Parabrachial-Forebrain Interactions in Conditioned Taste Aversion

 描述（由申请人提供）：两种机制防御自我中毒：味觉新恐惧症和条件性味觉厌恶（CTA）。味觉新恐惧症限制了对未知的、可能有毒的食物的摄入。如果新食物被证明是无害的，那么新恐惧症就会习惯。然而，如果发生了令人厌恶的摄食后后果，那么CTA就会发展，并且在以后的遭遇中避免食物。CTA可以学习后，只有一个味觉疾病配对，即使许多小时分开的组成事件，即使个人是无意识的摄入后。这些特性确保我们免受各种天然存在的毒药的伤害。然而，在某些临床人群中（例如，不幸的是，接受化疗或放疗的患者也会产生极其令人厌恶的胃肠道后果），这些相同的特性可能会错误地使真正无害的食物变得恶心和难吃。我们实验室的工作已经帮助确定了脑干核，臂旁内侧核（mPBN），是CTA采集的最重要的核; CTA不会在mPBN病变的大鼠中发展。此外，我们还发现前脑结构（即，基底外侧[BLA]和内侧[MeA]杏仁核、味觉岛叶皮层[GC]和味觉丘脑[GT]）对于味觉新恐怖症的正常发生是必不可少的。口味的新奇调节CTA的收购率：新的口味容易收购CTA，而熟悉和安全的口味是CTA的阻力。我们的工作表明，前脑味觉新恐惧症的结构调节mPBN的关联机制，管理CTA的形成。全面了解CTA学习需要了解这种相互作用，这是我们的第一个短期目标。这一目标将通过使用交叉断开损伤策略来实现，以确定味觉新恐惧症期间四个前脑结构之间的相互作用的性质（目标1）以及这些结构中的哪些结构在功能上与PBN相互作用以调节CTA采集（目标2）。我们最近发现，PBN内注入茴香霉素（一种蛋白质合成抑制剂）诱导CTA到先前的味道。基于这一发现，我们的第二个短期目标旨在了解PBN如何介导CTA学习。在目标3中，我们将通过拮抗PBN中的多巴胺能和多巴胺能活性来确定基于疾病的CTA的神经化学机制。目的4将研究PBN是否参与由其他形式的刺激（包括内部疼痛和一种常被滥用的阿片类药物，也用于临床管理疼痛）诱导的CTA，以确定PBN CTA机制的边界条件。拟议研究的结果将为我们理解CTA学习的神经化学和神经回路的长期目标提供重大进展，这将为临床干预措施的开发提供基础，以减轻 必要的药物治疗后产生的不需要的CTA。

 DESCRIPTION (provided by applicant): Two mechanisms defend against self-poisoning: taste neophobia and conditioned taste aversion (CTA). Taste neophobia limits the ingestion of an unknown, potentially poisonous food. If the new food proves harmless then neophobia habituates. However, if aversive postingestive consequences occur then a CTA develops and the food is avoided on later encounters. CTAs can be learned after only one taste-illness pairing, even when many hours separate the component events and even if the individual is unconscious after ingestion. Such properties ensure that we are protected from a wide range of naturally occurring poisons. However, in certain clinical populations (e.g., patients receiving chemotherapy or radiotherapy - which, unfortunately, also have extremely aversive gastrointestinal consequences) these same properties can, mistakenly, cause genuinely harmless foods to become disgusting and unpalatable. Work in our laboratory has helped establish that a brainstem nucleus, the medial parabrachial nucleus (mPBN), is the single most important nucleus for CTA acquisition; CTAs do not develop in rats with mPBN lesions. Furthermore, we have also discovered that forebrain structures (i.e., the basolateral [BLA] and medial [MeA] amygdala, gustatory insular cortex [GC] and gustatory thalamus [GT]) are essential for the normal occurrence of taste neophobia. Taste novelty regulates the rate of CTA acquisition: novel tastes readily acquire CTAs whereas familiar and safe tastes are CTA resistant. Our work suggests that the forebrain taste neophobia structures modulate the mPBN associative mechanism that governs CTA formation. A comprehensive understanding of CTA learning requires knowledge about this interaction, which represents our first short-term goal. This goal will be achieved by using a crossed- disconnection lesion strategy to determine the nature of the interaction between the four forebrain structures during taste neophobia (Aim 1) and which of these structures functionally interact with the PBN to modulate CTA acquisition (Aim 2). We recently discovered that intra-PBN infusions of anisomycin (a protein-synthesis inhibitor) induce a CTA to the preceding taste. Building on this finding, our second short-term goal seeks to understand how the PBN mediates CTA learning. In Aim 3, we will determine the neurochemical mechanisms of illness-based CTA by antagonizing serotonergic and dopaminergic activity in the PBN. Aim 4 will investigate whether the PBN is involved in CTAs induced by other forms of stimulation (including internal pain and a commonly abused opioid drug that is also used in the clinic to manage pain) to determine the boundary conditions of the PBN CTA mechanism. The results of the proposed studies will provide significant progress towards our long-term goal of understanding the neurochemistry and neurocircuitry of CTA learning, which will provide a foundation for the development of clinical interventions to mitigate the unwanted CTAs that develop consequent to essential medical therapies.