ERE-independent ERα signalling in feeding and exploratory behaviors

The reproductive steroid hormone, 17β-estradiol (E2), controls feeding and exploratory behaviors associated with mood disorders. The loss of circulating E2 puts menopausal women at an increased risk for developing obesity and mood disorders when compared to premenopausal women. Therefore, it is critically important to understand the role of sex steroids and their receptors in the neuroendocrine control of feeding and mood. The goal of this project is to understand the role of estrogen response Element (ERE)-dependent and ERE-independent ERα signaling on behavior by characterizing feeding patters and exploratory behaviors in male and female mice lacking either total ERα signaling or lacking ERE-dependent ERα signaling. We hypothesize that ERE-independent ERα is partially sufficient to restore feeding and exploratory behaviors that are lost in total ERα knockout mice. We tested three strains of mice: two ERα transgenic models, a total ERα knock out (ERKO) and a novel ERα knock in/knock out (KIKO) that lacks a functional DNA-binding domain) and their wild type (WT) C57 littermates using a real-time feeding behavior monitoring system and series of standard behavior tests (open field tests, elevated plus maze, forced swim test). To test our hypothesis FI and meal patterns were observed while the animals were given ad libitum access to a LFD (Experiment 1a) followed by HFD (Experiment 1b). A separate set of animals the response to fasting was monitored for 24 h after caloric restriction (Experiment 1c). Exploratory, depressive, and locomotor behavior testing was conducted on mice from Experiments 1a/b (open field, elevated plus maze, forced swim test). Each experiment was initially done with intact animals and then again repeated in ovariectomized (OVX) animals split into either an oil treated control group or an E2-treated group. We observed ERE-dependent mechanisms are the main modulator of homeostatic LFD feeding meal patterns while ERE- independent ERα signaling was involved in the control of palatable, high-fat diet food intake. During refeeding, ERE-independent mechanisms contribute to a decreased first meal food intake and slower rate of ingestion. When observed during a series of behavior tests, WT animals explored more, regardless of treatment (differences could be attributed to higher levels of locomotor activity in WT). However, similarities between WT and KIKO females in the EPM indicate that ERE-independent pathways may contribute towards reducing anxiety measures, independent of locomotor activity. WT females were shown to have a decreased free float time, indicating ERE dependent signaling may be influencing despair like tendencies. Collectively, these suggest that both ERE-dependent and -independent ERαsignaling are involved with both feeding and anxiety like homeostatic parameters.M.S.Includes bibliographical reference