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1 2 3 Behavioral responses to emotional challenges in female rats living in a seminatural 4 5 6 environment: The role of estrogen receptors 7 8 9 10 11 Olivia Le Moëne and Anders Ågmo 12 13 14 15 16 Department of Psychology, University of Tromsø, Norway 17 18 19 Corresponding author: [email protected] 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 2 61 62 Abstract: 63 64 65 Estrogen receptors (ERs) are involved in sexual as well as non-sexual behaviors. In the 66 67 present study we assessed the effects of stimuli inducing positive or negative affect on 68 69 sociosexual, exploratory and fear-related behaviors of female rats housed in groups (4 70 71 females, 3 males) in a seminatural environment. Ovariectomized females were treated with 72 73 74 oil, 17β-estradiol benzoate (EB, 18 μg/kg), the ERα agonist propylpyrazoletriol (PPT), or the 75 76 ERβ agonist diarylpropionitrile (DPN) (both 2 x 10 mg/rat). On the test day, the females were 77 78 exposed to a sequence of events consisting of lavender odor, Mozart’s Sonata for Two Pianos 79 80 K448, chocolate pellets, white noise and fox odor (2,3,5-Trimethyl-3-thiazoline, TMT). All 81 82 these events are known to induce positive or negative affect. Behavior was carefully observed 83 84 from the video record. White noise suppressed sexual behaviors and reduced the time spent in 85 86 the open area of the environment. TMT had no consistent effect whereas exposure to music 87 88 caused avoidance of the open area. Exposure to chocolate increased exploratory and social 89 90 91 behavior. Lavender odor enhanced exploratory behavior. PPT and EB stimulated sexual 92 93 behaviors, whereas DPN was ineffective. Co-occurrence analyses of the sequence of 94 95 behavioral patterns revealed that PPT and EB consistently belonged to clusters different from 96 97 oil and DPN, whereas DPN was separate from oil only under fear-inducing experimental 98 99 conditions. These data, from a procedure with external validity, confirm that the ERα is 100 101 crucial for sexual behaviors, that these behaviors are reduced under stressful conditions, and 102 103 that the ERβ may have some role in fear-related behaviors. 104 105 106 107 108 Key words: seminatural environment, sexual behavior, social behavior, fear, positive emotion, 109 110 co-occurrence analysis, propylpyrazoletriol, diarylpropionitrile 111 112 113 114 115 116 117 118 119 3 120 121 1. Introduction 122 123 Female rodents only express sexual behavior when their brain is exposed to 124 125 appropriate concentrations of ovarian hormones. Estrogens and progesterone normally act 126 127 synergistically, but high doses of estrogens can activate all aspects of female sexual behavior 128 129 130 in the absence of progesterone, whereas progesterone is ineffective in the absence of 131 132 estrogens regardless of dose (e.g. Södersten & Eneroth, 1982). It is known that all female 133 134 sexual behaviors, including being attractive for males and being attracted to males (reviewed 135 136 in Le Moëne & Ågmo, 2017) as well as the display of paracopulatory behaviors and lordosis 137 138 (e.g. Ogawa et al., 1998; Rissman et al., 1997), are dependent on the estrogen receptor α 139 140 (ERα). The estrogen receptor β (ERβ) does not contribute to these behaviors, since female 141 142 mice lacking this receptor show perfectly normal sexual behaviors (Ogawa et al., 1999; Walf 143 144 et al., 2008; Antal et al., 2012) and since ERβ agonists are unable to activate these behaviors 145 146 147 in ovariectomized female rats (Mazzucco et al., 2008). 148 149 In addition to being necessary for the display of sexual behaviors, estrogens have several 150 151 behavioral effects, some of which may be relevant for the sex behaviors. Among those, 152 153 modifications of fear and anxiety responses might be particularly important. There are also 154 155 data suggesting that estrogens may alter the response to events inducing positive affect, for 156 157 example the ingestion of tasty foods like sucrose or chocolate (e.g. Clarke & Ossenkopp, 158 159 1998; Reynaert et al., 2016). However, the effects of fear-inducing stimuli or situations or of 160 161 stimuli causing positive affect on sexual behavior in female rats have not been studied. In 162 163 fact, available data are limited to studies of the effects of stress on subsequent sexual 164 165 166 behavior. It can be argued that fear stimuli activate stress responses, and studies of stress 167 168 could therefore provide some information about the potential effects of fear on sexual 169 170 behavior. Acute stress in the form of short restraint