Abstract
Peripheral inputs continuously shape brain function and can influence memory acquisition, but the underlying mechanisms have not been fully understood. Cannabinoid type-1 receptor (CB1R) is a well-recognized player in memory performance, and its systemic modulation significantly influences memory function. By assessing low arousal/non-emotional recognition memory in mice, we found a relevant role of peripheral CB1R in memory persistence. Indeed, the peripherally-restricted CB1R specific antagonist AM6545 showed significant mnemonic effects that were occluded in adrenalectomized mice, and after peripheral adrenergic blockade. AM6545 also transiently impaired contextual fear memory extinction. Vagus nerve chemogenetic inhibition reduced AM6545-induced mnemonic effect. Genetic CB1R deletion in dopamine β-hydroxylase-expressing cells enhanced recognition memory persistence. These observations support a role of peripheral CB1R modulating adrenergic tone relevant for cognition. Furthermore, AM6545 acutely improved brain connectivity and enhanced extracellular hippocampal norepinephrine. In agreement, intra-hippocampal β-adrenergic blockade prevented AM6545 mnemonic effects. Altogether, we disclose a novel CB1R-dependent peripheral mechanism with implications relevant for lengthening the duration of non-emotional memory.
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Acknowledgements
We thank Dulce Real, Marta Linares, and Francisco Porrón for expert technical assistance, and the Laboratory of Neuropharmacology-NeuroPhar for helpful discussion.
Funding
SMT was the recipient of a predoctoral fellowship (Generalitat de Catalunya) [FI-B00531 2016], ABM was supported by pre-doctoral fellowship (Generalitat de Catalunya) [FI_B0052 2020]. This study was supported by: Ministerio de Economía, Innovación y Competitividad (MINECO), Spain (#RTI2018-099282-B-I00B to AO), # PID2020-120029GB-I00 to RM; Generalitat de Catalunya, Spain (2017SGR-669 to RM); Basque Government, Spain (IT-1211-19 to JJM); ICREA (Institució Catalana de Recerca i Estudis Avançats, Spain) Academia to AO and RM. MELIS is the recipient of a grant “Unidad de Excelencia María de Maeztu”, funded by the MINECO (#MDM-2014-0370). FEDER, European Commission funding is also acknowledged. HDAC3-EAE-SCI Project with ref. PID2020-119769RA-I00 funded by MCIN/AEI/10.13039/501100011033 to AH. PRPDEVTAU Project with ref. PID2021-123714OB-I00 funded by MCINN/AEI/10.13039/501100011033/ and by “ERDF A way of making Europe” the CERCA Program, and the Commission for Universities and Research of the Department of Innovation, Universities, and Enterprise of the Generalitat de Catalunya (SGR2017-648) to JADR. Instituto de Salud Carlos III (ISCIII), “PI18/00893”, co-funded by the European Union, to GS. IBEC is the recipient of a Severo Ochoa Award of Excellence from MINECO (CEX2018-000789-S). SMT and AH were supported by Severo Ochoa program at IBEC. The authors have nothing to disclose.
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Behavioral, biochemical, histological, confocal and surgery experiments, statistical analyses and graphs and writing of the manuscript: SMT and ABM. Bilateral hippocampal cannula implantation in mice: LGL. Generation and provide the conditional transgenic mice (DBH-CB1KO): FR and BL Adrenalectomy in mice: AOA. Design and performance of the chemogenetic experiment: AH and JADR. Behavioral approaches: LdlRR. Chemogenetic surgeries in the vagus nerve: AH. rsfMRI experiments and conectomics on c-Fos-based network: EMM and GS. Microdialysis in vivo experiments in mice: JEO and JJM.. In vivo recordings in mice: JARO. Supervision of the study: RM. Conceptualization, supervision of the study, and writing of the manuscript: AO. All authors revised the final version of the manuscript.
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Martínez-Torres, S., Bergadà-Martínez, A., Ortega, J.E. et al. Peripheral CB1 receptor blockade acts as a memory enhancer through a noradrenergic mechanism. Neuropsychopharmacol. 48, 341–350 (2023). https://doi.org/10.1038/s41386-022-01436-9
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DOI: https://doi.org/10.1038/s41386-022-01436-9
