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

Nicola Forte,Sabatino Maione,Raffaele Capasso,Fabio Arturo Iannotti,Lea Tunisi,Vincenzo Di Marzo,Paolo De Girolamo,Roberta Imperatore,Serena Boccella,Monica Iannotta,Luigia Cristino,Maria De Risi,Fabiana Piscitelli,Elvira De Leonibus,Alba Clara Fernández-Rilo

doi:10.1038/s41467-021-26388-4

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.

Highlights

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
Based on the results described we hypothesized that in obese mice: (1) elevated OxA release from LH afferents elicits postsynaptic Ox1-R-mediated biosynthesis and release of 2-AG via activation of diacylglycerol lipase α (DAGLα) at the postsynaptic dendritic spines of newborn neurons in the molecular layer (ML)-dentate gyrus (DG) area, and (2) 2-AG acts retrogradely at the CB1-positive medial perforant path (MPP) excitatory inputs to newborn neurons to inhibit glutamate release and action thereupon, with consequent long-term potentiation (LTP) impairment
Our data provide a mechanistic molecular framework in which OxA, a hypothalamic neuropeptide over-released during overweight and obesity[42,43], accelerates the onset of differentiation of immature granule cells (GCs) from the subgranular zone toward a neuronal fate, altering the synaptic plasticity of MPP-DG synapses via 2-AG-mediated CB1 receptor overactivation

Summary

Introduction

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. 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, providing a molecular and functional mechanism to explain alterations in episodic memory in obesity. Episodic memories are associated with the personal experience of everyday life, and the ability to distinguish between two similar past events is known as pattern separation (PS). This ability is regulated by the hippocampus, where inputs from the entorhinal cortex are transformed into distinct and relatively non-overlapping representations in the CA3 area.

Methods

Results

Conclusion