Palatable Food and Synaptic Plasticity

描述(申请人提供)：食物摄入量和能量平衡深受压力的影响，反之亦然。然而，这些效应背后的神经机制在很大程度上是未知的。该项目的长期目标是探索压力与食物/能量平衡相互作用的机制。更具体地说，这项建议试图了解美味食物如何提供压力缓解。这些机制是通过有限的可口食物摄入模型来研究的，在该模型中，自由获得食物和水的大鼠每天额外获得两次少量的蔗糖溶液或水作为对照。在这个模型中，蔗糖大鼠减弱了下丘脑-垂体-肾上腺(HPA)轴对应激的反应，并减少了应激诱导的脑奖赏区域神经元的激活。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，这表明大脑奖赏区域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中的神经活动对于蔗糖抑制应激是必要的，而且随着蔗糖摄入量的增加，与突触可塑性相关的基因在BLA中上调。总而言之，这表明美味的食物可能通过BLA中的突触重塑来抑制应激反应。因此，目前的建议解决了美味的食物导致BLA中突触重组的假说。我们预测，摄入蔗糖会增加血乳酸抑制张力，导致更少的应激-兴奋输出。此外，我们假设BLA中增强的抑制张力是由于对BLA内抑制中间神经元的驱动增加所致。该提案在两个具体目标上检验了这一假设。第一个特定的目标将检验这一假设，即蔗糖摄入以一种与加强抑制BLA输出一致的方式增加突触结合。这一目标将使用解剖学方法来识别和量化蔗糖摄入后BLA神经元上的突触对位。第二个特定目的将检验蔗糖诱导的BLA突触重组是由pCREB的AMPA受体激活所介导的假设。这一目的将通过阻断BLA内AMPA受体的活性和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。 与公共健康相关：当面临压力时，许多人会增加他们对美味(如美味、高糖或高脂肪)食物的摄入量，想必是为了帮助自己平静或安慰自己。然而，这种行为会增加体重，并有助于肥胖的发展。该项目旨在了解美味食物如何降低对压力的反应，从而提供对消费这些食物的动机的洞察，并有可能为预防和治疗肥胖症提供新的策略。

DESCRIPTION (provided by applicant): Food intake and energy balance are profoundly influenced by stress, and vice versa. However, the neural mechanisms underlying these effects are largely unknown. The long-term objective of this project is to pursue the mechanisms by which stress and food/energy balance interact. More specifically, this proposal seeks to understand how highly palatable foods provide stress relief. These mechanisms are studied using a model of limited palatable food intake in which rats with free access to food and water are given additional twice-daily access to a small amount of sucrose solution or water as a control. In this model, sucrose rats have attenuated hypothalamic-pituitary-adrenal (HPA) axis 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 regions 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 synaptic plasticity are up-regulated in the BLA following a history of sucrose intake. Collectively, this suggests that palatable foods may dampen stress responses via synaptic remodeling in the BLA. Thus, the current proposal addresses the hypothesis palatable food causes synaptic reorganization in the BLA. We predict that sucrose intake increases BLA inhibitory tone, leading to less stress-excitatory output. Furthermore, we hypothesize that enhanced inhibitory tone in the BLA is due to increased drive to the intra-BLA inhibitory interneurons. The proposal tests this hypothesis in two specific aims. The first specific aim will test the hypothesis that sucrose intake increases synaptic appositions in a manner consistent with enhanced inhibition of BLA output. This aim will use anatomical approaches to identify and quantify synaptic appositions onto BLA neurons following sucrose intake. The second specific aim will test that hypothesis that sucrose-induced BLA synaptic reorganization is mediated by AMPA receptor activation of pCREB. This aim will use intra-BLA blockade of AMPA receptor activity and CREB/pCREB expression to determine whether this signaling pathway mediates sucrose-induced synaptic reorganization. PUBLIC HEALTH RELEVANCE: When under stress, many people increase their intake of highly palatable (e.g., tasty, high-sugar or high-fat) foods, presumably to help calm or comfort themselves. However, this behavior can increase body weight and contribute to the development of obesity. This project seeks to understand how palatable foods act to decrease the response to stress, thereby providing insight into the motivation to consume these foods and potentially offering new strategies for the prevention and treatment of obesity.