Food Reward and Stress

描述（由申请人提供）：个体经常参与奖励行为，包括食用高美味、高热量的“安慰”食物或滥用药物，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，每天两次给予自由获取食物和水的大鼠少量可口的蔗糖溶液或水作为对照。使用该模型，我们发现蔗糖大鼠对压力的下丘脑-垂体-肾上腺（HPA）轴和行为-焦虑反应减弱，大脑奖励区应激诱导的神经元激活减少。此外，糖的热量和其他摄入后的后果对HPA抑制既不充分也不必要，这表明大脑奖励本身可能介导了这种反应。基底外侧杏仁核（BLA）是一个关键的大脑奖励区域，也涉及驱动应激反应。此外，BLA中的神经活动对于蔗糖的应激抑制是必要的，并且与结构和功能可塑性相关的基因在摄入蔗糖后在BLA中上调。为了支持这一观点，在蔗糖作用下，BLA中突触素（突触前末端的标记物）、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）和卟啉（抑制性突触后密度的突触后标记物）的免疫标记都增加了。目前的建议提出了一个假设，即美味食物通过在BLA中依赖pcreb的突触重塑来抑制应激反应。我们预测蔗糖摄入会增加BLA抑制张力，导致应激兴奋输出减弱。我们将在三个具体目标中检验这一假设。第一个目的是利用bla内阻断CREB/pCREB表达来确定该信号通路是否介导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的结构和功能可塑性（使用双免疫标记共聚焦显微镜量化BLA神经元上的突触连接，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抑制性张力增加的假设。第三个目标将结合通道追踪和病变方法来验证内侧前额叶皮层（mPFC）对BLA的投射对于蔗糖介导的突触重塑和应激抑制是必要的假设。

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.