| Ghrelin, a 28 amino acid peptide hormone promoting ingestion and growth hormone secretion, is mainly synthesized by gastric endocrine cells and hypothalamic arcuate nucleus. Gherlin is known to play its physiological function mainly through activation of ghrelin receptor, the type 1 a of growth hormone secretagogue receptor(GHS-R1a). GHS-R1 a 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-R1 a 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 play certain roles in multiple advanced brain functions such as memory and emotion. Previous studies have reported that ghrelin/GHS-R1 a 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-R1 a m RNA in rat lateral amygdala is much richer than that in the central nucleus, suggesting that ghrelin/GHS-R1 a 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, CTA) 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-R1 a signaling on CTA in rats and to explore the underlying neural circuit tmechanisms. 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.2.Pre-treatment with GHS-R1 a antagonists YIL718 reversed ghrelin’s blockage on CTA acquisition, while YIL718 itself had no effect on CTA.3.GHS-R1 a reverse agonist D-substance-p blocks ghrelin’s effect on CTA acquisition4.PLC inhibitor U73122 blocked ghrelin’s effect on CTA acquisition, while U73122 itself had no effect on CTA.5.Pre-treatment with Protein kinase C(PKC)inhibitor GF109203 X reversed ghrelin’s blockage on CTA acquisition, while itself had no effect on CTA.6.Pre-treatment with IP3 R antagonist 2-APB reversed ghrelin’s blockage on CTA acquisition, while 2-APB itself had no effect on CTA.Our results thus suggested that micro-infusion of ghrelin into the lateral amygdala blocks CTA acquisition in rats, which was mediated by endogenous GHS-R1 a activation. Among multiple downstream intracellular signaling pathways which may triggered by ghrelin/GHS-R1 a activation according to previous in vitro studies, PLC/PKC/IP3 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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