

    Article  Google Scholar 

  • Ward-Robinson J, Hall G (1996) Backward sensory preconditioning. J Exp Psychol Anim Behav Process 22:395

    Article  Google Scholar 

  • Wimmer GE, Shohamy D (2012) Preference by association: how memory mechanisms in the hippocampus bias decisions. Science 338:270–273

    Article  CAS  PubMed  Google Scholar 

  • Wong FS, Westbrook RF, Holmes NM 2019 ‘Online’ integration of sensory and fear memories in the rat medial temporal lobe. eLife 8 e47085

  • Wu JL, Haberman RP, Gallagher M, Koh MT (2020) Probing for conditioned hallucinations through neural activation in a ketamine mouse model of schizophrenia. Neurosci Bull 36:937–941

    Article  PubMed  PubMed Central  Google Scholar 

  • Xie R, Hong S, Ye Y, Wang X, Chen F, Yang L, Yan Y, Liao L (2020) Ketamine affects the expression of ErbB4 in the hippocampus and prefrontal cortex of rats. J Mol Neurosci 70:962–967

    Article  CAS  PubMed  Google Scholar 

  • Zeithamova D, Dominick AL, Preston AR (2012) Hippocampal and ventral medial prefrontal activation during retrieval-mediated learning supports novel inference. Neuron 75:168–179

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

LMF, SLT, PRC, and JRT contributed to study conception, design, and interpretation. LMF and F-JBJ performed the experiments. Data analysis was completed by LMF and F-JBJ, with guidance from SLT. Finally, LMF drafted the initial version of the manuscript and all authors provided revisions and feedback and approved the final version of the article for submission.

Funding

This work was supported by National Institute on Alcohol Abuse and Alcoholism (grant number: P50 AA12870 to JRT); National Institute on Drug Abuse (grant numbers: R01 DA043443, R01 DA041480 to JRT); National Institute of Mental Health (grant number R01 MH12887 to PRC); National Institute on Alcohol Abuse and Alcoholism (grant number: K99 AA029454 to SLT); and National Institute of Health (NIH) Training Grant (grant number: T32 NS41228 to LMF) funded by the Jointly Sponsored NIH Predoctoral Training Program in the Neurosciences. Additional support was provided by the State of Connecticut, Department of Mental Health and Addiction Services through its support of the Ribicoff Research Facilities and the Charles B.G. Murphy endowment fund (to JRT). The work described in this manuscript does not express the views of the Department of Mental Health and Addiction Services or the State of Connecticut. The views and opinions expressed are those of the authors.

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Authors and Affiliations

  1. Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA

    Leah M. Fleming, Frances-Julia B. Jaynes, Summer L. Thompson, Philip R. Corlett & Jane R. Taylor

  2. Interdepartmental Neuroscience Program, Yale University, New Haven, CT, USA

    Leah M. Fleming

  3. Department of Psychology, University of New Haven, New Haven, CT, USA

    Frances-Julia B. Jaynes

  4. Department of Psychiatry, University of Connecticut Health, Farmington, CT, USA

    Frances-Julia B. Jaynes

  5. Department of Psychology, Yale University, New Haven, CT, USA

    Philip R. Corlett & Jane R. Taylor

  6. Department of Neuroscience, Yale University, New Haven, CT, USA

    Jane R. Taylor

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  1. Leah M. Fleming
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Correspondence to Jane R. Taylor.

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Fleming, L.M., Jaynes, FJ.B., Thompson, S.L. et al. Targeted effects of ketamine on perceptual expectation during mediated learning in rats. Psychopharmacology 239, 2395–2405 (2022). https://doi.org/10.1007/s00213-022-06128-2

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