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Division of Endocrinology University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania 15261
Address all correspondence and requests for reprints to: Janet Amico, Professor of Medicine, Division of Endocrinology, University of Pittsburgh School of Medicine, 541A Salk Hall, 3501 Terrace Street, Pittsburgh, Pennsylvania 15261. E-mail: jamico{at}pitt.edu.
Oxytocin (OT), a nine-amino acid peptide, is synthesized primarily in magnocellular neurons of the hypothalamic supraoptic and paraventricular nuclei, and transported to the posterior lobe of the pituitary gland for storage and release into the peripheral circulation. Peripherally released OT is essential for milk ejection during lactation and also facilitates contraction of the gravid uterus. OT that is synthesized in parvocellular neurons of the paraventricular nuclei and select forebrain areas is released within the central nervous system and believed to influence complex behaviors. OT is proposed to foster social interaction (1, 2), induce the onset of maternal behavior (3), lessen anxiety (4, 5) and aggression (6), and attenuate the neuroendocrine response to psychogenic stress (7, 8, 9, 10).
OT produces its biological actions by attaching to and activating its receptor (11). The OT receptor (OTR) belongs to the family of G protein-coupled receptors, and contains seven transmembrane domains. Activation of the receptor by OT leads to stimulation of phospholipase C and activation of G 
-q/11 (11). To date, a single gene has been identified that encodes the OTR. The OTR is expressed in reproductive-related tissues such as the mammary gland, uterus, ovary, and testis, as well as many nonreproductive-associated tissues such as the kidney, heart, osteoblast, thymus, vascular endothelium, and brain (11, 12). Species differences have been identified in the regional distribution and number of OTR binding sites in the brain. However, in most species the OTR is abundant in brain regions such as the amygdala, hippocampus, olfactory lobe, and hypothalamus (11, 12), which regulate many of the social, emotional, and neuroendocrine behaviors that OT is hypothesized to influence. The distribution and number of OTR binding sites in the brain have been reported to change during development. For example, OTRs that were identified in certain brain regions of infant rats were not identified in the same area of adult rats; the opposite has also been observed (11). Gonadal steroids regulate brain OTRs. Estrogen positively influences brain OTR expression, whereas progesterone has the opposite effect (11).
In this issue, Lee et al. (13) report the development of a conditional knockout (KO) of the OTR in selected forebrain regions of the mouse, and the physiological and behavioral consequences of this genetic manipulation. This important step forward adds to the already existing KO mouse lines in which either OT or OTR is completely absent from all tissues (total KO mice). Lee et al. (13) created OTR KO mouse lines by flanking the coding sequence of the OTR gene with loxP sites that enable Cre recombinase-mediated inactivation of the OTR gene. To create conditional OTR KO mice, the "floxed" mice were bred with a transgenic line in which Ca/calmodulin-dependent protein kinase II -promoter drives Cre recombinase to high levels only in selective areas of the forebrain, commencing at 3–4 wk of age. As a result, conditional OTR KO mice expressed OTR in peripheral tissues, but OTR binding was markedly reduced in certain brain regions (lateral septum, hippocampus, and ventral pallidum) but not others (medial amygdala, olfactory bulb, or neocortex). Total OTR KO mice expressed Cre recombinase in all tissues and, thus, lacked OTR in all tissues.
Total OTR KO mice reported by Lee et al. (13), similar to total OT KO mice (14, 15) or total OTR KO mice (16) that have been reported previously, cannot milk eject. In contrast, the conditional OTR KO mouse was able to nurse its young, indicating functionality of both mammary OTR and magnocellular OT signaling pathways that are essential for peripheral release of OT and milk ejection. Although peripherally released OT also facilitates uterine contractility during labor and delivery, parturition is not impeded in mice totally lacking either OT (14, 15) or the OTR (16), and the same was observed for total and conditional OTR KO mice generated by Lee et al. (13).
The behavioral consequences of diminished OTR binding in specific forebrain regions of a conditional OTR KO mouse are of particular interest. Numerous studies in rats suggest that central OT signaling pathways influence social, sexual, and emotional behaviors, and neuroendocrine responses to stress. Although studies in mice with total KO of either OT or OTR reaffirm this belief, the conditional OTR KO mouse has the potential to pinpoint those brain areas where OT exerts its various effects. Furthermore, by varying the temporal onset of the forebrain loss of the OTR, a conditional OTR KO line has the potential to improve our understanding of the role of OT signaling pathways upon these behaviors at various stages of development.
Both total OT KO (2) and total OTR KO (16) male mice have been reported previously to have defective social memory, although their olfactory acuity and ability to acquire other memories were indistinguishable from wild-type (WT) mice. Lee et al. (13) report impaired social recognition but with differences between the conditional and total OTR KO line. Like prior reports, total OTR KO male mice manifested social amnesia for familiar female mice, but conditional OTR KO male mice spent less time than WT cohorts investigating female mice, regardless of previous exposure. Thus, conditional OTR KO male mice appear unable to recognize or remember individual mice. Possible reasons for these differences may relate to the spatial or temporal differences in diminished OTR expression between total and conditional OTR KO mice lines (e.g. postnatal delay and incomplete loss of forebrain binding in conditional mice).
Compared with WT cohorts, neither total nor conditional OTR KO mice displayed greater sucrose consumption, which had been reported previously in OT KO mice (17). Therefore, OT deficiency alone is not likely to explain enhanced consumption of sweet solution by OT KO mice. Heterogeneity of taste receptors among mice strains and individual mice can also influence preference for sweet solutions (18).
Centrally released OT is believed to be anxiolytic, and estrogen enhances the anxiolytic effect of OT (4). OT KO female mice spend more time in the closed arms of an elevated plus maze (EPM) (a spatial test of anxiety) than WT mice, which suggests greater anxiety, and anxiety is lessened with centrally injected OT (5). In contrast, OT KO male mice spend more time in the open arms of the EPM than WT mice (5, 6). This "less fearful" behavior of OT KO vs. WT male mice in an EPM is consistent with the enhanced aggression that has been identified in OT KO vs. WT male mice during intruder tests (6). OTR KO male mice also displayed heightened aggression (intruder tests) compared with WT male mice. Lee et al. (13) tested male and female conditional and total OTR KO mice in plus maze and open field tests but found no differences from WT mice. Future anxiety related studies will be of interest in mice with targeted disruption of OTR in brain areas such as the amygdala, which is activated by anxiety and expresses OTR binding sites that are regulated by gonadal steroids (11).
Central OT facilitates maternal behavior, which was not studied in the conditional OTR KO mouse. However, maternal behavior is partially impaired in virgin OT KO mice tested with adoptive pups. OT KO dams retrieved fewer foster pups to secure locations and had diminished licking of foster pups compared with WT mice (19). Similar defects in maternal behavior were identified in OTR KO mice (16). Because the inability to milk eject has always been a limitation of studying maternal care of OT KO or OTR KO lines, the conditional OTR KO will be a valuable tool for future studies. Moreover, the enhanced neuroendocrine responses to psychogenic stress (10) and the heightened anxiety (5) and aggression (6) that have been identified in adult OT KO mice can now be assessed in the context of maternal care received in the neonatal period.
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Abbreviations: EPM, Elevated plus maze; KO, knockout; OT, oxytocin; OTR, oxytocin receptor; WT, wild type.
Received April 2, 2008.
Accepted for publication April 3, 2008.
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