An fMRI Test of the Dynamic Vulnerability Model of Obesity: Risk Factor Plasticit

描述（由申请人提供）：肥胖人与瘦人相比，对可口的食物图像/线索显示出更大的味觉/口腔体感和奖励区域响应性，这预测了未来的体重增加（Yokum等人，在印刷中; Stice等人，2008 a，d，2010 b; Stoeckel等人，2008），与肥胖的奖励过度和激励敏感化模型（Berridge， 2009; Davis等人，2004年）。然而，肥胖人与瘦人相比，在纹状体奖赏区中具有较少的多巴胺（DA）受体，显示出对可口食物摄入的降低的纹状体响应，并且低纹状体响应预测了具有降低的DA信号传导的遗传风险的那些人未来的体重增加（Felsted et al.，2010; Stice等人，2008 a，d; Wang等人，2001年; Wavelow等人，2008），与肥胖的奖赏赤字模型一致（Wang et al.，2002年b）。对这些混合结果的一种解释是，其中一些结果反映了最初的风险因素，而另一些则是暴饮暴食造成的。DA的射击 奖赏区域中的神经元从食物摄入转变为预测条件反射后食物摄入的线索（Kiyatkin等人，1994; Schultz等人，1993），并且过量进食导致大鼠中D2受体密度、D2敏感性和奖赏敏感性降低（Alsio等，2010; Kelley et al.2003;约翰逊和肯尼，2010）和人类对食物的纹状体反应（Stice et al.，2010a），这意味着暴饮暴食导致奖励敏感性增加和奖励区域的下调。此外，对食物图像/线索的抑制性区域反应的降低预示着未来的暴饮暴食和体重增加（科尼尔等人，2010年;《生物学研究》）。数据表明，有肥胖风险的年轻人最初表现出对食物线索的奖励价值编码区域的更大反应性，加上对食物的糖和脂肪含量编码的味觉/口腔体感区域的更大反应性，以及抑制区域反应性降低，这导致暴饮暴食/体重增加，产生钝化的纹状体DA信号，奖励评估区域对食物线索的反应性增加，以及响应于食物刺激的抑制性激活减少，从而增加进一步暴饮暴食/体重增加的风险。我们建议使用一种新颖的重复测量fMRI设计对这种动态脆弱性模型进行严格的测试，在这种设计中，青少年在4年内每年完成扫描。目标1：在130名瘦青少年中，测试味觉/口腔体感和奖励区域反应性的升高和抑制区域对可口食物图像、线索和不同糖/脂肪含量食物摄入的反应性的降低，以及行为抑制控制缺陷/立即奖励偏差是否预测体脂%的初始增加。目标二：使用生长曲线模型来测试%体脂和能量密集食物摄入的初始增加是否预测未来对可口食物接收的纹状体响应的降低、对可口食物图像/线索的奖励回路响应的增加、对食物图像/线索的抑制区域响应的降低以及行为抑制控制缺陷/即时奖励偏差的增加。目标3：测试纹状体对可口食物的反应降低、奖赏区对食物图像/线索的反应增加、抑制区对食物图像/线索的反应降低、行为抑制控制缺陷/立即奖赏偏差是否预测体脂%的进一步增加。

DESCRIPTION (provided by applicant): Obese vs lean humans show greater gustatory/oral somatosensory and reward region responsivity to palatable food images/cues and this predicts future weight gain (Yokum et al., in press; Prelim Studies; Stice et al., 2008a,d, 2010b; Stoeckel et al., 2008), in line with reward surfeit and incentive sensitization models of obesity (Berridge, 2009; Davis et al., 2004). Yet, obese vs lean humans have fewer dopamine (DA) receptors in striatal reward regions, show reduced striatal response to palatable food intake, and low striatal response predicts future weight gain in those at genetic risk for reduced DA signaling (Felsted et al., 2010; Stice et al., 2008a,d; Wang et al., 2001; Volkow et al., 2008), in line with the reward deficit model of obesity (Wang et al., 2002b). One explanation for the mixed findings is that some of these findings reflect initial risk factors and others result from overeating. Firing of DA neurons in reward regions shifts from food intake to cues that predict food intake after conditioning (Kiyatkin et al., 1994; Schultz et al., 1993) and overeating leads to reduced D2 receptor density, D2 sensitivity, and reward sensitivity in rats (Alsio et al., 2010; Kelley et al. 2003; Johnson & Kenny, 2010) and striatal response to food in humans (Stice et al., 2010a), implying that overeating leads to increased incentive sensitization and down-regulation of reward regions. Further, reduced inhibitory region response to food images/cues predicts future overeating and weight gain (Cornier et al., 2010; Prelim Studies). Data imply that youth at risk for obesity initially show greater responsivity of regions that encode the reward value of food cues, coupled with greater responsivity of gustatory/oral somatosensory regions that encode the sugar and fat content of foods, and with reduced inhibitory region responsivity, which lead to overeating/weight gain that produces blunted striatal DA signaling, increased responsivity of reward valuation regions to food cues, and reduced inhibitory activation in response to food stimuli, increasing risk for further overeating/weight gain. We propose to conduct a rigorous test of this dynamic-vulnerability model using a novel repeated measures fMRI design in which teens complete scans annually over 4 years. Aim 1: test whether elevated gustatory/oral somatosensory and reward region responsivity and reduced inhibitory region responsivity to palatable food images, cues, and intake of food varying in sugar/fat content, and behavioral inhibitory control deficits/immediate reward bias predict initial increases in % body fat in 130 lean teens. Aim 2: use growth curve models to test whether initial increases in % body fat and energy dense food intake predict future decreases in striatal response to palatable food receipt, increases in reward circuitry response to palatable food images/ cues, decreased inhibitory region response to food images/cues, and increased behavioral inhibitory control deficits/immediate reward bias. Aim 3: test whether decreased striatal response to palatable food, increased reward region response to food images/cues, reduced inhibitory region response to food images/cues, behavioral inhibitory control deficits/immediate reward bias predict further escalation in % body fat.