The role of oxytocin in modulating activity of the supramammillary nucleus and social recognition memory

ABSTRACT. Deficiencies in social recognition are common in psychiatric disorders such as schizophrenia and autism spectrum disorder. Effective treatments for these deficits are scarce, largely due to limited understanding of the brain circuitry governing social recognition memory. Gaining a comprehensive understanding of this circuitry is crucial for advancing our knowledge of this specific type of memory and pinpointing potential targets for treatment. The supramammillary nucleus (SuM) of the hypothalamus is a critical brain region that integrates spatial and social information. Our preliminary findings show decreased SuM activity during social interaction and the inhibition of SuM neurons projecting to the hippocampal CA2 region has been shown to play a pivotal role in promoting social novelty. Together, these results suggest a significant role of SuMàCA2 neurons in social recognition memory. However, the cellular, synaptic, and circuit mechanisms within the SuM that drive the SuMàCA2 neurons’ inhibition and memory formation, remain elusive. Social recognition memory is modulated by the oxytocin (OT) neuropeptide. Previous research has shown an abundance of OT fibers and OT receptors (OTRs) in the SuM, and recently we demonstrated that OTRs activity within the SuM is necessary for social recognition memory in rats. However, it remains unknown whether and how OT affects activity of SuM OTR- expressing neurons (SuM-OTR+) and SuMàCA2 projection neurons to facilitate social recognition memory. This proposal aims to address these key knowledge gaps by investigating the cellular and synaptic (Aim 1), as well as circuit mechanisms (Aim 2) through which OTR activation and SuM-OTR+ neurons impact the activity of SuMàCA2 projecting neurons to drive the formation of social recognition memory. Based on the scientific premise and our preliminary data, our overarching hypothesis proposes that by exciting SuM-OTR+ interneurons, OTRs inhibit SuMàCA2 activity, thereby facilitating the acquisition of social recognition memory. To test this hypothesis, we will employ a novel OTR-Cre rat line combined with in vitro electrophysiology and peptide optogenetics to test if, by exciting SuM-OTR+ GABA-ergic interneurons, OTR indirectly inhibits SuMàCA2 projection neurons in vitro (Aim 1). We will also use projection-specific chemogenetics to directly examine whether activating SuM-OTR+ neurons facilitates the acquisition of social recognition memory and whether this effect is abolished by the concurrent activation of SuMàCA2 neurons. Additionally, we will apply fiber photometry in behaving rats, combined with manipulation of OTR activity, to test the hypothesis that OTR excites SuM-OTR+ neurons and inhibits SuMàCA2 neurons in vivo. Since SuM also projects to the dentate gyrus (DG), we will examine if and how OT influences SuMàDG neuron activity during social memory acquisition and retrieval (Aim 2). This proposal will elucidate the SuM’s role within the broader network of social recognition memory, uncovering the cellular and circuit mechanisms that drive this process. Therefore, it holds significant translational potential for addressing social deficits commonly observed in many neuropsychiatric disorders.