Orexin-A and endocannabinoids are involved in obesity-associated alteration of hippocampal neurogenesis, plasticity, and episodic memory in mice

Nicola Forte, Serena Boccella, Lea Tunisi, Alba Clara Fernández-Rilo, Roberta Imperatore, Fabio Arturo Iannotti, Maria Risi, Monica Iannotta, Fabiana Piscitelli, Raffaele Capasso, Paolo Girolamo, Elvira Leonibus, Sabatino Maione, Vincenzo Marzo () and Luigia Cristino ()
Additional contact information
Nicola Forte: Consiglio Nazionale delle Ricerche (CNR)
Serena Boccella: University of Campania Luigi Vanvitelli
Lea Tunisi: Consiglio Nazionale delle Ricerche (CNR)
Alba Clara Fernández-Rilo: Consiglio Nazionale delle Ricerche (CNR)
Roberta Imperatore: University of Sannio
Fabio Arturo Iannotti: Consiglio Nazionale delle Ricerche (CNR)
Maria Risi: Telethon Institute of Genetics and Medicine
Monica Iannotta: University of Campania Luigi Vanvitelli
Fabiana Piscitelli: Consiglio Nazionale delle Ricerche (CNR)
Raffaele Capasso: University of Naples Federico II
Paolo Girolamo: University Federico II
Elvira Leonibus: Telethon Institute of Genetics and Medicine
Sabatino Maione: University of Campania Luigi Vanvitelli
Vincenzo Marzo: Consiglio Nazionale delle Ricerche (CNR)
Luigia Cristino: Consiglio Nazionale delle Ricerche (CNR)

Nature Communications, 2021, vol. 12, issue 1, 1-20

Abstract: Abstract The mammalian brain stores and distinguishes among episodic memories, i.e. memories formed during the personal experience, through a mechanism of pattern separation computed in the hippocampal dentate gyrus. Decision-making for food-related behaviors, such as the choice and intake of food, might be affected in obese subjects by alterations in the retrieval of episodic memories. Adult neurogenesis in the dentate gyrus regulates the pattern separation. Several molecular factors affect adult neurogenesis and exert a critical role in the development and plasticity of newborn neurons. Orexin-A/hypocretin-1 and downstream endocannabinoid 2-arachidonoylglycerol signaling are altered in obese mice. Here, we show that excessive orexin-A/2-arachidonoylglycerol/cannabinoid receptor type-1 signaling leads to the dysfunction of adult hippocampal neurogenesis and the subsequent inhibition of plasticity and impairment of pattern separation. By inhibiting orexin-A action at orexin-1 receptors we rescued both plasticity and pattern separation impairment in obese mice, thus providing a molecular and functional mechanism to explain alterations in episodic memory in obesity.

Date: 2021
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DOI: 10.1038/s41467-021-26388-4

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