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Abstract

Spatial navigation and social behavior are two core processes throughout the life of animals and humans. The hippocampal subregions and the medial entorhinal cortex are known as the hub structures for spatial navigation and spatial memory. Locations and territorial borders encoded in spatial maps are often social in nature. However, it remains largely unknown how these social locations become encoded in the spatial maps.

Oxytocin (OT) is the evolutionarily conserved hypothalamic neuropeptide involved in emotional behaviors, such as anxiety and fear, as well as complex social behaviors. In mammals OT is produced exclusively in the hypothalamic nuclei, which project axons to the posterior pituitary, while axon collaterals target more than 50 forebrain regions, including the entorhinal cortex (EC). My PhD project aimed to explore the role of OT signaling within the MEC and to reveal its possible role in regulation of spatial and goal-directed navigation in a social context.

Employing cell-type specific recombinant adeno-associated viruses (AAVs), I identified profound axonal innervation of all layers of MEC by axons of OT neurons in adult female rats. Next, I investigated types of OTR-expressing neurons in the MEC utilizing newly generated female OT receptor (OTR)-IRES-Cre knockin-rats in combination with Cre-dependent AAVs. At anatomical level I found two distinct types of OTR+ neurons in the MEC: principal pyramidal cells (PCs) located predominantly in layer III and parvalbumin-positive interneurons scattered throughout the extend of the entire MEC.

To tackle the functional role of MEC OTR+ neurons, I initially used the AAV-based Designer Receptors Exclusively Activated by Designer Drugs (DREADD) system to specifically silence OTR+ neurons in the MEC of adult female OTR-IRES-Cre rats in social recognition and T-maze tests. I did not observe a significant difference between animals with silenced OTR+ MEC cells and controls in both behavioral tests. However, OTR+ cells were only silenced during the testing in the T-Maze, thus, not affecting the memory acquisition phase. To cover the entirety of the memory process, in the next set of experiments, I eliminated OTR+ MEC neurons by Cre-dependent AAV, expressing modified Caspase 3, injected to OTR-IRES-Cre female rats followed by the same behavioral tests. After confirmed elimination of virtually all OTR+ MEC neurons, no differences between groups were found in the social memory test. However, in the T-Maze test the group with ablated OTR+ MEC neurons was impaired in learning of the location of a conspecific but not of a food reward. This suggests that OTR+ MEC neurons might be involved in the generation of a memory engram for the spatial location of a conspecific and in the navigation towards this location, and that the OT-sensitive MEC→CA1 pathway can modulate spatial-social navigation in rats.