reduces the display of female copulatory 171 172 behavior in females rendered sexually receptive with estradiol alone, whereas no effect was 173 174 observed in females given estradiol + progesterone (Truitt et al., 2003). When females can 175 176 177 178 4 179 180 pace sexual interaction, restraint reduces the time spent with the male as well as the number 181 182 183 of mounts received regardless of the presence or absence of progesterone. Receptivity was not 184 185 modified, though (Uphouse et al., 2005). Interestingly, restraint stress had no effect in a test 186 187 for sexual incentive motivation (Uphouse et al., 2008). It appears, then, that acute stress has 188 189 minor or no consequences for female sexual behavior. Chronic stress, however, has 190 191 consistently been found to facilitate the display of lordosis and paracopulatory behavior and 192 193 to reduce rejections (Brotto et al., 1999; Williams et al., 1992). 194 195 A common feature of all these studies is that they have evaluated the effects of prior, 196 197 but not present, stress. Thus, the immediate consequences of fear-inducing stimuli for sexual 198 199 behavior remains unknown. There is, however, abundant evidence for a role of estrogens in 200 201 202 non-sexual, anxiety-like responses. Treatment of ovariectomized mice and rats with estradiol 203 204 has been reported to enhance the time spent on the open arms of an elevated plus maze (e.g. 205 206 Nomikos & Spyraki, 1988), or in the center of an open field (e.g. Walf & Frye, 2007), and to 207 208 reduce a passive avoidance response (Díaz-Véliz et al., 1997). All these effects are usually 209 210 interpreted as suggesting reduced fear or anxiety. Other studies have failed to find an effect of 211 212 estradiol in anxiety tests (e.g. Walf & Frye, 2008; Martínez-Mota et al., 2000), and still others 213 214 found anxiogenic effects (Mora et al., 1996). One hypothesis proposed to account for these 215 216 contradictory observations is that estrogens are anxiogenic in threatening environments and 217 218 219 anxiolytic in safe environments (Morgan & Pfaff, 2001). Such an effect could conceivably be 220 221 useful for assuring that another ERα dependent behavior, copulation, occurs more easily in 222 223 safe than in dangerous environments (see, e.g. Frye et al., 2006, for an elaboration of this 224 225 argument). Direct experimental evidence for this conjecture is lacking, though. 226 227 The anxiolytic-like effects of estrogens are often attributed to actions at the ERβ. Mice 228 229 without a functional ERβ are more fearful than the wildtype (Krezel et al., 2001), and 230 231 treatment with a selective ERβ agonist reduces fear in female rats (Kudwa et al., 2014) and 232 233 234 235 236 237 5 238 239 mice (Krezel et al., 2001; Oyola et al., 2012; Walf et al., 2008b), whereas selective ERα 240 241 242 agonists are ineffective. It has also been reported that ERα knock-out mice are not different 243 244 from the wildtype in several of the anxiety procedures (Krezel et al., 2001). However, 245 246 anxiogenic effects of a selective ERα agonist in fear-inducing environments (elevated plus 247 248 maze and novel open field) have been reported (Lund et al., 2005). It has also been found that 249 250 the ERα is anxiogenic in the light/dark box and in a brightly lit open field (Spiteri et al., 251 252 2010b; Spiteri et al., 2012). Thus, it can be proposed that ERα and ERβ agonists might have 253 254 opposite effects in fear-inducing contexts. 255 256 One of the purposes of the present study was to determine whether fear-inducing 257 258 stimuli actually inhibit female sexual behavior, and if agonists selective for the ERα and ERβ 259 260 261 would have different effects on the nonsexual responses to these stimuli. To that end, 262 263 ovariectomized females were given either estradiol or selective ER agonists. Fear was induced 264 265 by exposing the females to a 90 dB white noise or to synthetic fox odor. Loud noise as well as 266 267 2,5-dihydro-2,4,5-trimethylthiazoline (TMT) produce strong fear responses in rats (e.g. 268 269 Endres et al., 2005; Fendt et al, 2005; Homiack et al., 2017; Weyers et al., 1994). 270 271 Another purpose of this study was to evaluate the effects of stimuli inducing positive 272 273 affect rather than fear, and the potential role of the ERs for responses to such stimuli. 274 275 Estrogen-modulation of responses to attractive, non-sexual stimuli have only been 276 277 278 systematically studied with regard to food ingestion. It is well known that estrogens reduce 279 280 food intake (e.g. Butera, 2010).

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