Parabrachial-Forebrain Interactions in Conditioned Taste Aversion

 描述(申请人提供)：两种防御自我中毒的机制：味觉新恐惧症和条件性味觉厌恶(CTA)。新口味恐惧症限制了对未知的、可能有毒的食物的摄入。如果这种新食物被证明是无害的，那么新恐惧症就成了人们的习惯。然而，如果发生令人厌恶的进食后后果，则会发生CTA，并且在以后的相遇中避免进食。CTA可以在只有一次味觉和疾病配对后学会，即使在成分事件分开许多小时，即使个体在摄入后昏迷也是如此。这样的特性确保我们免受各种自然产生的毒物的伤害。然而，在某些临床人群中(例如，接受化疗或放射治疗的患者--不幸的是，这些患者也会产生极其令人反感的胃肠道后果)，这些相同的特性可能会错误地导致真正无害的食物变得令人恶心和难吃。我们实验室的工作帮助建立了脑干核，即臂旁内侧核(MPBN)，是CTA获得的最重要的核；CTA在MPBN病变的大鼠中不会发生。此外，我们还发现，前脑结构(即基底外侧[BLA]和内侧[Mea]杏仁核、味觉岛叶皮质[GC]和味觉丘脑[GT])对于味觉新恐惧症的正常发生是必不可少的。口味新颖性调节CTA的获得速度：新奇口味容易获得CTA，而熟悉和安全的口味对CTA具有抵抗力。我们的工作表明，前脑的味觉新恐惧症结构调节了支配CTA形成的MPBN关联机制。全面理解CTA学习需要了解这种交互作用，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确定味觉新恐惧症期间四个前脑结构之间相互作用的性质(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的获得(目标2)。我们最近发现，在PBN内注入茴香霉素(一种蛋白质合成抑制剂)会诱导CTA到之前的味道。在这一发现的基础上，我们的第二个短期目标试图了解PBN是如何调节CTA学习的。在目标3中，我们将通过拮抗PBN中的5-羟色胺和多巴胺能活动来确定基于疾病的CTA的神经化学机制。目的4将调查PBN是否参与由其他形式的刺激(包括内痛和一种临床上也用于止痛的阿片类药物)引起的CTA，以确定PBN CTA机制的边界条件。拟议的研究结果将为我们了解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发展提供基础。 因基本医疗治疗而产生的不受欢迎的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.