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

Alexander W. Johnson, Hanna Jaaro-Peled, Neelam Shahani, Thomas W. Sedlak, Sandra Zoubovsky, Daniel Burruss, Francesco Emiliani, Akira Sawa, Michela Gallagher

Research output: Contribution to journalArticlepeer-review

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 dominantnegative 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.

Original languageEnglish (US)
Pages (from-to)12462-12467
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number30
DOIs
StatePublished - Jul 23 2013

Keywords

  • Cognition
  • Depression
  • Orbitofrontal cortex

ASJC Scopus subject areas

  • General

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