Hormones and Behavior 31, 221–231 (1997) Article No. HB971377 Gene Targeting Approaches to Neuroendocrinology: Oxytocin, Maternal Behavior, and Affiliation Larry J. Young, 1 James T. Winslow, Zuoxin Wang, Brenden Gingrich, Qiuxia Guo,* Martin M. Matzuk,* , ² , ‡ and Thomas R. Insel Department of Psychiatry and Behavioral Sciences and Yerkes Regional Primate Center, Emory University School of Medicine, Atlanta, Georgia 30322; and *Department of Pathology, †Department of Molecular and Human Genetics, and ‡Department of Cell Biology, Baylor College of Medicine, Houston, Texas 77030 Transgenic technology affords exciting new opportuni- 1982), milk ejection (Smith, 1989), and maternal behav- ties in the field of behavioral neuroendocrinology. We ior (Van Leengoed, Kerker, and Swanson, 1987; Ped- have extended our research into the behavioral function ersen and Prange, 1979; Pederson, Caldwell, Walker, of oxytocin in maternal and social behavior using two Ayers, and Mason, 1994). Oxytocin appears also to play transgenic approaches: (i) targeted deletion of the oxyto- a role in social behaviors, such as separation distress cin gene in mice and (ii) augmented oxytocin receptor and affiliation (Insel, 1992; Insel and Winslow, 1991; expression in the brain. Mice genetically deficient in oxy- Witt, Winslow, and Insel, 1992), as well as species-spe- tocin can mate, give birth, and display normal maternal cific social behaviors, such as pair bonding in monoga- behavior; however, milk ejection and certain aspects of mous species (Insel, 1992; Insel and Hulihan, 1995). social behavior are affected. Comparative studies of Oxytocin is a nonapeptide produced primarily in the oxytocin receptors have led to the observation that spe- cies differences in social organization are associated paraventricular (PVN) and supraoptic (SON) nuclei of with differences in receptor distribution. Specifically, the hypothalamus (Gainer and Wray, 1994). Although monogamous prairie voles and nonmonogamous, aso- OT was originally characterized as a neurohypophyseal cial montane voles exhibit different patterns of OT recep- hormone, it is now clear that OT fibers project through- tor expression in the brain. Transgenic mice have been out the brain and that OT functions as a neurotransmit- created with a reporter gene driven by the prairie vole ter. The central effects of OT are mediated by a seven- oxytocin receptor gene promoter. Analysis of the expres- transmembrane domain, G-protein-coupled receptor sion pattern suggests that it should be possible to ma- (Kimura, Tanizawa, Mori, Brownstein, and Okayama, nipulate receptor expression in the vole brain in order to 1992) that is localized in discrete brain nuclei (Barberis examine the effects of receptor distribution on behavior. and Tribollet, 1996). One of the most interesting fea-  1997 Academic Press tures of brain oxytocin pathways is the species diversity in the neuroanatomical distribution of the receptor (In- sel, Young, Witt, and Crews, 1993). This plasticity in Oxytocin (OT) has been implicated in several aspects receptor distribution suggests that OT function may of reproduction, including sexual behavior (Caldwell, vary among species and may be related to species dif- Prange, and Pederson, 1986; Witt and Insel, 1991), in- ferences in social behavior (Insel and Shapiro, 1992). duction of labor (Fuchs, Fuchs, Husslein, and Soloff, Transgenic technology now provides powerful tools for investigating the role of neuropeptides in control- 1 To whom correspondence should be addressed at Department of ling behaviors. We have begun using two strategies to Psychiatry and Behavioral Sciences, P.O. Drawer AF, Emory Univer- investigate the function of OT in reproductive and so- sity School of Medicine, Atlanta, GA 30322. Fax: (404) 727-3233. E- mail: lyoun03@unix.cc.emory.edu. cial behaviors in rodents. First, we are characterizing 0018-506X/97 $25.00 Copyright  1997 by Academic Press All rights of reproduction in any form reserved. 221