Food Reward and Stress

个人描述(由申请者提供)：个人经常从事奖励行为，包括食用高度可口的、高热量密度的“舒适”食物或服用滥用药物，作为一种自我药物缓解压力的手段，但美味食物缓解压力的神经机制在很大程度上是未知的。我们建议使用一个模型来研究这些机制，在这个模型中，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。利用这一模型，我们发现蔗糖大鼠下丘脑-垂体-肾上腺(HPA)轴和行为焦虑对应激的反应减弱，大脑奖赏区应激诱导的神经元激活减少。此外，摄入蔗糖后的卡路里和其他后果既不足以抑制HPA，也不是必要的，这表明大脑奖励本身可能介导了这一反应。杏仁基底外侧核(BLA)是大脑的一个关键奖赏区域，也与驾驶应激反应有关。此外，BLA中的神经活动是蔗糖抑制压力所必需的，随着蔗糖摄入量的增加，与结构和功能可塑性相关的基因在BLA中上调。支持这一观点的是，在蔗糖后的BLA中，突触素(突触前终末的标记物)、磷酸化的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)和吉菲林(突触后抑制性突触后密度的标记物)的免疫标记都增加了。目前的建议提出了一种假设，即美味的食物通过依赖pCREB的BLA突触重塑来抑制应激反应。我们预测，摄入蔗糖会增加血乳酸抑制张力，导致应激兴奋输出减弱。我们将在三个具体目标上检验这一假设。第一个目的是通过白带内阻断CREB/pCREB的表达来确定这一信号通路是否介导了蔗糖诱导的突触重组和应激抑制。第二个目标将评估蔗糖后BLA的结构和功能的可塑性(使用双重免疫标记和共聚焦显微镜来量化BLA神经元上的突触结合，以及BLA切片制备的全细胞电生理记录)，以验证蔗糖诱导的突触重塑导致BLA抑制张力增加的假设。第三个目标将结合束追踪和损伤方法来检验内侧前额叶皮质(MPFC)投射到BLA对于蔗糖介导的突触重塑和应力抑制是必要的假设。 与公共健康相关：当面临压力时，许多人会从事愉快的行为(例如，吸毒或吃美味的、高卡路里的“舒适”食物)，想必是为了帮助自己平静或安慰自己。然而，这种自我用药的行为可能会有负面的副作用(例如，持续增加的卡路里摄入量和肥胖的发展)。这个项目试图了解快乐的行为是如何减少压力的，从而为驱动这些行为的动机提供洞察，并可能为预防和/或治疗肥胖、药物成瘾和其他与压力相关的疾病提供新的策略。

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.