Obesogenic diet impairs social memory through alterations of hippocampal CA2 excitability and oxytocin signaling.

While obesity induces cardio-metabolic disorders and cognitive deficits, the underlying neural mechanisms remain unexplored. In mice, exposure to an obesogenic high-fat and sugar diet (HFD) resulted in social recognition memory deficits in both males and females, a process that is dependent upon hippocampal area CA2 and oxytocin signaling. HFD-fed mice had stronger inputs onto CA2 pyramidal neurons that led to increased action potential firing, without altering intrinsic properties or inhibitory transmission. Chemogenetic CA2 pyramidal neuron inhibition in HFD-fed mice rescued social novelty discrimination, with novelty preference in males and familiarity preference in females. We also observed that HFD in both males and females impaired the ability of oxytocin receptor activation to be permissive for endocannabinoid-mediated plasticity. Furthermore, chemogenetic inhibition of CA2 pyramidal neurons rescued oxytocin-induced endocannabinoid plasticity in both HFD-fed male and female mice, whereas it prevented endocannabinoid plasticity in control diet-fed mice. In a concentration-dependent manner, oxytocin restored potentiation of excitatory responses, allowed for endocannabinoid plasticity at CA2 inhibitory synapses, and rescued social novelty discrimination in HFD-fed mice. This study uncovers mechanisms linking neuromodulation and endocannabinoid-mediated plasticity in social memory processes and reveals the deleterious consequences of an obesogenic diet on this process.