Parabrachial-Forebrain Interactions in Conditioned Taste Aversion

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 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.