Stimulation of median raphe terminals in dorsal CA2 reduces social investigation in male mice specifically investigating social stimulus of ovariectomized female mice.

The cornu ammonis area 2 (CA2) region is essential for social behaviors, especially in social aggression and social memory. Recently, we showed that targeted CA2 stimulation of vasopressin presynaptic fibers from the paraventricular nuclei of hypothalamus strongly enhances social memory in mice. In addition, the CA2 area of the mouse hippocampus receives neuronal inputs from other regions including the septal nuclei, the diagonal bands of Broca, supramammillary nuclei, and median raphe nucleus. However, the functions of these projections have been scarcely investigated. A functional role of median raphe (MR) - CA2 projection is supported by the MR to CA2 projections and 82% reduction of hippocampal serotonin (5-HT) levels following MR lesions. Thus, we investigated the behavioral role of presynaptic fibers from the median raphe nucleus projecting to the dorsal CA2 (dCA2). Here, we demonstrate the optogenetic stimulation of 5-HT projections to dCA2 from the MR do not alter social memory, but instead reduce social interaction. We show that optical stimulation of MR fibers excites interneurons in the stratum radiatum (SR) and stratum lacunosum moleculare (SLM) of CA2 region. Consistent with these observations, we show that bath application of 5-HT increases spontaneous GABA release onto CA2 pyramidal neurons and excites presumed interneurons located in the SR/SLM. This is the first study, to our knowledge, which investigates the direct effect of 5-HT release from terminals onto dCA2 neurons on social behaviors. This highlights the different roles for these inputs (i.e., vasopressin inputs regulating social memory versus serotonin inputs regulating social interaction).