Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: OXT
Cytogenetic location: 20p13 Genomic coordinates (GRCh38): 20:3,071,620-3,072,517 (from NCBI)
OXT is a 9 amino-acid peptide produced by the sympathetic nervous system (SNS) that functions as an endogenous regulator of adipose and systemic metabolism (Li et al., 2024).
The nonapeptide hormones arginine vasopressin (AVP; 192340) and oxytocin are synthesized in the supraoptic and paraventricular nuclei of the hypothalamus together with their respective 'carrier' proteins, the neurophysins (Brownstein et al., 1980). Vasopressin and oxytocin are produced by separate populations of magnocellular neurons in both nuclei. Together with the neurophysins they are packaged into neurosecretory vesicles and transported axonally to the nerve endings in the neurohypophysis, where they are either stored or secreted into the bloodstream.
The paraventricular nucleus (PVN) and the supraoptic nucleus (SON) in the rat contain estrogen-regulated oxytocin and arginine-vasopressin systems, but little or no estrogen receptor-alpha (133430). Using estradiol-treated ovariectomized young adult Sprague-Dawley rats and dual-labeled immunocytochemistry, Alves et al. (1998) showed that OXT-ir (OXT-immunoreactivity) colocalized with ESR-beta (601663)-ir in the parvicellular subnuclei of PVN but there was little AVP-/ESR-beta-ir. In contrast, in the SON, most nuclear ESR-beta-ir colocalized with AVP-ir, whereas few OXT-/ESR-beta-ir dual-labeled cells were observed. These results suggested that estrogen can directly modulate specific OXT and AVP systems through an ESR-beta-mediated mechanism, in a tissue-specific manner.
Kosfeld et al. (2005) analyzed the effect of exogenously administered oxytocin by internasal spray on individuals' decisions in a trust game with real monetary stakes. In this trust game, 2 subjects interacting anonymously played the role of either an investor or a trustee. Subjects who received oxytocin were much more likely to exhibit trust in the transfer of funds. Kosfeld et al. (2005) also showed that the effect of oxytocin on trust was not due to a general increase in the readiness to bear risks. On the contrary, they showed that oxytocin specifically affects an individual's willingness to accept social risks arising through interpersonal interactions. Kosfeld et al. (2005) concluded that their results concurred with animal research suggesting an essential role for oxytocin as a biologic basis of prosocial approach behavior.
Tyzio et al. (2006) reported a signaling mechanism in rats between mother and fetus aimed at preparing fetal neurons for delivery. In immature neurons, GABA is the primary excitatory neurotransmitter. Tyzio et al. (2006) found that shortly before delivery there was a transient reduction in the intracellular chloride concentration and an excitatory-to-inhibitory switch of GABA actions. These events were triggered by oxytocin, an essential maternal hormone for labor. In vivo administration of an oxytocin receptor antagonist before delivery prevented the switch of GABA actions in fetal neurons and aggravated the severity of anoxic episodes. Thus, maternal oxytocin inhibits fetal neurons and increases their resistance to insults during delivery.
Carbillon (2007) commented on the paper by Tyzio et al. (2006) and suggested that there is a body of evidence supporting the possibility that oxytocin is released not only from the mother, but from the fetal pituitary during delivery, particularly under conditions of hypoxic stress. Tyzio et al. (2007) tested the hypothesis that cortisol-induced release of fetal oxytocin triggers a perinatal inhibitory switch in GABA signaling. The cortisol analog methylprednisolone did not modify GABA driving force and intracellular chloride concentration in 1-day-old rat hippocampal neurons. Tyzio et al. (2007) concluded that, together with the immaturity of the fetal rat hypothalamo-neurohypophysial system, their results suggested that oxytocin in the rat fetal brain is mainly provided by the mother.
De Dreu et al. (2010) linked oxytocin to the regulation of intergroup conflict in humans. In 3 experiments using double-blind placebo-controlled designs, male participants self-administered oxytocin or placebo and made decisions with financial consequences to themselves, their in-group, and a competing out-group. Results showed that oxytocin drives a 'tend and defend' response in that it promoted in-group trust and cooperation and defensive, but not offensive, aggression toward competing out-groups.
Viviani et al. (2011) combined fluorescent retrograde tracing of central amygdala projections to nuclei that modulate fear-related freezing or cardiovascular responses with in vitro electrophysiologic recordings and with in vivo monitoring of related behavioral and physiologic parameters in rat. Central amygdala projections emerged from separate neuronal populations with different electrophysiologic characteristics and different response properties to oxytocin. In vivo, oxytocin decreased freezing responses in fear-conditioned rats without affecting the cardiovascular response. Thus, Viviani et al. (2011) concluded that neuropeptidergic signaling can modulate the central amygdala outputs through separate neuronal circuits and thereby individually steer the various aspects of the fear response.
