Functional magnetic resonance imaging in awake transgenic fragile X rats: evidence of dysregulation in reward processing in the mesolimbic/habenular neural circuit.
Functional magnetic resonance imaging in awake transgenic fragile X rats: evidence of dysregulation in reward processing in the mesolimbic/habenular neural circuit.
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DOI：
10.1038/tp.2016.15
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发表时间：
2016-03-22
影响因子：
6.8
通讯作者：
Ferris CF
中科院分区：
文献类型：
--
作者：
Kenkel WM;Yee JR;Moore K;Madularu D;Kulkarni P;Gamber K;Nedelman M;Ferris CF
焦虑和社交缺陷（通常涉及沟通障碍）是脆性 X 综合征的基本临床特征。越来越多的证据表明，奖励处理的失调是许多精神疾病中观察到的社交缺陷的一个促成因素。因此，我们假设转基因脆性 X 智力低下 1 基因 (fmr1) KO (FX) 大鼠会表现出奖励处理的改变。为此，对清醒的对照组和 FX 大鼠进行成像，以观察杏仁气味响应的血氧水平依赖性 (BOLD) 信号强度的变化，杏仁气味是引发先天奖励反应的刺激。受试者对这种进化上保守的刺激是“天真”的。由此产生的大脑活动变化被记录到三维分段、带注释的大鼠图谱上，描绘了 171 个大脑区域。野生型 (WT) 和 FX 大鼠均表现出对有益的杏仁气味的强烈大脑激活，尽管 FX 大鼠表现出改变的时间模式，并且往往具有更多数量的体素与基线相比出现负 BOLD 信号变化。这种更大的负面 BOLD 模式在帕佩兹回路中尤其明显，该回路对情绪处理和中脑边缘/缰核奖励回路至关重要。 WT大鼠在乳头上区显示出更大的正BOLD反应，而FX大鼠在背外侧纹状体中显示出更大的正BOLD反应，并且在压后皮质、伏隔核和外侧视前区显示出更大的负BOLD反应。当在自由行为的气味研究范式中进行测试时，FX 大鼠未能表现出对 WT 大鼠典型的杏仁气味的偏好。然而，当出现社交气味时，FX 大鼠表现出与 WT 相似的调查特征。这些数据表明 FX 表型中这种高度显着的新气味的处理过程发生了改变，并进一步支持了这样的观点：大脑中奖励系统的改变可能会导致脆性 X 综合征症状。
Anxiety and social deficits, often involving communication impairment, are fundamental clinical features of fragile X syndrome. There is growing evidence that dysregulation in reward processing is a contributing factor to the social deficits observed in many psychiatric disorders. Hence, we hypothesized that transgenic fragile X mental retardation 1 gene (fmr1) KO (FX) rats would display alterations in reward processing. To this end, awake control and FX rats were imaged for changes in blood oxygen level dependent (BOLD) signal intensity in response to the odor of almond, a stimulus to elicit the innate reward response. Subjects were ‘odor naive' to this evolutionarily conserved stimulus. The resulting changes in brain activity were registered to a three-dimensional segmented, annotated rat atlas delineating 171 brain regions. Both wild-type (WT) and FX rats showed robust brain activation to a rewarding almond odor, though FX rats showed an altered temporal pattern and tended to have a higher number of voxels with negative BOLD signal change from baseline. This pattern of greater negative BOLD was especially apparent in the Papez circuit, critical to emotional processing and the mesolimbic/habenular reward circuit. WT rats showed greater positive BOLD response in the supramammillary area, whereas FX rats showed greater positive BOLD response in the dorsal lateral striatum, and greater negative BOLD response in the retrosplenial cortices, the core of the accumbens and the lateral preoptic area. When tested in a freely behaving odor-investigation paradigm, FX rats failed to show the preference for almond odor which typifies WT rats. However, FX rats showed investigation profiles similar to WT when presented with social odors. These data speak to an altered processing of this highly salient novel odor in the FX phenotype and lend further support to the notion that altered reward systems in the brain may contribute to fragile X syndrome symptomology.