More Is Less: A Disinhibited Prefrontal Cortex Impairs Cognitive Flexibility
Open accessAbstract
The prefrontal cortex (PFC) is critical for decision making, and it becomes dysfunctional in many neuropsychiatric disorders. Studies in schizophrenia patients and relevant animal models suggest loss of PFC inhibitory interneuron function. For instance, rats with a neonatal ventral hippocampal lesion (NVHL) show a deficient modulation of PFC interneurons by dopamine (DA). Whether the PFC becomes disinhibited in this model and alters decision making remains to be determined. Here, we recorded neural activity in the medial PFC of NVHL rats during a reward-discounting choice task that activated DA systems. Rats were trained to sample odors that instructed them to select one of two feeders that delivered unequal amounts of liquid. Putative pyramidal neurons in the PFC were hyperactive whereas task-related field potential oscillations were significantly reduced in NVHL rats, consistent with impaired interneuron activation by DA during odor sampling leading to disorganized processing. Cognitive flexibility was tested by examining response bias and errors after reversing reward outcomes. NVHL rats demonstrated impaired flexibility as they were less able to track changes in reward outcome and made more response errors than controls did. Reducing cortical excitability with the metabotropic glutamate receptor 2/3 agonist LY379268 (1 mg/kg, i.p.) improved behavioral flexibility in NVHL rats but not controls. Furthermore, D2 dopamine receptors were involved, as the antagonist eticlopride (0.02 mg/kg, i.p.) reduced the ability to switch only in control animals. We conclude that NVHL rats present PFC disinhibition, which affects neural information processing and the selection of appropriate behavioral responses.
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A reduction in PFC inhibition has previously been linked to impaired cognitive flexibility.
“A reduction in PFC inhibition has previously been linked to impaired cognitive flexibility (Gruber et al., 2010)”
From Social Play Behavior Is Critical for the Development of Prefrontal Inhibitory Synapses and Cognitive Flexibility in Rats (2022) · cites this paper as Gruber et al., 2010
In that study, NVHL rats showed deficits in reversal learning, a process that correlated with the increase in beta power in controls.
“In that study, NVHL rats showed deficits in reversal learning, a process that correlated with the increase in beta power in controls.”
From Adolescent Onset of Cortical Disinhibition in Schizophrenia: Insights From Animal Models (2011) · cites this paper as [72]
In NVHL rats, there is loss of transient increase in beta oscillations and excessive pyramidal cell firing during the decision instance of a choice task.
“In NVHL rats, we have recently shown loss of transient increase in beta oscillations and excessive pyramidal cell firing during the decision instance of a choice task.72”
From Adolescent Onset of Cortical Disinhibition in Schizophrenia: Insights From Animal Models (2011) · cites this paper as [72]
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Cites
The Rat Brain in Stereotaxic Coordinates
Paxinos, G., & Watson, C. (1983) · Elsevier eBooks · doi:10.1016/c2009-0-63235-9 · Cited by 28,585 · see citing works
Shrestha, S., & Offer, S. M. (2016) · Medical Epigenetics · doi:10.1159/000444713 · Cited by 8,949 · see citing works
AChE-stained horizontal sections of the rat brain in stereotaxic coordinates
Paxinos, G., WATSON, C. R. R., & Emson, P. C. (1980) · Journal of Neuroscience Methods · doi:10.1016/0165-0270(80)90021-7 · Cited by 4,497 · see citing works
Driving fast-spiking cells induces gamma rhythm and controls sensory responses
Cardin, J. A., Carlén, M., Meletis, K., Knoblich, U., Zhang, F., Deisseroth, K., Tsai, L.-H., & Moore, C. I. (2009) · Nature · doi:10.1038/nature08002 · Cited by 2,603 · see citing works
Cortical inhibitory neurons and schizophrenia
Lewis, D. A., Hashimoto, T., & Volk, D. W. (2005) · Nature Reviews Neuroscience · doi:10.1038/nrn1648 · Cited by 2,297 · see citing works
Effects of Different Brain Lesions on Card Sorting: The Role of the Frontal Lobes
MILNER, B. (1963) · Archives of Neurology · doi:10.1001/archneur.1963.00460070100010 · Cited by 2,217 · see citing works
Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence
