Abstract
Ghrelin is a circulating orexigenic hormone that promotes feeding behavior and regulates metabolism in humans and rodents. We previously reported that local infusion of ghrelin into the basolateral amygdala (BLA) blocked memory acquisition for conditioned taste aversion (CTA) by activating growth hormone secretagogue receptor 1a. In this study, we further explored the underlying mechanism and signaling pathways mediating ghrelin modulation of CTA memory in rats. Pharmacological agents targeting distinct signaling pathways were infused into the BLA during conditioning. We showed that preadministration of the PI3K inhibitor LY294002 abolished the repressive effect of ghrelin on CTA memory. Moreover, LY294002 pretreatment prevented ghrelin from inhibiting Arc and zif268 mRNA expression in the BLA triggered by CTA memory retrieval. Preadministration of rapamycin eliminated the repressive effect of ghrelin, while Gsk3 inhibitors failed to mimic ghrelin’s effect. In addition, PLC and PKC inhibitors microinfused in the BLA blocked ghrelin’s repression of CTA acquisition. These results demonstrate that ghrelin signaling in the BLA shapes CTA memory via the PI3K/Akt/mTOR and PLC/PKC pathways. We conducted in vivo multichannel recordings from mouse BLA neurons and found that microinjection of ghrelin (20 µM) suppressed intrinsic excitability. By means of whole-cell recordings from rat brain slices, we showed that bath application of ghrelin (200 nM) had no effect on basal synaptic transmission or synaptic plasticity of BLA pyramidal neurons. Together, this study reveals the mechanism underlying ghrelin-induced interference with CTA memory acquisition in rats, i.e., suppression of intrinsic excitability of BLA principal neurons via the PI3K/Akt/mTOR and PLC/PKC pathways.
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Acknowledgements
This work was supported by NNSFC (Grant no. 32071141 and 91732110 to YZ, 31900854 to MY), China Postdoctoral Science Foundation (Grant no. 2019M662292 to MY), and NSFC of SD province (Grant no. ZR2019ZD34 and 2019GGX101045 to YZ, ZR201911120651 to NL). We thank Ms. Jennifer Li for native language editing.
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YZ designed and supervised the experiments. MY, QQZ and MLN performed behavioral experiments. ZSZ and JDG designed and performed electrophysiological experiment, NL and BQR helped with data analysis. YZ and TBY wrote the manuscript. All authors read and approved the final manuscript.
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Yu, M., Zhu, Qq., Niu, Ml. et al. Ghrelin infusion into the basolateral amygdala suppresses CTA memory formation in rats via the PI3K/Akt/mTOR and PLC/PKC signaling pathways. Acta Pharmacol Sin 43, 2242–2252 (2022). https://doi.org/10.1038/s41401-022-00859-w
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DOI: https://doi.org/10.1038/s41401-022-00859-w
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