Li et al. (2024) demonstrated that OXT is a direct inducer of lipolysis, as treatment with OXT significantly increased glycerol release from differentiated mouse adipocytes in vitro and from human adipocytes ex vivo. The authors confirmed the effect of OXT on lipolysis in vivo, as administration of OXT to wildtype mice increased serum free fatty acid levels to a degree comparable with that seen in vitro. Moreover, OXT was an endogenous regulator of lipolysis, and lipolysis promotion by OXT was synergistic to beta-agonist-induced lipolysis, as OXT facilitated and enhanced beta-adrenergic agonists to exert their full effect on lipolysis. Further analysis demonstrated that Oxt within adipose tissue originated from sympathetic neurons in mice. In corroboration, direct activation of SNS caused Oxt release from neurons innervating white adipose tissue and promoted lipolysis in adipose tissue in mice.
Sausville et al. (1985) found that the genes for prepro-arginine-vasopressin-neurophysin I and II (192340) have a similar intron-exon structure, are linked (on chromosome 20) with 12 kb intervening DNA, and are transcribed from opposite DNA strands. In a human small cell lung cancer (182280) cell line, they found that the first but not the second strand was actively transcribed. It appears that the AVP, PDYN (131340) and OXT genes constitute a cluster.
Repaske et al. (1990) identified a RFLP with XbaI within 15 kb of AVP and used this as a marker in linkage studies. They demonstrated that the AVP/OXT loci map to the distal short arm of chromosome 20 about 15 cM toward the telomere from the D20S5 locus, which is located near the middle of the short arm at 20p12.21. Summar et al. (1990) presented linkage data that placed the AVP and OXT loci at 20pter-p12.21. Growth hormone-releasing factor (139190) maps to the same general area.
Rao et al. (1992) used isotopic and fluorescence in situ hybridization to map the OXT locus to 20p13.
In the mouse, Marini et al. (1993) noted that Avp and Oxt are separated by only 3.5-kb of intergenic sequence. By interspecific backcross analysis, they mapped this pair of genes to mouse chromosome 2.
The development of social familiarity in rodents depends predominantly on olfactory cues and can critically influence reproductive success. This memory is operationally defined by a reliable decrease in olfactory investigation in repeated or prolonged encounters with a conspecific. Brain oxytocin and AVP seemed to modulate a range of social behavior from parental care to mate guarding. AVP administration may enhance social memory, whereas OXT administration may either inhibit or facilitate social memory, depending on dose, route, or paradigm. Ferguson et al. (2000) found that male mice mutant for the Oxt gene failed to develop social memory, whereas wildtype mice showed intact social memory. These and other observations indicated that oxytocin is necessary for the normal development of memory in mice and supported the hypothesis that social memory has a neural basis distinct from other forms of memory.
Kavaliers et al. (2006) demonstrated that female mice use olfactory input to acquire what is known as 'inadvertent social information' (ISI), or indirect social cues, to determine their social interest in males and mate choice. Compared to wildtype female mice, Oxt-null females showed an impaired ability to use olfactory information to modulate their response to males, suggesting that Oxt is necessary for proper processing of ISI and for integration of both direct and indirect social information.
Jin et al. (2007) showed that adult Cd38 (107270) knockout female and male mice showed marked defects in maternal nurturing and social behavior, respectively, with higher locomotor activity. Consistently, the plasma level of oxytocin, but not vasopressin (192340), was strongly decreased in Cd38-null mice. Replacement of oxytocin by subcutaneous injection or lentiviral vector-mediated delivery of human CD38 in the hypothalamus rescued social memory and maternal care in Cd38-null mice. Depolarization-induced oxytocin secretion and calcium ion elevation in oxytocinergic neurohypophysial axon terminals were disrupted in Cd38-null mice. This was mimicked by Cd38 metabolite antagonists in Cd38 wildtype mice. Jin et al. (2007) concluded that CD38 has a key role in neuropeptide release, thereby critically regulating maternal and social behaviors, and may be an element in neurodevelopmental disorders.