Harrison, P. J., & Weinberger, D. R. (2005) · Molecular Psychiatry · doi:10.1038/sj.mp.4001558 · Cited by 2,020 · see citing works
GABAergic Interneurons Implications for Understanding Schizophrenia and Bipolar Disorder
Benes, F. (2001) · Neuropsychopharmacology · doi:10.1016/s0893-133x(01)00225-1 · Cited by 1,082 · see citing works
Choice, uncertainty and value in prefrontal and cingulate cortex
Rushworth, M. F. S., & Behrens, T. E. J. (2008) · Nature Neuroscience · doi:10.1038/nn2066 · Cited by 866 · see citing works
Physiological Dysfunction of the Dorsolateral Prefrontal Cortex in Schizophrenia Revisited
Callicott, J. H. (2000) · Cerebral Cortex · doi:10.1093/cercor/10.11.1078 · Cited by 810 · see citing works
Decision-making processes following damage to the prefrontal cortex
Manes, F., Sahakian, B., Clark, L., Rogers, R., Antoun, N., Aitken, M., & Robbins, T. (2002) · Brain · doi:10.1093/brain/awf049 · Cited by 799 · see citing works
A mechanism for generation of long-range synchronous fast oscillations in the cortex
Traub, R. D., Whittington, M. A., Stanford, I. M., & Jefferys, J. G. R. (1996) · Nature · doi:10.1038/383621a0 · Cited by 701 · see citing works
Lipska, B. K., Jaskiw, G. E., & Weinberger, D. R. (1993) · Neuropsychopharmacology · doi:10.1038/npp.1993.44 · Cited by 697 · see citing works
Abnormal neural synchrony in schizophrenia
Spencer, K. M., Nestor, P. G., Niznikiewicz, M. A., Salisbury, D. F., Shenton, M. E., & McCarley, R. W. (2003) · The Journal of Neuroscience · doi:10.1523/jneurosci.23-19-07407.2003 · Cited by 624 · see citing works
Roesch, M. R., Calu, D. J., & Schoenbaum, G. (2007) · Nature Neuroscience · doi:10.1038/nn2013 · Cited by 597 · see citing works
Self-citationKetamine-Induced Loss of Phenotype of Fast-Spiking Interneurons Is Mediated by NADPH-Oxidase
Behrens, M. M., Ali, S. S., Dao, D. N., Lucero, J., Shekhtman, G., Quick, K. L., & Dugan, L. L. (2007) · Science · doi:10.1126/science.1148045 · Cited by 585 · see citing works
Reward Processing in Schizophrenia: A Deficit in the Representation of Value
Gold, J. M., Waltz, J. A., Prentice, K. J., Morris, S. E., & Heerey, E. A. (2008) · Schizophrenia Bulletin · doi:10.1093/schbul/sbn068 · Cited by 521 · see citing works
Lodge, D. J., Behrens, M. M., & Grace, A. A. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.5419-08.2009 · Cited by 488 · see citing works
Hikida, T., Jaaro-Peled, H., Seshadri, S., Oishi, K., Hookway, C., Kong, S., Wu, D., Xue, R., Andradé, M., Tankou, S. K., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0704774104 · Cited by 417 · see citing works
Functional hypofrontality and working memory dysfunction in schizophrenia
Carter, C. S., Perlstein, W., Ganguli, R., Brar, J., Mintun, M., & Cohen, J. D. (1998) · American Journal of Psychiatry · doi:10.1176/ajp.155.9.1285 · Cited by 403 · see citing works
Traub, R. D., Kopell, N., Bibbig, A., Buhl, E. H., LeBeau, F. E. N., & Whittington, M. A. (2001) · Journal of Neuroscience · doi:10.1523/jneurosci.21-23-09478.2001 · Cited by 357 · see citing works
Dopamine Modulation of Prefrontal Cortical Interneurons Changes during Adolescence
Tseng, K.-Y., & O'Donnell, P. (2006) · Cerebral Cortex · doi:10.1093/cercor/bhl034 · Cited by 339 · see citing works
Self-citationA beta2-frequency (20-30 Hz) oscillation in nonsynaptic networks of somatosensory cortex
Roopun, A. K., Middleton, S. J., Cunningham, M. O., LeBeau, F. E. N., Bibbig, A., Whittington, M. A., & Traub, R. D. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0607443103 · Cited by 338 · see citing works
Top-Down Control of Motor Cortex Ensembles by Dorsomedial Prefrontal Cortex
Narayanan, N. S., & Laubach, M. (2006) · Neuron · doi:10.1016/j.neuron.2006.10.021 · Cited by 311 · see citing works
Encoding of Time-Discounted Rewards in Orbitofrontal Cortex Is Independent of Value Representation
Roesch, M. R., Taylor, A. R., & Schoenbaum, G. (2006) · Neuron · doi:10.1016/j.neuron.2006.06.027 · Cited by 297 · see citing works
Self-citationLewis, B. L. (2000) · Cerebral Cortex · doi:10.1093/cercor/10.12.1168 · Cited by 287 · see citing works
Arvesen, J. N. (1969) · The Annals of Mathematical Statistics · doi:10.1214/aoms/1177697287 · Cited by 286 · see citing works
Using animal models to test a neurodevelopmental hypothesis of schizophrenia
Lipska, B. K. (2004) · Journal of Psychiatry and Neuroscience · doi:10.1139/jpn.0429 · Cited by 248 · see citing works
Involvement of rodent prefrontal cortex subregions in strategy switching.
