Stress-Induced Executive Dysfunction in GDNF-Deficient Mice, A Mouse Model of Parkinsonism.
Stress-Induced Executive Dysfunction in GDNF-Deficient Mice, A Mouse Model of Parkinsonism.
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DOI：
10.3389/fnbeh.2016.00114
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发表时间：
2016
影响因子：
3
通讯作者：
Buhusi CV
中科院分区：
文献类型：
--
作者：
Buhusi M;Olsen K;Yang BZ;Buhusi CV
对压力的适应不良反应与决策不当、冲动和延迟奖励的折扣有关。慢性不可预测压力（CUS）会改变多巴胺能功能，重塑参与决策的关键区域的多巴胺能回路，并损害前额皮质依赖性反应抑制和工作记忆。胶质源性神经营养因子 (GDNF) 对于调节基底神经节中多巴胺 (DA) 的释放以及多巴胺能神经元的生存至关重要； GDNF 缺陷小鼠被认为是衰老相关帕金森症的动物模型。最近，纹状体中 GDNF 的表达与压力恢复能力有关。在这里，我们研究了 CUS 对 GDNF 杂合子 (HET) 小鼠及其野生型同窝对照 (WT) 小鼠决策的影响。在 CUS 之前，未发现基因型之间的时间贴现 (TD) 存在差异。然而，在 CUS GDNF HET 小鼠中，GDNF 水平部分降低，显示出冲动选择增加，表现为 TD 范式中较大后期 (LL) 选择百分比的减少以及 TD 曲线下面积的减少。此外，应激的 GDNF HET 小鼠（而非其 WT 对照组）表现出眶额皮质 (OFC)、伏隔核 (NA) 核心和 NA 壳中神经元激活（cFos 阳性神经元数量）减少，表明对应激的适应不良反应。有趣的是，TD 曲线下面积与 NA 核心和 NA 壳中的 cFos 激活呈正相关，但与眶额活动无关。这些结果进一步证明了 OFC、NA 核心和 NA 壳在冲动选择中的不同参与，并将 GDNF 缺陷小鼠确定为压力相关执行功能障碍的双重打击（基因 × 环境）模型，特别是与药物滥用和帕金森病 (PD) 有关。
Maladaptive reactivity to stress is linked to improper decision making, impulsivity, and discounting of delayed rewards. Chronic unpredictable stress (CUS) alters dopaminergic function, re-shapes dopaminergic circuits in key areas involved in decision making, and impairs prefrontal-cortex dependent response inhibition and working memory. Glial-derived neurotrophic factor (GDNF) is essential for regulating dopamine (DA) release in the basal ganglia and for the survival of dopaminergic neurons; GDNF-deficient mice are considered an animal model for aging-related Parkinsonism. Recently, GDNF expression in the striatum has been linked to resilience to stress. Here we investigated the effects of CUS on decision making in GDNF-heterozygous (HET) mice and their wild-type littermate controls (WT). Before CUS no differences in temporal discounting (TD) were found between genotypes. However, following CUS GDNF HET mice, having a partial reduction of GDNF levels, showed increased impulsive choice indexed by a reduction in percent Larger-Later (LL) choices in the TD paradigm, and a reduction in area under the TD curve. Moreover, stressed GDNF HET mice, but not their WT controls, showed decreased neuronal activation (number of cFos positive neurons) in the orbitofrontal cortex (OFC), nucleus accumbens (NA) core, and NA shell, suggestive of a maladaptive response to stress. Interestingly, area under the TD curve positively correlated with cFos activation in the NA core, and NA shell, but not with orbitofrontal activity. These results provide further evidence of the differential involvement of the OFC, NA core, and NA shell in impulsive choice, and identify GDNF-deficient mice as a double-hit (gene × environment) model of stress-related executive dysfunction, particularly relevant to substance abuse and Parkinson’s disease (PD).
影响因子：
2.8
作者：
Hubbard, Raymond D.;Martinez, Joan J.;Burdick, Jason A.;Winkelstein, Beth A.
通讯作者：
Winkelstein, Beth A.