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

描述（由申请人提供）：已知在生命早期暴露于尼古丁和乙醇会增加青春期对这些药物的使用，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特别严重，并且与涉及奖励和依赖的中脑边缘脑区域的类似神经化学变化相关。我们最近对成年动物的研究揭示了药物使用和富含脂肪的饮食之间的正相关关系，以及它们对大脑系统影响的相似性，特别是阿片类脑啡肽（ENK），它在药物奖励和成瘾中起着重要作用。他们还表明，在子宫内暴露于膳食脂肪，这显着提高循环脂肪酸，可以刺激神经发生，增殖和分化 的ENK神经元的下丘脑室旁核（PVN）的后代，同时增强随后的偏好脂肪。基于这一证据，我们建议在这里测试新的想法，母亲消费的脂肪丰富的饮食，即使是很短的一段时间，有一个强大的刺激作用的脂质敏感的转录因子，过氧化物酶体增殖物激活受体（PPAR），在胚胎的大脑，然后重新编程ENK系统，以诱导持续的过度表达和增加使用和依赖尼古丁和乙醇的青少年后代。这一假设得到了我们的初步结果的支持，该结果首次表明，产前暴露于富含脂肪的饮食增加了尼古丁和乙醇的消耗，刺激了神经发生和ENK神经元在延髓核（NAc）以及PVN中的表达，并增强了特定的PPAR <$/<$在这些相同区域中的表达。为了验证这一假设，我们建议在以下两个目标中进行六个实验。在目标1中，我们计划描述产前脂肪暴露引起的变化，并确定后代自我给药和依赖尼古丁和乙醇的倾向是否与新生儿的出生、分化和增殖有关。 在NAc和PVN中共表达ENK和PPAR的神经元。基于我们额外的新发现，即体外和体内脂肪酸可以刺激胚胎前脑和下丘脑中的PPAR <$/<$和ENK表达，并且PPAR <$/<$反过来刺激前脑ENK，我们计划在目标2中提供更直接的测试，以了解这种基于脂质的机制在介导产前脂肪暴露对尼古丁和乙醇自我给药和依赖性的影响中的重要性。首先，我们将研究暴露于富含脂肪的饮食中的几天，正好是NAc或PVN中神经发生达到峰值的时候，是否足以刺激青春期ENK和PPAR神经发生和药物滥用，其次，大脑中的PPAR是否实际上是ENK表达增强现象的关键。随着近几十年来美国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，因为它们与后代的行为障碍有关，然后采取初步措施进行测试和开发可能抵消这些变化的方法。 公共卫生相关性：目前拨款申请的目标是研究这样一种观点，即母亲在怀孕期间食用富含脂肪的饮食会对大脑发育产生深远的影响，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一个特定的假设，即母亲的饮食会导致循环脂质升高， 饮食激活了胎儿大脑中的脂肪敏感信号，这反过来又刺激了阿片类神经元的发育，这些神经元后来增加了青少年后代的药物摄入。这些研究的结果应该提供新的信息和新的研究方向，以调查富含脂肪的饮食在子宫内编程的机制，这不仅可能导致暴饮暴食和肥胖，而且还增加了尼古丁和酒精共同依赖的风险。

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.