Ragozzino, M. E., Wilcox, C., Raso, M., & Kesner, R. P. (1999) · Behavioral Neuroscience · doi:10.1037//0735-7044.113.1.32 · Cited by 231 · see citing works
Flores, G., Alquicer, G., Gómez, A. B. S., Zaldivar, G. A., Stewart, J., Quirion, R., & Srivastava, L. K. (2005) · Neuroscience · doi:10.1016/j.neuroscience.2005.02.021 · Cited by 220 · see citing works
Neonatal Damage of the Ventral Hippocampus Impairs Working Memory in the Rat
Lipska, B. K. (2002) · Neuropsychopharmacology · doi:10.1016/s0893-133x(02)00282-8 · Cited by 211 · see citing works
Cognitive Effects of Neonatal Hippocampal Lesions in a Rat Model of Schizophrenia
Chambers, R. (1996) · Neuropsychopharmacology · doi:10.1016/s0893-133x(96)00132-7 · Cited by 210 · see citing works
Involvement of rodent prefrontal cortex subregions in strategy switching.
Ragozzino, M. E., Wilcox, C., Raso, M., et al. (1999) · Behavioral Neuroscience · doi:10.1037/0735-7044.113.1.32 · Cited by 201 · see citing works
Decision-Making Impairments in the Context of Intact Reward Sensitivity in Schizophrenia
Heerey, E. A., Bell-Warren, K. R., & Gold, J. M. (2008) · Biological Psychiatry · doi:10.1016/j.biopsych.2008.02.015 · Cited by 197 · see citing works
Sensory-Evoked Gamma Oscillations in Chronic Schizophrenia
Spencer, K. M., Niznikiewicz, M. A., Shenton, M. E., & McCarley, R. W. (2008) · Biological Psychiatry · doi:10.1016/j.biopsych.2007.10.017 · Cited by 182 · see citing works
O'Donnell, P. (2002) · Cerebral Cortex · doi:10.1093/cercor/12.9.975 · Cited by 172 · see citing works
Self-citationThe performance of young schizophrenics and young normals on the Wisconsin Card Sorting Test.
Fey, E. T. (1951) · Journal of Consulting Psychology · doi:10.1037/h0061659 · Cited by 146 · see citing works
Tseng, K. Y., Lewis, B. L., Hashimoto, T., Sesack, S. R., Kloc, M., Lewis, D. A., & O'Donnell, P. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.4166-08.2008 · Cited by 144 · see citing works
Self-citationHomayoun, H., Jackson, M., & Moghaddam, B. (2005) · Journal of Neurophysiology · doi:10.1152/jn.00875.2004 · Cited by 137 · see citing works
Szabadics, J., Lörincz, A., & Tamás, G. (2001) · Journal of Neuroscience · doi:10.1523/jneurosci.21-15-05824.2001 · Cited by 134 · see citing works
Tseng, K.-Y., Lewis, B. L., Lipska, B. K., & O’Donnell, P. (2007) · Biological Psychiatry · doi:10.1016/j.biopsych.2006.10.012 · Cited by 132 · see citing works
Self-citationLipska, B. K., Lerman, D. N., Khaing, Z. Z., Weickert, C. S., & Weinberger, D. R. (2003) · European Journal of Neuroscience · doi:10.1046/j.1460-9568.2003.02738.x · Cited by 104 · see citing works
Prefrontal Cortex Lesions Disrupt the Contextual Control of Response Conflict
Haddon, J. E., & Killcross, S. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.3243-05.2006 · Cited by 101 · see citing works
Cabungcal, J.-H., Nicolas, D., Kraftsik, R., Cuénod, M., Do, K. Q., & Hornung, J.-P. (2006) · Neurobiology of Disease · doi:10.1016/j.nbd.2006.01.003 · Cited by 96 · see citing works
Rorick‐Kehn, L. M., Johnson, B. G., Burkey, J., Wright, R. A., Calligaro, D. O., Marek, G. J., Nisenbaum, E. S., Catlow, J. T., Kingston, A. E., Giera, D. D., et al. (2007) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.106.110809 · Cited by 93 · see citing works
Prefrontal Electrophysiologic “Noise” and Catechol-O-Methyltransferase Genotype in Schizophrenia
Winterer, G., Egan, M. F., Kolachana, B. S., Goldberg, T. E., Coppola, R., & Weinberger, D. R. (2006) · Biological Psychiatry · doi:10.1016/j.biopsych.2006.03.023 · Cited by 69 · see citing works
Neonatal ventral hippocampal lesions disrupt set-shifting ability in adult rats
