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

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.

An assessment of olfaction and responses to novelty in three strains of mice.

In rodents, the initial exposure to a novel stimulus or environment typically induces exploration. After prolonged exposure the level of exploration decreases. Recently we developed an odor-based novelty detection paradigm that broadly screens for functions such as olfactory perception, olfactory driven exploration and habituation, and novelty preference and memory. The advantage of such a paradigm is that it exploits the innate olfactory abilities of mice. Here we studied three strains of mice C57BL/6 (C57), 129/SvImJ (129), and a hybrid cross of these two strains (F1 hybrids), all of which are commonly used in the generation of genetically modified mice. In the first phase of this task mice are permitted to explore the test environment in order to habituate to it. This is followed by a sample phase in which two identical odor cubes are introduced to the test environment and the mice are allowed to explore both odor cubes. Finally during the test phase one of the odor cues is replaced with a cube that contains a different novel odor, and the mice are again allowed to explore. Typically, mice will express a preference for the novel stimulus, or in this case the novel odor cube. We also separately assessed simple odor detection. Our results show that compared to the C57 mice, 129 and F1 mice showed reduced levels of exploration and odor driven novelty preference.