C-FOS CHANGES FOLLOWING AN AGGRESSIVE ENCOUNTER IN FEMALE CALIFORNIA MICE: A SYNTHESIS OF BEHAVIOR, HORMONE CHANGES AND NEURAL ACTIVITY E. S. DAVIS* AND C. A. MARLER Department of Psychology, University of Wisconsin-Madison, Madison, WI, USA Abstract—Although there has been growing interest in the neuroanatomical and physiological mechanisms underlying aggressive behavior, little work has focused on possible mechanisms controlling natural plasticity in aggression. In the current study, we used naturally occurring changes in aggression level displayed by female Peromyscus californi- cus across the estrous cycle and parallel changes in c-fos expression to examine possible brain regions involved in mediating this plasticity. We found that c-fos expression was increased in females exposed to a conspecific female in- truder compared with control females in numerous brain regions thought to be involved in the control of aggression. More importantly, we found that c-fos increased in the bed nucleus of the stria terminalis (BNST) and ventral lateral septum (LSv) only in the more aggressive, diestrous females, and not in the less aggressive, proestrous and estrous fe- males. Conversely, c-fos increased in the medial amygdala (MeA) across all stages of estrus compared with controls, suggesting the MeA is not involved in mediating changes in individual levels of aggression. Moreover, we found correla- tions between several measures of aggression and c-fos expression in the BNST and LSv but not the MeA, again suggesting a role in mediating aggression plasticity for the former two but not the latter brain region. We further hypoth- esize that the BNST and the LSv may be involved more generally in mediating natural changes in aggression, such as increases often observed after individuals win aggressive interactions against conspecifics. © 2004 IBRO. Published by Elsevier Ltd. All rights reserved. Key words: aggression, c-fos, bed nucleus of the stria terminalis, lateral septum, plasticity, estrous cycle. Much of the current research on aggression has con- cerned the underlying physiological mechanisms, both hormonal and neural, that control the expression of ag- gression. From attempts to detail possible neural net- works involved in aggression (e.g. Delville et al., 2000), to research on the influence of exogenous steroid abuse on aggression (DeLeon et al., 2002), researchers have identified a number of peripheral hormones, neuro- chemicals and brain regions important to aggression. However, one important aspect of aggression control has received little attention to date. That is, the neural and physiological mechanisms underlying naturally oc- curring, individual plasticity in aggression are largely unknown. For example, winning aggressive encounters against conspecifics often leads to increased future ag- gression in many species (fish: McDonald et al., 1968; Chase et al., 1994; Hsu and Wolf, 1999; birds: Ratner, 1961; Drummond and Canales, 1998; rodents: Ginsburg and Allee, 1942; Scott and Marsden, 1953; Bevan et al., 1960; Meisel et al., 1988; Meisel and Sterner, 1990; Kudryavtseva, 2000); yet, no neural mechanisms ex- plaining these changes have been identified. In addition, females of many species exhibit predictable changes in aggression that parallel stages of estrus (reviewed by Floody, 1983). Although some of the hormonal changes associated with the estrous cycle have been correlated with changes in aggression, the neural control of these changes remains largely unknown. In the current study, we investigate possible brain regions involved in medi- ating plasticity in aggression by analyzing variation in neural activity following aggression across the estrous cycle of female California mice, Peromyscus californi- cus. We previously reported differences in aggression across the estrous cycle in female California mice (Davis and Marier, 2003), a strictly monogamous species (Ribble and Salvioni, 1990; Ribble, 1991), in which both males and females exhibit high levels of aggression and parental care (Eisenberg, 1963; Dudley, 1974; Guber- nick and Alberts, 1987; Ribble and Salvioni, 1990; Bester-Meredith et al.1999; Trainor and Marler, 2001; Bester-Meredith and Marler, 2003; Davis and Marler, 2004). We found that aggression was greatest when females were in diestrus and lower when females were in proestrus (Pro) and estrus, with most proestrous fe- males failing to attack an intruder (Davis and Marler, 2003). Also, we found that progesterone (P 4 ) decreased following an encounter in both the most aggressive and, surprisingly, the least aggressive group, whereas the ratio of P 4 to testosterone (P 4 /T) decreased only in the more aggressive, diestrous females (Davis and Marler, 2003). A decrease in either the P 4 or P 4 /T ratio is *Correspondence to: E. S. Davis, Biological Sciences Department, Upham Hall, University of Wisconsin-Whitewater, Whitewater, WI, 53190, USA. E-mail address: davise@uww.edu (E. S. Davis). Abbreviations: AccN, nucleus accumbens; AH, anterior hypothalamus; ANCOVA, analysis of covariance; AVP, arginine vasopressin; BNST, bed nucleus of the stria terminalis; Cort, corticosterone; D2, diestrus day 2; D3+, diestrus day 3 or greater; DEn, endopiriform nucleus; E 2 , estradiol; LSv, lateral septum, ventral; MeA, medial amygdala; MPN, medial preoptic nucleus; NGS, normal goat serum; P 4 , progesterone; PBS-X, 2 ml Triton X-100 dissolved in 1 l PBS; Pir, piriform nucleus; Pro, proestrus; PVN, paraventricular nucleus; SCN, suprachiasmatic nucleus; T, testosterone; VMH-l, lateral ventromedial hypothalamus; ZI, zona incerta. Neuroscience 127 (2004) 611– 624 0306-4522/04$30.00+0.00 © 2004 IBRO. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.neuroscience.2004.05.034 611