Mechanisms of nicotine and alcohol use: Focus on in utero exposure to dietary fat

描述(由申请人提供)：众所周知，在生命早期接触尼古丁和乙醇会增加青春期这些药物的使用，导致依赖。这两种药物引起的这些行为障碍在子宫内暴露时尤其严重，并与涉及奖赏和依赖的中脑边缘区域类似的神经化学变化有关。我们最近在成年动物身上的研究揭示了药物使用和富含脂肪的饮食之间的积极关系，以及它们对大脑系统的影响方面的相似之处，特别是阿片脑啡肽(ENK)，它在药物奖励和成瘾中具有重要作用。他们还表明，在子宫内暴露于饮食脂肪，显著增加循环中的脂肪酸，可以刺激神经发生、增殖和分化。 子代下丘脑室旁核(PVN)中ENK神经元的数量增加，同时增强了随后对脂肪的偏好。基于这一证据，我们建议在这里测试一个新的想法，即母亲食用高脂肪饮食，即使是很短的一段时间，也会对胚胎大脑中的脂质敏感转录因子--过氧化物酶体增殖物激活受体(PPAR)产生强有力的刺激作用，然后对ENK系统进行重新编程，以诱导青少年后代持续过度表达，并增加对尼古丁和乙醇的使用和依赖。这一假说得到了我们的初步结果的支持，该结果首次表明，产前暴露于高脂肪饮食增加了尼古丁和乙醇的消耗，刺激了伏核(NAC)和下丘脑室旁核(PVN)内ENK神经元的神经发生和表达，并增强了PPAR？/？在这些区域的特异性表达。为了验证这一假设，我们建议在以下两个目标上进行六个实验。在目标1中，我们计划表征产前脂肪暴露引起的变化，并确定后代自我管理的倾向和对尼古丁和乙醇的依赖是否与神经细胞的出生、分化和增殖有关 NAC和PVN内有ENK和PPAR共同表达的神经元。基于我们在体外和体内的其他新发现，即脂肪酸可以刺激胚胎前脑和下丘脑中PPAR？和ENK的表达，以及PPAR/？反过来刺激前脑ENK，我们计划在目标2中更直接地测试这种基于脂质的机制在调节产前脂肪暴露对尼古丁和乙醇自我给药和依赖的影响方面的重要性。首先，我们将研究，在NAC或PVN神经发生达到高峰时，暴露在高脂肪饮食中的几天，是否足以刺激ENK和PPAR？/？神经发生和青春期的药物滥用；其次，大脑中的PPAR/？是否实际上对ENK表达增强的现象是必不可少的。近几十年来，随着美国人饮食中脂肪含量的增加，了解大脑发育的早期变化变得越来越重要，因为这些变化与后代的行为障碍有关，然后采取初步步骤，测试和开发可能抵消这些变化的方法。 与公共健康相关：目前拨款申请的目标是研究孕妇在怀孕期间食用富含脂肪的饮食会导致大脑发育的深刻变化，从而促进对尼古丁和酒精的使用和依赖。拟议中的研究将检验特定的假设，即母亲的血液循环中的血脂升高 饮食会激活胎儿大脑中的脂肪敏感信号，进而刺激阿片类神经元的发育，从而增加青少年后代的药物摄入量。这些研究的结果应该为研究高脂肪饮食在子宫内编程的机制提供新的信息和新的研究方向，这不仅可能导致暴饮暴食和肥胖，还可能增加尼古丁和酒精相互依赖的风险。

DESCRIPTION (provided by applicant): Exposure to nicotine and ethanol early in life is known to increase the use of these drugs during adolescence, leading to dependence. These behavioral disturbances induced by both drugs are particularly profound with in utero exposure and are associated with similar neurochemical changes in mesolimbic brain regions involved in reward and dependence. Our recent studies in adult animals are revealing positive relationships between drug use and the consumption of a diet rich in fat and also similarities in their effects on brain systems, notably the opioid enkephalin (ENK), which has an important role in drug reward and addiction. They also show that in utero exposure to dietary fat, which markedly elevates circulating fatty acids, can stimulate the neurogenesis, proliferation and differentiation of ENK neurons in the hypothalamic paraventricular nucleus (PVN) of the offspring, while enhancing subsequent preference for fat. Building on this evidence, we propose to test here the novel idea that maternal consumption of a fat-rich diet, even for a short period, has a potent stimulatory effect on the lipid-sensitive transcription factor, peroxisome proliferator-activated receptor (PPAR), in the embryonic brain, which then reprograms the ENK system to induce persistent overexpression and increased use and dependence on nicotine and ethanol in the adolescent offspring. This hypothesis is supported by our preliminary results showing, for the first time, that prenatal exposure to a fat-rich diet increases the consumption of both nicotine and ethanol, stimulates neurogenesis and expression of ENK neurons in the nucleus accumbens (NAc) as well as PVN, and potentiates the expression specifically of PPAR ¿/¿ in these same areas. To test this hypothesis, we propose to conduct six experiments in the following two aims. In Aim 1, we plan to characterize the changes induced by prenatal fat exposure and determine if the offspring's predisposition to self-administer and become dependent on nicotine and ethanol can be related to the birth, differentiation and proliferation of neurons co-expressing ENK and PPAR ¿/¿ in the NAc and PVN. Building on our additional new findings that fatty acids in vitro and in vivo can stimulate both PPAR ¿/¿ and ENK expression in embryonic forebrain and hypothalamus and that PPAR ¿/¿ in turn stimulates forebrain ENK, we plan in Aim 2 to provide a more direct test of the importance of this lipid-based mechanism in mediating the effect of prenatal fat exposure on nicotine and ethanol self-administration and dependence. We will examine, first, whether a few days of exposure to the fat-rich diet, precisely when neurogenesis peaks in the NAc or PVN, is sufficient to stimulate ENK and PPAR ¿/¿ neurogenesis and drug abuse during adolescence and, second, whether PPAR ¿/¿ in the brain is, in fact, essential to the phenomenon of enhanced ENK expression. With the increase in fat content of the American diet in recent decades, it is becoming increasingly important to understand early changes in brain development as they relate to behavioral disturbances in the offspring and then take initial steps toward testing and developing methods that may counteract these changes. PUBLIC HEALTH RELEVANCE: The goal of the current grant application is to examine the idea that maternal consumption of a fat-rich diet during pregnancy produces profound changes in brain development that later promote the use and dependence on nicotine and alcohol. The proposed studies will test the specific hypothesis that circulating lipids elevated by the mother's diet activate a fat-sensitive signal in the fetal brain, which in turn stimulates the development o opioid neurons that later enhance drug intake in adolescent offspring. The results of these studies should provide new information and a new direction of research for investigating mechanisms programmed in utero by a fat-rich diet, which may lead not only to overeating and obesity but also to increased risk for nicotine and alcohol co-dependence.