It has been well established that testosterone facilitates aggression during social conflict, typically seen between male mice. Testosterone exerts its neural action not only by activating androgen receptors (AR), as its original form or as 5alpha-reduced metabolite, dihydrotesterone, but also by acting through estrogen receptors (ER), after being aromatized to estradiol. It has been previously described that activation of ER at the time of testing as well as during perinatal development plays a critical role in the induction of aggressive behavior in male mice and determines the sex differences in the levels of testosterone-inducible aggression. Two forms of ERs, a classical ER-alpha and a recently discovered ER-beta, are localized in the brain areas known to be involved in testosterone-inducible aggression. The main objective of the proposed studies is to determine the specific roles played by ER-alpha and ER-beta in the regulation of aggressive behavior. In the first part, we will determine the role of ER-beta activation, at the time of testing in adulthood, in the regulation of aggressive behavior of MALE mice by: 1) comparing the levels of estrogen-inducible aggression of ER-beta gene knockout (BERKO) mice (ER-alpha specific activation) with those of their wild type littermates (BWT; ER-alpha and ER-beta activation); and 2) examining the effects of an ER-beta specific agonist on aggressive behavior induced by an ER-alpha specific agonist or an AR-specific agonist in WT male mice. In the second part of the proposal, we will determine the roles of ER-alpha and ER-beta in testosterone-inducible aggression (toward male intruder mice) in FEMALE mice. The effects of testosterone treatment will be tested in three types of knockout mice: ER-alpha knockout (aERKO), BERKO, and double knockout of ER-alpha and ER-beta genes (dERKO). In the third part of the proposal, the possibility will be tested that aERKO FEMALE mice are """"""""endogenously"""""""" sensitized for testosterone-inducible aggression by elevated levels of testosterone as a result of ER-alpha gene disruption. In the last part, we will test the hypothesis that neonatal ER-alpha, but not ER-beta, activation determines the responsiveness to aggression-promoting action of testosterone and its metabolites in adulthood, by manipulating neonatal steroid levels in FEMALE mice. The findings of the proposed studies will provide new insights concerning the specific roles and mechanisms played by the two types of ERs in the sex-specific regulation of aggressive behavior by gonadal steroids.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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Special Emphasis Panel (ZRG1-IFCN-1 (01))
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Winsky, Lois M
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Rockefeller University
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New York
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