Brady, A. M. (2009) · Behavioural Brain Research · doi:10.1016/j.bbr.2009.07.025 · Cited by 34 · see citing works
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Euston, D. R., Gruber, A. J., & McNaughton, B. L. (2012) · Neuron · doi:10.1016/j.neuron.2012.12.002 · Cited by 1,541 · see citing works
Self-citationAdolescence as a neurobiological critical period for the development of higher-order cognition
Larsen, B., & Luna, B. (2018) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2018.09.005 · Cited by 853 · see citing works
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Jardri, R., & Denève, S. (2013) · Brain · doi:10.1093/brain/awt257 · Cited by 201 · see citing works
Adolescent Onset of Cortical Disinhibition in Schizophrenia: Insights From Animal Models
O'Donnell, P. (2011) · Schizophrenia Bulletin · doi:10.1093/schbul/sbr028 · Cited by 145 · see citing works
Self-citationEarly Cognitive Experience Prevents Adult Deficits in a Neurodevelopmental Schizophrenia Model
Lee, H., Dvorak, D., Kao, H.-Y., Duffy, Á. M., Scharfman, H. E., & Fenton, A. A. (2012) · Neuron · doi:10.1016/j.neuron.2012.06.016 · Cited by 122 · see citing works
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Lewis, D. A., Fish, K. N., Arion, D., & Gonzalez-Burgos, G. (2011) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2011.05.013 · Cited by 87 · see citing works
Kougias, D. G., Sellinger, E. P., Willing, J., & Juraska, J. M. (2018) · The Journal of Neuroscience · doi:10.1523/jneurosci.0607-18.2018 · Cited by 72 · see citing works
Cass, D. K., Thomases, D. R., Caballero, A., & Tseng, K. Y. (2013) · Biological Psychiatry · doi:10.1016/j.biopsych.2013.02.021 · Cited by 63 · see citing works
Bijlsma, A., Omrani, A., Spoelder, M., Verharen, J. P. H., Bauer, L., Cornelis, C., de Zwart, B., van Dorland, R., Vanderschuren, L. J. M. J., & Wierenga, C. J. (2022) · The Journal of Neuroscience · doi:10.1523/jneurosci.0524-22.2022 · Cited by 54 · see citing works
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- Authors
- Gruber, A. J., Calhoon, G. G., Shusterman, I., Schoenbaum, G., Roesch, M. R., & O'Donnell, P.
- Affiliations
- University of Maryland, Baltimore (US)
- University of Maryland, College Park (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2010-12-15
- Volume
- 30
- Issue
- 50
- Pages
- 17102-17110
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3073623
- OpenAlex
- W1965655488
- Cited by
- 160
- References
- 47
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 4 · 2023: 5 · 2022: 6 · 2021: 10 · 2020: 15 · 2019: 3 · 2018: 8 · 2017: 11 · 2016: 16 · 2015: 15 · 2014: 13 · 2013: 13 · 2012: 16
- FWCI
- 6.33
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Eli Lilly and Company
- Fondation pour la Recherche Médicale
- National Institutes of Health (MH57683)
- National Institute on Aging (R01AG027097)
- National Institute of Mental Health (MH57683, R56MH057683, R01MH057683)
- National Institute on Drug Abuse (R01DA015718, K01DA021609)
- National Institute of General Medical Sciences (T34GM008663)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Keywords
- cognitive flexibility, medial prefrontal cortex, cortical excitability, mGluR2/3, dopamine D2 receptor, response bias, behavioral flexibility, schizophrenia model
- MeSH terms
- Action Potentials, Amino Acids, Animals, Behavior, Animal, Choice Behavior, Cognition, Disease Models, Animal, Male, Neural Inhibition, Salicylamides, Schizophrenic Psychology, Prefrontal Cortex, Pyramidal Cells, Dopamine Antagonists, Excitatory Amino Acid Agonists, Bridged Bicyclo Compounds, Heterocyclic, Rats, Long-Evans, Rats
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