Species and sex differences in brain distribution of corticotropin-releasing factor receptor subtypes 1 and 2 in monogamous and promiscuous vole species

Microtine rodents offer a well-established animal model for the comparative study of social behaviors (Insel and Young, 2001; Young and Wang, 2004). Prairie voles (Microtus ochrogaster) and pine voles (Microtus pinetorum), which exhibit monogamous social structure in nature, show species-typical social behaviors such as pair bonding, affiliation, and biparental care (Getz et al., 1981; Gruder-Adams and Getz, 1985). In contrast, congener meadow voles (Microtus pennsylvanicus) and montane voles (Microtus montanus) show a strikingly opposite social structure, demonstrating behaviors such as promiscuity, social isolation, and minimal paternal care of offspring (Salo et al., 1993; Shapiro and Dewsbury, 1990). Genetic differences that have evolved between prairie, pine, meadow, and montane voles are thought to contribute to species differences in social organization and brain receptors; these species differences in social behavior have been linked to the brain distribution of the neuropeptide receptors for oxytocin and vasopressin (Insel and Shapiro, 1992; Insel et al., 1994; Lim et al., 2004b; Young et al., 1999). Much of the research in the last decade has focused very closely on these neurohypophysial peptides and pair bonding in monogamous prairie voles. However, more recent research has uncovered another candidate neuropeptide, the corticotropin-releasing factor (CRF) system, which also appears to regulate pair bonding in monogamous prairie voles (DeVries et al., 2002). There is extensive literature linking CRF to stress, anxiety, and the regulation of the hypothalamic-pituitary-adrenal (HPA) axis. However, there are relatively few studies implicating the CRF system in social behavior. One study using prairie voles found that exogenous corticosterone administered to male prairie voles facilitated pair bond formation (DeVries et al., 1996). This effect was mimicked by swim stress, which had been previously shown to activate the HPA axis in voles, prior to pairing (DeVries et al., 1995). Adrenalectomy blocked pair bond formation, and this effect was rescued by corticosterone replacement (DeVries et al., 1996). Interestingly, the opposite phenomenon was observed in female prairie voles, where exogenous corticosterone actually inhibited partner preference formation (DeVries et al., 1996). Since CRF released from the paraventricular nucleus of the hypothalamus causes the release of ACTH from the anterior pituitary, and in turn corticosterone from the adrenal cortex, these data suggest that CRF release may play a role in stress-induced activation of the HPA axis during pair bond formation. However, a later study by the same group found that CRF administered intracerebroventricularly (i.c.v.), at doses too low to facilitate anxiety, were sufficient to facilitate partner preference in male prairie voles (DeVries et al., 2002). Central administration of alpha-helical CRF, an antagonist that binds to both CRFR1 and CRFR2, blocked partner preference in males (DeVries et al., 2002). These data suggest that CRF may play a role in pair bond formation via anxiety-independent mechanisms and through the involvement of centrally acting brain receptors. Since the CRF system has been shown to be critical for the regulation of pair bonding, one might predict that neural circuits for this peptide system would differ between monogamous and promiscuous species. In addition, because corticosterone exerts opposite effects on pair bond formation in male and female prairie voles, one might predict that sex differences could potentially exist at the level of central CRF receptors in the brain. Given that corticosterone can exert canonical feedback at both hypothalamic as well as suprahypothalamic brain regions, it is possible that corticosterone could affect CRF release centrally within the brain and, thus, depending on gender-specific CRF receptor expression, activate different neural circuits in male versus female pair bond formation (McEwen et al., 1968; Sapolsky et al., 1990). To test these hypotheses, we first mapped the distributions of CRFR1 and CRFR2 in male and female prairie and meadow voles using receptor autoradiography. As an additional axis of comparison, we mapped CRFR1 and CRFR2 brain distribution in a different species pair, the monogamous pine vole and the promiscuous montane vole. We show evidence for both species and sex differences in several brain regions that could be related to the differences in their social structure across the four species. Based on a semiquantitative comparison of CRF receptor distributions found in the four vole species to rat, mouse, and rhesus macaque distributions found in previous studies (Aguilera et al., 1987; De Souza et al., 1985; Potter et al., 1994; Primus et al., 1997; Rominger et al., 1998; Sanchez et al., 1999; Steckler and Holsboer, 1999; Van Pett et al., 2000), we discuss putative brain CRF systems that appear to be 1) evolutionarily conserved across species, 2) plastic between species, and 3) potentially associated with monogamous social organization.