| Ghrelin. a28amino acid peptide hormone promoting ingestion and growth hormone secretion, is mainly synthesized by gastric endocrine cells and hypothalamie arcuate nucleus. Gherlin is known to play its physiological function mainly through activation of ghrelin receptor, the type1a of growth hormone secretagogue receptor (GHS-Rla). GHS-Rla is one of the typical G protein (Gq/11)-coupled receptors which consists of seven transmembrane domains. In central nervous system, besides abundance in the hypothalamus. GHS-Rla was also found to be expressed in multiple brain regions including the hippocampus, amygdala, substantia nigra dense zone, the midbrain ventral tegmental area and so on. Its broad expression prompts that ghrelin and its receptor may plays certain roles in multiple advanced brain functions such as memory and emotion. Previous studies have reported that ghrelin/GHS-Rla activation regulates memory and emotion, however the underlying mechanisms are uncertain yet.The amygdala is considered to be the most important brain structure involved in emotional learning and memory. Amygdala accepts ghrelin neuronergic projections, and the expression of GHS-Rla mRNA in rat lateral amygdala is far more rich than that in the central nucleus, suggesting that ghrelin/GHS-Rla activation and the downstream signaling pathways may adjust neuronal activities in the lateral amygdala and thus affect the emotional memory processing. Conditioned taste aversion (conditioned taste aversion. CIA).is a well-accepted behavioral paradigm to study the acquisition, consolidation and extinction of emotional memory in laboratories. Studies have shown that the lateral amygdala is a key brain structure mediating the formation and storage of both conditioned fear and conditioned taste aversion. Therefore, in combination of local micro-infusion and CTA paradigam. we proposed here to study the effects of ghrelin/GHS-Rla signaling on CTA in rats and to explore the underlying molecular mechanisms. We found that:1. Micro-infusion of a single low dose of ghrelin (12ng/0.5ul/side) into the lateral amygdala blocked CTA memory acquisition in rats, while same treatment had no significant effect on CTA memory consolidation or retrieval.2. Pre-treatment with GHS-Rla antagonists YIL718reversed ghrelin’s blockage on CTA acquisition, while YIL718itself had no effect on CTA.3. PLC inhibitor U73122blocked ghrelin’s effect on CTA acquisition, while U73122 itself had no effect on CTA.4. PKC inhibitor chelerythrine chlorine did not suppress ghrelin’s effect on CTA acquisition.5. P13Kinase inhibitor LY294002blocked ghrelin’s effect on CTA acquisition, while its negative control LY303511had no such effect. Neither LY294002nor LY303511itself had effect on CTA acquisition.6. Rapamycin (mTOR inhibitor) blocked ghrelin’s effect on CTA acquisition, while rapamycin itself had no effect on CTA.7. GSK3β inhibitor SB216763and CHIR99021did not inhibit CTA acquisition, suggesting that GSK3β inhibition could not mimic ghrelin’s effect on CTA.8. None of MEK inhibitor (PD98059), PKA inhibitor (H-89dihydrochloride). Dl receptor inhibitors (SCH23390hydrochloride). D2receptor inhibitors (Haloperidol hydrochloride) inhibited ghrelin’s effect on CTA acquisition. Our results thus suggested that micro-infusion of ghrelin into the lateral amygdala blocks CTA acquisition in rats, which was mediated by endogeous GHS-Rla activation. Among multiple downstream intracellular signaling pathways which may triggered by ghrelin/GHS-Rl a activation according to previous in vitro studies. PLC and P13K/AKt/mTOR pathways in the lateral amygdala may play essential roles to mediate ghrelin’s regulation on taste aversive behavior. However, the specific molecular targets controlled by those pathways activation remain to be further studied. Our studies will not only shed light on the understandings about multiple brain functions of ghrelin besides feeding and energy balance controls, it may also contribute to the development of new treatment for certain affective and cognitive disorders. |
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