Alves, S. E., Lopez, V., McEwen, B. S., Weiland, N. G. Differential colocalization of estrogen receptor beta (ER-beta) with oxytocin and vasopressin in the paraventricular and supraoptic nuclei of the female rat brain: an immunocytochemical study. Proc. Nat. Acad. Sci. 95: 3281-3286, 1998. [PubMed: 9501254] [Full Text: https://doi.org/10.1073/pnas.95.6.3281]
Brownstein, M. J., Russell, J. T., Gainer, H. Synthesis, transport, and release of posterior pituitary hormones. Science 207: 373-378, 1980. [PubMed: 6153132] [Full Text: https://doi.org/10.1126/science.6153132]
Carbillon, L. Comment on "Maternal oxytocin triggers a transient inhibitory switch in GABA signaling in the fetal brain during delivery." Science 317: 197 only, 2007. [PubMed: 17626868] [Full Text: https://doi.org/10.1126/science.1141090]
De Dreu, C. K. W., Greer, L. L., Handgraaf, M. J. J., Shalvi, S., Van Kleef, G. A., Baas, M., Ten Velden, F. S., Van Dijk, E., Feith, S. W. W. The neuropeptide oxytocin regulates parochial altruism in intergroup conflict among humans. Science 328: 1408-1411, 2010. [PubMed: 20538951] [Full Text: https://doi.org/10.1126/science.1189047]
Ferguson, J. N., Young, L. J., Hearn, E. F., Matzuk, M. M., Insel, T. R., Winslow, J. T. Social amnesia in mice lacking the oxytocin gene. Nature Genet. 25: 284-288, 2000. [PubMed: 10888874] [Full Text: https://doi.org/10.1038/77040]
Jin, D., Liu, H.-X., Hirai, H., Torashima, T., Nagai, T., Lopatina, O., Shnayder, N. A., Yamada, K., Noda, M., Seike, T., Fujita, K., Takasawa, S., and 20 others. CD38 is critical for social behaviour by regulating oxytocin secretion. Nature 446: 41-45, 2007. [PubMed: 17287729] [Full Text: https://doi.org/10.1038/nature05526]
Kavaliers, M., Choleris, E., Agmo, A, Braun, W. J., Colwell, D. D., Muglia, L. J., Ogawa, S., Pfaff, D. W. Inadvertent social information and the avoidance of parasitized male mice: a role for oxytocin. Proc. Nat. Acad. Sci. 103: 4293-4298, 2006. [PubMed: 16537524] [Full Text: https://doi.org/10.1073/pnas.0600410103]
Kosfeld, M., Heinrichs, M., Zak, P. J., Fischbacher, U., Fehr, E. Oxytocin increases trust in humans. (Letter) Nature 435: 673-676, 2005. [PubMed: 15931222] [Full Text: https://doi.org/10.1038/nature03701]
Li, E., Wang, L., Wang, D., Chi, J., Lin, Z., Smith, G. I., Klein, S., Cohen, P., Rosen, E. D. Control of lipolysis by a population of oxytocinergic sympathetic neurons. Nature 625: 175-180, 2024. [PubMed: 38093006] [Full Text: https://doi.org/10.1038/s41586-023-06830-x]
Marini, J. C., Nelson, K. K., Battey, J., Siracusa, L. D. The pituitary hormones arginine vasopressin-neurophysin II and oxytocin-neurophysin I show close linkage with interleukin-1 on mouse chromosome 2. Genomics 15: 200-202, 1993. [PubMed: 8432536] [Full Text: https://doi.org/10.1006/geno.1993.1034]
Rao, V. V. N. G., Loffler, C., Battey, J., Hansmann, I. The human gene for oxytocin-neurophysin I (OXT) is physically mapped to chromosome 20p13 by in situ hybridization. Cytogenet. Cell Genet. 61: 271-273, 1992. [PubMed: 1486803] [Full Text: https://doi.org/10.1159/000133420]
Repaske, R., Phillips, J. A., III, Kirby, L. T., Tze, W. J., D'Ercole, A. J., Battey, J. Molecular analysis of autosomal dominant neurohypophyseal diabetes insipidus. J. Clin. Endocr. Metab. 70: 752-757, 1990. [PubMed: 1968469] [Full Text: https://doi.org/10.1210/jcem-70-3-752]
Sausville, E., Carney, D., Battey, J. The human vasopressin gene is linked to the oxytocin gene and is selectively expressed in a cultured lung cancer cell line. J. Biol. Chem. 260: 10236-10241, 1985. [PubMed: 2991279]
Summar, M. L., Phillips, J. A., III, Battey, J., Castiglione, C. M., Kidd, K. K., Maness, K. J., Weiffenbach, B., Gravius, T. C. Linkage relationships of human arginine vasopressin-neurophysin-II and oxytocin-neurophysin-I to prodynorphin and other loci on chromosome 20. Molec. Endocr. 4: 947-950, 1990. [PubMed: 1978246] [Full Text: https://doi.org/10.1210/mend-4-6-947]
Tyzio, R., Cossart, R., Khalilov, I., Minlebaev, M., Hubner, C. A., Represa, A., Ben-Ari, Y., Khazipov, R. Maternal oxytocin triggers a transient inhibitory switch in GABA signaling in the fetal brain during delivery. Science 314: 1788-1792, 2006. [PubMed: 17170309] [Full Text: https://doi.org/10.1126/science.1133212]
Tyzio, R., Cossart, R., Khalilov, I., Represa, A., Ben-Ari, Y., Khazipov, R. Response to comment on "Maternal oxytocin triggers a transient inhibitory switch in GABA signaling in the fetal brain during delivery." Science 317: 197 only, 2007.
Viviani, D., Charlet, A., van den Burg, E., Robinet, C., Hurni, N., Abatis, M., Magara, F., Stoop, R. Oxytocin selectively gates fear responses through distinct outputs from the central amygdala. Science 333: 104-107, 2011. [PubMed: 21719680] [Full Text: https://doi.org/10.1126/science.1201043]