Laboratory of NeuroGenetics, Department of Psychology and Neuroscience; Institute for Genome Sciences & Policy, Duke University, Durham, NC 27705, USA.
Genes Brain Behav. 2013 Jul;12(5):516-24. doi: 10.1111/gbb.12035. Epub 2013 Apr 4.
The neuropeptide galanin has been implicated in the regulation of appetitive and consummatory behaviors. Prior studies have shown that direct injection of galanin into the hypothalamus results in increased release of dopamine (DA) in the nucleus accumbens (NAcc), and parallel increases in food and alcohol consumption. These studies are consistent with a role of hypothalamic galanin in regulating reward system reactivity. In humans, a common functional haplotype (GAL5.1) within a remote enhancer region upstream of the galanin gene (GAL) affects promoter activity and galanin expression in hypothalamic neurons in vitro. Given the effects of hypothalamic galanin on NAcc DA release and the effects of the GAL5.1 haplotype on GAL expression, we examined the impact of this functional genetic variation on human reward-related ventral striatum (VS) reactivity. Using an imaging genetics strategy in Caucasian individuals (N = 138, 72 women) participating in the ongoing Duke Neurogenetics Study, we report a significant gender-by-genotype interaction (right hemisphere: F1,134 = 8.08, P = 0.005; left hemisphere: F1,134 = 5.39, P = 0.022), such that homozygosity for the GG haplotype, which predicts greater GAL expression, is associated with relatively increased VS reactivity in women (n = 50, right hemisphere: P = 0.015; left hemisphere: P = 0.060), but not in men (N = 49, P-values > 0.10). Furthermore, these differences in VS reactivity correlated positively with differences in alcohol use, such that VS reactivity mediated a gender-specific association between GAL5.1 haplotype and problem drinking. Our current results support those in animal models implicating galanin signaling in neural pathways associated with appetitive and consummatory behaviors of relevance for understanding risk for substance use and abuse.
神经肽甘丙肽参与调节食欲和享受行为。先前的研究表明，甘丙肽直接注射到下丘脑会导致伏隔核（NAcc）中多巴胺（DA）的释放增加，同时食物和酒精的摄入量也会增加。这些研究表明，下丘脑甘丙肽在调节奖励系统反应性方面发挥作用。在人类中，甘丙肽基因（GAL）上游远程增强子区域的一个常见功能单倍型（GAL5.1）会影响体外下丘脑神经元中的启动子活性和甘丙肽表达。鉴于下丘脑甘丙肽对 NAcc DA 释放的影响以及 GAL5.1 单倍型对 GAL 表达的影响，我们研究了这种功能性遗传变异对人类与奖励相关的腹侧纹状体（VS）反应性的影响。我们使用正在进行的杜克神经遗传学研究中的白种人个体（N=138，72 名女性）的影像遗传学策略，报告了一个显著的性别-基因型相互作用（右侧半球：F1,134=8.08，P=0.005；左侧半球：F1,134=5.39，P=0.022），即 GG 单倍型纯合子预测 GAL 表达增加，与女性（n=50，右侧半球：P=0.015；左侧半球：P=0.060）相对增加的 VS 反应性相关，但与男性（N=49，P 值>0.10）无关。此外，这些 VS 反应性的差异与酒精使用的差异呈正相关，因此 VS 反应性介导了 GAL5.1 单倍型与问题饮酒之间的性别特异性关联。我们目前的结果支持动物模型中甘丙肽信号在与食欲和享受行为相关的神经通路中的作用，这些作用与理解物质使用和滥用风险有关。
