Cognitive and motivational deficits together with prefrontal oxidative stress in a mouse model for neuropsychiatric illness
Cognitive and motivational deficits together with prefrontal oxidative stress in a mouse model for neuropsychiatric illness
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DOI：
10.1073/pnas.1307925110
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发表时间：
2013-07-23
影响因子：
11.1
通讯作者：
Gallagher, Michela
中科院分区：
文献类型：
--
作者：
Johnson, Alexander W.;Jaaro-Peled, Hanna;Gallagher, Michela
在临床研究中，分子、细胞和电路功能障碍影响前额叶皮层的特征指导下，我们在神经精神疾病模型研究中使用表达精神分裂症1（DN-DISC 1）中假定显性阴性干扰的转基因小鼠，靶向前额叶皮层。我们检测到在DISC 1小鼠中GAPDH-7的缺席同源物Siah蛋白结合的显著增强，这是响应于氧化应激而激活的核GAPDH级联的主要标志。此外，赤字被观察到在定义明确的测试的认知控制的适应性行为，使用逆转学习和更好的贬值范式。即使DN-DISC 1小鼠在简单的联想学习中表现出完整的表现，在奖励消费中表现出正常的反应，这些缺陷也会发生。在另外一系列的评估中，DN-DISC 1小鼠的动机功能也被削弱，包括通过努力行动、渐进比率表现和社会行为对奖励价值的动态调节的测试。氧化应激相关级联反应的增强（例如，一种核GAPDH级联）指出了一种潜在的状况，该状况可能通过影响前额皮质的功能完整性和其连接网络内的功能障碍而导致DN-DISC 1小鼠的认知和动机障碍的概况。因此，这个模型应该是有用的，进一步的临床前研究和药物发现的努力有关的神经精神疾病的前额叶功能障碍的负担。
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.