title: Cognitive and motivational deficits together with prefrontal oxidative stress in a mouse model for neuropsychiatric illness.
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.
authors.affiliation: Department of Psychology, Michigan State University, East Lansing, MI 48824, USA.
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Johnson
authors.forename: Hanna
authors.initials: H
authors.lastname: Jaaro-Peled
authors.forename: Neelam
authors.initials: N
authors.lastname: Shahani
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Sedlak
authors.forename: Sandra
authors.initials: S
authors.lastname: Zoubovsky
authors.forename: Daniel
authors.initials: D
authors.lastname: Burruss
authors.forename: Francesco
authors.initials: F
authors.lastname: Emiliani
authors.forename: Akira
authors.initials: A
authors.lastname: Sawa
authors.forename: Michela
authors.initials: M
authors.lastname: Gallagher
mesh_terms: D000818:Animals; D003072:Cognition Disorders / Q000378:metabolism*; D001523:Mental Disorders / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009042:Motivation; D018384:Oxidative Stress; D017397:Prefrontal Cortex / Q000378:metabolism* / Q000473:pathology; D012919:Social Behavior
keywords: cognition; depression; orbitofrontal cortex