عامل آزاد کننده کورتیکوتروپین باعث القا ترجیحات اجتماعی در موش های صحرایی نر

Abstract Exposure to stressors facilitates the formation of social preferences in monogamous male prairie voles (Microtus ochrogaster). In the present study, the hypothesis was tested that treatment with corticotropin-releasing factor (CRF), a neuropeptide released during stress, is capable of inducing social preferences in male prairie voles. The effects of five doses of CRF (0.01, 0.1, 1.0, 10 and 100 ng; i.c.v.) on social preference were assessed. Exogenous CRF did not alter the amount of social contact that occurred between the experimental animal and partner during the initial cohabitation period. However, when tested after 3 h of cohabitation, animals that had been treated with 0.1 or 1.0 ng CRF spent significantly more time in physical contact with the partner than a stranger. In contrast, 3 h of cohabitation was not sufficient to induce social preferences in animals pre-treated with an artificial CSF vehicle or other doses of CRF. Furthermore, co-administration of a CRF receptor antagonist prevented the formation of CRF-induced social preferences. These data provide support for a role of the hypothalamic–pituitary–adrenal axis in social bonding in prairie voles.

Introduction Monogamy is rare among mammals, and is particularly uncommon among rodents (Kleiman, 1977). Prairie voles (Microtus ochrogaster) are small rodents that exhibit many characteristics of monogamy, including the formation of selective social bonds (reviewed in Carter et al., 1995). In the laboratory, social preferences can be induced by housing a male and female prairie vole together for several hours ( Williams et al., 1992, DeVries et al., 1995 and DeVries et al., 1996) or pharmacologically induced in a shorter period of time by treating animals prior to pairing with vasopressin ( Winslow et al., 1993 and Cho et al., 1999), oxytocin ( Williams et al., 1994, Cho et al., 1999, Cushing and Carter, 2000 and Insel and Hulihan, 1995), corticosterone ( DeVries et al., 1996), or a dopamine (D2) receptor agonist ( Wang et al., 1999 and Gingrich et al., 2000). Whether these neurochemicals act through a common pathway or distinct pathways to induce social preferences in prairie voles remains to be determined. Exposing male prairie voles to a moderate stressor also facilitates the induction of social preferences (DeVries et al., 1996). The effects of stress on social preference can be replicated by treatment with exogenous corticosterone, the predominant glucocorticoid released by prairie vole adrenal glands during stress (DeVries et al., 1996). Another potential mediator of stress-induced social bonding is corticotropin releasing factor (CRF). CRF is released from the paraventricular nucleus (PVN) of the hypothalamus and subsequently acts on the hypophysis to cause the release of adrenocorticotropic hormone (ACTH) into the bloodstream; ACTH in turn induces the synthesis and release of glucocorticoids from the adrenal cortex (reviewed in Jacobson and Sapolsky, 1991). In addition to its endocrine role, CRF is a behaviorally active compound. In rats and mice, treatment with exogenous CRF decreases exploratory behavior (Berridge and Dunn, 1987 and Berridge and Dunn, 1989) and increases anxiety (Schulz et al., 1996). The present study examines the hypothesis that CRF is capable of facilitating the development of social preferences in male prairie voles. The goal of the current study was to determine if central administration of CRF (i) alters social interaction, (ii) facilitates the onset of social preferences and (iii) depends on CRF receptors to induce changes in social preference. Taken together, these data offer a more complete understanding of the role of the hypothalamic–pituitary–adrenal axis in social bonding in prairie voles.

Results 3.1. Effects of CRF on social interaction during cohabitation period There were no significant differences among experimental groups treated with exogenous CRF versus the vehicle in latency to establish physical contact (F(5,42)=0.56, P>0.05 Fig. 1A) or duration of physical contact (F(5,42)=1.17, P>0.05, Fig. 1B) during the 3 h cohabitation period. Furthermore, animals treated with a cocktail mixture of 1 ng CRF+1 ng CRF antagonist did not differ from animals treated with 1 ng CRF in latency to establish physical contact (t=0.14, P>0.05) or duration of physical contact (t=0.09, P>0.05). The average number of aggressive encounters during the cohabitation period was less than one in each experimental group, thus the aggression data did not warrant statistical analysis. The cohabitation data for two animals (0.1 ng and 100 ng) were lost due to equipment failure. Data are presented as (A) latency to initiate physical contact (in s; mean±SEM) ... Fig. 1. Data are presented as (A) latency to initiate physical contact (in s; mean±SEM) and (B) duration of physical contact (in min; mean±SEM). Male prairie voles received an ICV injection of the vehicle (VEH; aCSF), CRF (0.01, 0.1, 1.0, 10 or 100 ng) or a cocktail mixture of CRF+CRF antagonist (1 ng CRF +1 ng α-helical CRF9-41) then were housed with their partner for 3 h during which time their behavior was recorded. There were no statistically significant differences among treatment groups in either measure (P>0.05). Figure options 3.2. Effects of CRF on social preference Treatment with either 1 ng CRF (t=2.54, P<0.05; n=8) or 0.1 ng CRF (t=3.13, P<0.05; n=8; Fig. 2) resulted in a significant social preference for the familiar partner. In contrast, there was no difference in the amount of time spent in physical contact with the partner versus the stranger in groups treated with the vehicle (t=0.99, P>0.05; n=9), 0.01 CRF (t=0.60, P>0.05, n=8), 10 ng CRF (t=0.50, P>0.05; n=9), or 100 ng CRF (t=0.37, P>0.05; n=8). Also, there were no significant differences among groups in total time spent in physical contact (F(5,44)=0.82, P>0.05) or general activity (F(5,44)=2.34, P>0.05). CRF (1 ng) induced a partner preference (t=2.54, P<0.05, n=8) that was blocked when CRF was co-administered with 1 ng of a CRF receptor antagonist (t=0.04, P>0.05, n=8; Fig. 2). There were no significant differences between 1 ng CRF and 1 ng CRF+Antagonist groups in total time spent in physical contact (F(1,14)=0.02, P>0.05) or general activity (F(1,14)=1.87, P>0.05). Data are presented as time in physical contact (in min, mean±SEM) during a 3 h ... Fig. 2. Data are presented as time in physical contact (in min, mean±SEM) during a 3 h social preference test. Male prairie voles received an ICV injection of the vehicle (VEH; aCSF), CRF (0.01, 0.1, 1.0, 10 or 100 ng) or a mixture of CRF and the antagonist (1 ng CRF +1 ng α-helical CRF9-41). Following injection, the experimental animals were housed with their partner for a 3 h cohabitation period then tested for social preference. Treatment with either 1 ng or 0.1 ng CRF resulted in a significant preference for the familiar partner. Animals that were treated with the mixture of CRF+CRF antagonist spent a similar amount of time in physical contact with the partner and stranger. An asterisk indicates statistical significance at P<0.05. Figure options 3.3. Effects of CRF antagonist on social interaction and preferences During the 3 h cohabitation period, there were no differences among groups in latency to initiate physical contact (F(3,26)=0.86, P>0.05) or duration of physical contact (F(3,26)=2.22, P>0.05). Furthermore, during the preference test, there were no significant social preferences exhibited by animals treated with aCSF (t=0.32, n=8, P>0.05), 1 ng CRF antagonist (t=0.18, n=8, P>0.05), 10 ng CRF antagonist (t=0.0.76, n=8, P>0.05) or 100 ng CRF antagonist (t=0.81, n=8, P>0.05).