Parabrachial-Forebrain Interactions in Conditioned Taste Aversion

描述（由申请人提供）：面对一种新的食物，动物面临着一个不能掉以轻心的决定。虽然摄入这些食物可能会使人营养丰富，但如果这些食物有毒，可能会导致死亡。强大的学习过程已经进化到指导摄食行为。这些过程中最重要的是条件性味觉厌恶（CTA）学习，它不仅可以防止有毒食物的重复摄入，因此对日常生活中的饮食选择有着广泛的影响，而且还涉及到与我们的健康有关的许多其他情况。例如，癌症患者经常对他们的饮食产生强烈的厌恶（导致厌食症和恶病质），因为化疗的内脏副作用与治疗前食用的食物有关。我们的研究鼓励了这样一种观点，即慢性失觉大鼠CTA的缺失是失觉诱导的臂旁核（PBN）神经元功能丧失的无意后果。事实上，我们认为PBN是CTA学习中最重要的大脑结构，前脑通过调节味觉新奇/熟悉感来促进PBN联想机制。本研究的目的是：(1)确定PBN中CTA学习的药理学基础；(2)确定前脑结构在味觉新奇感知中的作用。我们的第一个目标是利用apbn内药物输注来确定CTA获取和/或再巩固是PBN中蛋白质合成（Specific Aim 1）和/或谷氨酸受体（Specific Aim 2）依赖的过程。我们的第二个短期目标的研究将研究前脑结构（岛叶皮质，基底外侧杏仁核和内侧杏仁核）在新颖性识别过程（味觉恐惧症）中的作用，使用涉及不对称病变（特定目标3）或暂时失活（特定目标4）的断开策略。通过研究上述大脑操作导致的行为崩溃，我们期望在定义负责CTA学习的神经系统的长期目标方面取得重大进展。

DESCRIPTION (provided by applicant): Faced with a novel food, an animal is confronted with a decision that cannot be taken lightly. While ingestion of the food may lead to a nutritious meal, it may, if the food is poisonous, cause death. Powerful learning processes have evolved to guide ingestive behavior. The most important of these processes, conditioned taste aversion (CTA) learning, not only prevents the repeated ingestion of toxic food, and therefore has wide reaching implications for dietary choices in everyday life, but also is implicated in many other situations relevant to our well being. For instance, cancer patients oftentimes develop strong aversions to their diets (leading to anorexia and cachexia) because the aversive visceral side effects of chemotherapy are associated with the foods consumed before treatment. Our research encourages the view that the absence of CTA in chronic decerebrate rats is the inadvertent consequence of a decerebration-induced functional loss of neurons in the parabrachial nucleus (PBN). Indeed, we believe that the PBN is the single most important brain structure for CTA learning and that the forebrain contributes to the PBN associative mechanism by modulating the perception of taste novelty/familiarity. The goals of the proposed research are to: (1) determine the pharmacological substrates of CTA learning in the PBN and (2) establish the roles of forebrain structures in taste novelty perception. The research of our first goal utilizes intraPBN drug infusions to determine whether CTA acquisition and/or reconsolidation is a protein synthesis- (Specific Aim 1) and/or a glutamate receptor- (Specific Aim 2) dependent process in the PBN. The research of our second short-term goal will investigate the roles of forebrain structures (insular cortex, basolateral amygdala and medial amygdala) in a novelty recognition procedure (taste neophobia) using a disconnection strategy involving asymmetric lesions (Specific Aim 3) or temporary inactivation (Specific Aim 4). By studying the behavioral breakdowns consequent to the stated brain manipulations, we expect to make significant progress in our long-term goal of defining the neural system responsible for CTA learning. PUBLIC HEALTH RELEVANCE: Conditioned taste aversions (CTAs), which are rapidly acquired when ingestion of a novel food is followed by gastrointestinal malaise, are manifest as a diminished intake of that food on subsequent encounters. Understanding the neural substrates of this profoundly important learning process will yield insights into the neural integration of gustatory and visceral functions and may provide a foundation for the development of treatments and interventions that might ameliorate, for example, the unwanted, and oftentimes debilitating, nutritional side effects of invasive medical therapies such as chemo- or radiation therapy for cancer.