Department of Clinical Neuroscience (CNS), Karolinska Institutet, Stockholm, Sweden.
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
Soc Cogn Affect Neurosci. 2017 Oct 1;12(10):1658-1667. doi: 10.1093/scan/nsx089.
Dopaminergic pathways play a crucial role in reward processing, and advanced age can modulate its efficiency. DARPP-32 controls dopaminergic function and is a chemical nexus of reward processing. In 61 younger (20-30 years) and older adults (54% ♀) (65-74 years), we examined how blood-oxygen-level dependent (BOLD) activation to emotional faces, vary over genotypes at three single nucleotide polymorphism (SNPs), coding for DARPP-32 (rs879606; rs907094; 3764352). We also assessed age-magnification of DARPP-32 effects on BOLD activation. We found that major homozygote G, T or A genotypes, with higher cortical expression of DARPP-32, higher dopamine receptor efficacy, and greater bias toward positive cues, had increased functional connectivity in cortical-subcortical circuits in response to happy faces, engaging the dorsal prefrontal cortex (DLPFC), fusiform gyrus (FG) and the midbrain (MB). Local BOLD response to happy faces in FG, and MB was age-dependent, so that older carriers of the major G, T or A alleles showed lesser activation than minor genotypes. These genetic variants of DARPP-32 did not modulate BOLD response to angry faces, or engagement of the inferior occipital gyrus, to happy or angry faces. Taken together our results lend support for a potential role of DARPP-32 genetic variants in neural response to potential reward triggering cues.
多巴胺能通路在奖励处理中起着至关重要的作用，而年龄的增长会影响其效率。DARPP-32 控制多巴胺能功能，是奖励处理的化学枢纽。在 61 名年轻（20-30 岁）和老年人（54%♀）（65-74 岁）中，我们研究了三种单核苷酸多态性（SNP）编码的 DARPP-32（rs879606；rs907094；3764352）的基因型如何影响情绪面孔的血氧水平依赖（BOLD）激活。我们还评估了 DARPP-32 对 BOLD 激活的年龄放大效应。我们发现，DARPP-32 皮质表达较高的主要纯合 GG、TT 或 AA 基因型，多巴胺受体效能较高，对正性线索的偏向较大，在对快乐面孔的反应中，大脑皮质下回路的功能连接增加，涉及背外侧前额叶皮质（DLPFC）、梭状回（FG）和中脑（MB）。FG 和 MB 中对快乐面孔的局部 BOLD 反应随年龄而变化，因此，主要 GG、TT 或 AA 等位基因的老年携带者的激活程度低于次要基因型。这些 DARPP-32 的遗传变异并未调节对愤怒面孔的 BOLD 反应，或对下枕叶的参与，对快乐或愤怒的面孔。总的来说，我们的研究结果为 DARPP-32 遗传变异在潜在奖励触发线索的神经反应中可能发挥作用提供了支持。
