Cited by 96Schizophrenia research and treatmentNeurotransmitter Receptor Influence on BehaviorNeural and Behavioral Psychology Studies

Cognitive and motivational deficits together with prefrontal oxidative stress in a mouse model for neuropsychiatric illness

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Johnson, Alexander W., Jaaro-Peled, Hanna, Shahani, Neelam, Sedlak, Thomas W., Zoubovsky, Sandra, Burruss, Daniel, Emiliani, Francesco, Sawa, Akira +1 more·2013·Proceedings of the National Academy of Sciences

Abstract

Guided by features of molecular, cellular, and circuit dysfunction affecting the prefrontal cortex in clinical investigations, we targeted prefrontal cortex in studies of a model for neuropsychiatric illness using transgenic mice expressing a putative dominant-negative disrupted in schizophrenia 1 (DN-DISC1). We detected marked augmentation of GAPDH–seven in absentia homolog Siah protein binding in the DISC1 mice, a major hallmark of a nuclear GAPDH cascade that is activated in response to oxidative stress. Furthermore, deficits were observed in well-defined tests for the cognitive control of adaptive behavior using reversal learning and reinforcer devaluation paradigms. These deficits occurred even though DN-DISC1 mice showed intact performance in simple associative learning and normal responses in consumption of reward. In an additional series of assessments, motivational functions also were impoverished in DN-DISC1 mice, including tests of the dynamic modulation of reward value by effortful action, progressive ratio performance, and social behavior. Augmentation of an oxidative stress-associated cascade (e.g., a nuclear GAPDH cascade) points to an underlying condition that may contribute to the profile of cognitive and motivational impairments in DN-DISC1 mice by affecting the functional integrity of the prefrontal cortex and dysfunction within its connected networks. As such, this model should be useful for further preclinical research and drug discovery efforts relevant to the burden of prefrontal dysfunction in neuropsychiatric illness.

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Authors
Johnson, A. W., Jaaro-Peled, H., Shahani, N., Sedlak, T. W., Zoubovsky, S., Burruss, D., Emiliani, F., Sawa, A., & Gallagher, M.
Affiliations
  • Michigan State University (US)
  • Departments of bPsychiatry and Behavioral Sciences, and
  • Johns Hopkins University (US)
Venue
Proceedings of the National Academy of Sciences
Published
2013-07-09
Volume
110
Issue
30
Pages
12462-12467
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
OpenAlex
W2008139571
Cited by
96
References
51
Citations by year
2026: 2 · 2025: 2 · 2024: 1 · 2023: 1 · 2022: 7 · 2021: 5 · 2020: 7 · 2019: 7 · 2018: 7 · 2017: 15 · 2016: 10 · 2015: 15 · 2014: 14 · 2013: 3
FWCI
9.95
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Brain and Behavior Research Foundation (MH-092443)
  • Johns Hopkins University (MH-94268)
  • Maryland Stem Cell Research Fund
  • National Institute of Mental Health (R21MH085226, 092443, MH084018, MH085226, RC1MH088753, MH‑94268, MH 092443, MH‑088753, P20MH084018, R01MH069853, P50MH094268, MH069853, R01MH092443)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK084415, R21DK084415)
  • National Institute of Neurological Disorders and Stroke (K08NS057824)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
Keywords
DISC1, prefrontal cortex, oxidative stress, cognitive impairment, motivational deficits, reversal learning, reinforcer devaluation, progressive ratio, social behavior, neuropsychiatric disorders, mouse model
MeSH terms
Animals, Mental Disorders, Cognition Disorders, Mice, Inbred C57BL, Motivation, Social Behavior, Prefrontal Cortex, Oxidative Stress, Mice

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