Palatable Food and Synaptic Plasticity

描述（申请人提供）：食物摄入和能量平衡受到压力的深刻影响，反之亦然。然而，这些影响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应激与食物/能量平衡相互作用的机制。更具体地说，这个提议试图理解美味的食物是如何缓解压力的。这些机制是通过有限的美味食物摄入模型来研究的，在这个模型中，自由获取食物和水的大鼠每天额外两次获得少量蔗糖溶液或水作为对照。在这个模型中，蔗糖大鼠的下丘脑-垂体-肾上腺（HPA）轴对应激的反应减弱，大脑奖赏区应激诱导的神经元激活减少。此外，蔗糖的热量和其他摄入后的后果对HPA的抑制既不充分也不必要，这表明大脑的奖励区域可能调节了这种反应。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，并且与突触可塑性相关的基因在摄入蔗糖的历史中在BLA中上调。总的来说，这表明美味的食物可能会通过在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食物导致BLA突触重组的假设。我们预测，蔗糖的摄入增加了BLA抑制张力，导致较少的应激兴奋输出。此外，我们假设BLA抑制性张力的增强是由于BLA内抑制性中间神经元的驱动增加。该提案在两个具体目标上验证了这一假设。第一个具体目标将测试假设，即蔗糖摄入增加突触的方式与增强抑制BLA输出一致。该目的将使用解剖学方法来识别和量化蔗糖摄入后突触与BLA神经元的关联。第二个特定目标将验证蔗糖诱导的BLA突触重组是由pCREB的AMPA受体激活介导的这一假设。本研究将利用bla内阻断AMPA受体活性和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。

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.