Food Reward and Stress

描述（由申请人提供）：个体经常参与奖励行为，包括食用高可口、热量密集的“舒适”食物或服用滥用药物，作为缓解压力的自我药物治疗手段，但可口食物缓解压力的神经机制在很大程度上是未知的。我们建议使用一种模型来研究这些机制，在该模型中，自由获得食物和水的大鼠每天两次获得少量可口的蔗糖溶液或水作为对照。使用这个模型，我们已经发现，蔗糖大鼠有衰减下丘脑-垂体-肾上腺（HPA）轴和行为焦虑反应的压力和减少的压力诱导的神经元激活的大脑奖励区。此外，蔗糖的卡路里和其他摄入后后果对于HPA抑制既不充分也不必要，这表明大脑奖励本身可能介导该反应。基底外侧杏仁核（BLA）是一个关键的大脑奖励区域，也与驱动压力反应有关。此外，在BLA的神经活动是必要的应力阻尼蔗糖，和基因相关的结构和功能的可塑性上调BLA以下的蔗糖摄入量的历史。为了支持这一观点，免疫标记突触素（突触前末梢的标记物），磷酸化cAMP反应元件结合蛋白（pCREB;与突触可塑性相关的突触后标记物），和桥蛋白（抑制性突触后密度的突触后标记物）都增加了BLA后蔗糖。目前的建议解决了这一假设，可口的食物通过pCREB依赖的突触重塑BLA抑制应激反应。我们预测，蔗糖摄入量增加BLA抑制音，导致衰减的应激兴奋输出。我们将在三个具体目标中检验这一假设。第一个目的将使用CREB/pCREB表达的BLA内阻断来确定该信号传导途径是否介导蔗糖诱导的突触重组和应力抑制。第二个目的将评估蔗糖后BLA的结构和功能可塑性（使用双免疫标记和共聚焦显微镜来量化BLA神经元上的突触并置，以及来自BLA切片制备物的全细胞电生理记录），以测试蔗糖诱导的突触重塑导致BLA中抑制性张力增加的假设。第三个目标将结合联合收割机束追踪和损伤的方法来测试的假设，即内侧前额叶皮层（mPFC）的预测BLA是必要的蔗糖介导的突触重塑和压力阻尼。 公共卫生相关性：当处于压力之下时，许多人会从事愉快的行为（例如，吸毒或吃美味的、高热量的“安慰”食物），大概是为了帮助冷静或安慰自己。然而，这种自我用药行为可能具有负面副作用（例如，持续增加的热量摄入和肥胖的发展）。该项目旨在了解愉快的行为如何减轻压力，从而深入了解驱动这些行为的动机，并可能为预防和/或治疗肥胖、药物成瘾和其他压力相关疾病提供新的策略。

DESCRIPTION (provided by applicant): Individuals often engage in rewarding behaviors, including consuming highly-palatable, calorically- dense "comfort" foods or taking drugs of abuse, as a means of self-medication for stress relief, but the neural mechanisms underlying stress relief by palatable foods are largely unknown. We propose to study these mechanisms using a model in which rats with free access to food and water are given twice-daily access to a small amount of palatable sucrose solution or water as a control. Using this model, we have found that sucrose rats have attenuated hypothalamic-pituitary-adrenal (HPA) axis and behavioral-anxiety responses to stress and diminished stress-induced neuronal activation in brain reward regions. Moreover, the calories and other post- ingestive consequences of sucrose are neither sufficient nor necessary for the HPA dampening, suggesting that brain reward per se may mediate the response. The basolateral amygdala (BLA) is a key brain reward region that is also implicated in driving stress responses. Moreover, neural activity in the BLA is necessary for stress-dampening by sucrose, and genes related to structural and functional plasticity are up-regulated in the BLA following a history of sucrose intake. In support of this idea, immunolabeling for synaptophysin (a marker of presynaptic terminals), phosphorylated cAMP response element-binding protein (pCREB; a postsynaptic marker associated with synaptic plasticity), and gephyrin (a postsynaptic marker of inhibitory postsynaptic densities) are all increased in the BLA following sucrose. The current proposal addresses the hypothesis that palatable food dampens stress responses via pCREB-dependent synaptic remodeling in the BLA. We predict that sucrose intake increases BLA inhibitory tone, leading to attenuated stress-excitatory output. We will test this hypothesis in three specific aims. The first aim will use intra-BLA blockade of CREB/pCREB expression to determine whether this signaling pathway mediates sucrose-induced synaptic reorganization and stress- dampening. The second aim will assess structural and functional plasticity in the BLA after sucrose (using dual immunolabeling with confocal microscopy to quantify synaptic appositions onto BLA neurons, as well as whole- cell electrophysiological recordings from BLA slice preparations) to test the hypothesis that sucrose-induced synaptic remodeling results in increased inhibitory tone in BLA. The third aim will combine tract-tracing and lesion approaches to test the hypothesis that medial prefrontal cortex (mPFC) projections to BLA are necessary for sucrose-mediated synaptic remodeling and stress dampening. PUBLIC HEALTH RELEVANCE: When under stress, many people engage in pleasurable behaviors (e.g., drug taking or eating tasty, high-calorie "comfort" foods), presumably to help calm or comfort themselves. However, this self-medicating behavior can have negative side-effects (e.g., persistent increased caloric intake and the development of obesity). This project seeks to understand how pleasurable behaviors reduce stress, thereby providing insight into the motivation driving these behaviors and potentially offering new strategies for the prevention and/or treatment of obesity, drug addiction, and other stress-related disorders.