ARCHIVAL REPORT Long-Term Social Recognition Memory Is Mediated by Oxytocin-Dependent Synaptic Plasticity in the Medial Amygdala Rotem Gur, Alex Tendler, and Shlomo Wagner Background: Recognition of specific individuals is fundamental to mammalian social behavior and is mediated in most mammals by the main and accessory olfactory systems. Both these systems innervate the medial amygdala (MeA), where activity of the neuropeptide oxytocin is thought to mediate social recognition memory (SRM). The specific contribution of the MeA to SRM formation and the specific actions of oxytocin in the MeA are unknown. Methods: We used the social discrimination test to evaluate short-term and long-term SRM in adult Sprague-Dawley male rats (n ¼ 38). The role of protein synthesis in the MeA was investigated by local application of the protein synthesis blocker anisomycin (n ¼ 11). Synaptic plasticity was assessed in vivo by recording the MeA evoked field potential responses to stimulation of the main (n ¼ 21) and accessory (n ¼ 56) olfactory bulbs before and after theta burst stimulation. Intracerebroventricular administration of saline, oxytocin, or oxytocin receptor antagonist was used to measure the effect of oxytocin on synaptic plasticity. Results: Anisomycin application to the MeA prevented the formation of long-term SRM. In addition, the responses of MeA neurons underwent long-term depression (LTD) after theta burst stimulation of the accessory olfactory bulb, but not the main accessory bulb, in an oxytocin-dependent manner. No LTD was found in socially isolated rats, which are known to lack long-term SRM. Finally, accessory olfactory bulb stimulation before SRM acquisition blocked long-term SRM, supporting the involvement of LTD in the MeA in formation of long-term SRM. Conclusions: Our results indicate that long-term SRM in rats involves protein synthesis and oxytocin-dependent LTD in the MeA. Key Words: Long-term depression, long-term memory, medial amygdala, oxytocin, social recognition, synaptic plasticity M ammalian social organizations require the ability of an individual to recognize and remember other individuals of the same species (conspecifics) (1). In rodents, this social recognition memory (SRM) is mediated mainly by chemical cues (semiochemicals) perceived via the main olfactory system and accessory olfactory system (AOS) (2). When semiochemicals bind to the receptors expressed by the sensory neurons of the main olfactory epithelium and vomeronasal organ, these neurons convey sensory information to the main olfactory bulb (MOB) and accessory olfactory bulb (AOB), respectively (3). Both the MOB and the AOB project to the medial amygdala (MeA), which transfers the information to the hippocampus through the lateral septum (4). The contribution of each of these brain stations to the processing of social information is still unclear. The innate tendency of rodents to investigate novel conspe- cifics more persistently than familiar ones enables quantitative assessment of SRM (5). Using the social recognition paradigm, SRM was initially shown to be retained for 2 hours (6). However, we and others demonstrated that both mice and rats retain SRM for at least 1 week if housed in groups. In contrast, socially isolated animals lose their ability to acquire long-term SRM within 24 hours (7,8). Long-term memory storage in the brain is mediated by a molecular process termed memory consolidation (9). This process is associated with protein synthesis that supports long-term synaptic plasticity, the most common forms of which are long- term potentiation (LTP) and long-term depression (LTD) of the synaptic current (10). These two types of synaptic plasticity were well studied in the CA3-CA1 synaptic pathway of the hippo- campus, where LTP is induced by application of several brief high- frequency (50–100 Hz) stimuli, and LTD is induced by a prolonged (5–15 min) low-frequency (1–3 Hz) stimulation protocol (11). The long-term SRM formation was found to be dependent on the hippocampus and mediated by protein synthesis (7). How- ever, the brain regions where protein synthesis occurs during SRM consolidation have remained elusive. Also involved in SRM acquisition is the neuropeptide oxytocin, best known for its role in enhancing contractions of the uterus during labor and mediating milk release from mammary glands during suckling (12). Oxytocin activity in the brain plays an important role in mammalian social behavior (13). It acts through binding to the oxytocin receptor, a G protein–coupled receptor that is encoded in mammals by a single gene (14). In rodents, oxytocin activity in the MeA is crucial for SRM acquisition (15,16), but its mode of action is unknown. In the present study, we hypothesized that at least some of the molecular processes that are required for long- term SRM consolidation, such as protein synthesis, occur in the MeA and that they are augmented by the activity of oxytocin to enhance SRM consolidation. Methods and Materials Animals Adult Sprague-Dawley male rats (8–10 wk, 270–340 g) were housed in groups of two to five animals per cage (60 cm  40 cm  20 cm) and handled daily for 2 weeks before behavioral testing. From the Sagol Department of Neurobiology, University of Haifa, Haifa, Israel. Address correspondence to Shlomo Wagner, Ph.D., Department of Neurobiology and Ethology, Faculty of Natural Sciences, University of Haifa, Mt. Carmel, Haifa 31905, Israel; E-mail: shlomow@research.haifa. ac.il. Received Nov 6, 2013; revised and accepted Mar 19, 2014. 0006-3223/$36.00 BIOL PSYCHIATRY 2014;]:]]]–]]] http://dx.doi.org/10.1016/j.biopsych.2014.03.022 & 2014 Society of Biological Psychiatry