A Reevaluation of the Concept of Separable Periods of Organizational and Activational Actions of Estrogens in Development of Brain and Behavior^a

Sex differences in anxiety and depression: Role of testosterone

“…The influence of these gonadal hormones in adulthood, traditionally known as activational effects (Arnold and Breedlove, 1985, Williams, 1986) or hormonally modulated responses (McCarthy and Konkle, 2005), may also activate sex differences in many biological processes. Various animal models and methods can be utilized to distinguish between organizational and activational effects of hormones that may ameliorate the display of anxiety- and depressive-like behaviors.…”

Estrogen Actions in the Brain and the Basis for Differential Action in Men and Women: A Case for Sex-Specific Medicines

“…For example, in humans and in species used in research, administration of androgens to females may induce aspects of male-typical behavior that revert to normal once hormone treatment ceases; the cyclical rise and fall in levels of ovarian hormones in women and animal species used in research also influences many behaviors (Kelly et al, 1999;Halpern and Tan, 2001;Cahill, 2006;Goldstein, 2006;Wilson and Davies, 2007). These are traditionally called activational (reversible) effects (Arnold and Breedlove, 1985;Williams, 1986) or hormonally modulated responses (McCarthy and Konkle, 2005), which dictate sex differences at molecular, cellular, and functional levels but are not in themselves true dimorphisms. However, not all features of adult brain activity that exhibit sex differences are trans-sexual; that is, they cannot be equalized if an equivalent hormonal environment is created experimentally in both sexes by the administration of sex hormones to gonadectomized animals.…”

“…With increasing attention on the sexually dimorphic nature of other brain regions, it is now apparent that the critical period for hormonal influences on sex differentiation may extend later into development and may involve androgen-as well as estrogen-dependent mechanisms. In particular, pubertal hormones may exert organizational influences on structures such as the hippocampus and amygdala as well as hypothalamic regions, including the anteroventricular periventricular nucleus and sexually dimorphic nucleus of the preoptic area (POA), where sex differences in regional volumes and the addition of new cells have been identified in humans and animals used in research (Williams, 1986; Gonad-intact-intact female brain: compared with young rats (10 weeks), numbers of ER␤ mRNA-positive cells were reduced in the olfactory bulb, cerebral cortex, hippocampus, N.Acc, parts of the amygdala and raphe nuclei in middle-age (12 months), but did not decline further in aged animals (24 months); by contrast, numbers in hippocampus, striatum, claustrum, SN and cerebellum did not change by middle-age, but decreased in old rats: age-dependent changes are region specific (Yamaguchi-Shima and Yuri, 2007).…”

Estradiol Activates Group I and II Metabotropic Glutamate Receptor Signaling, Leading to Opposing Influences on cAMP Response Element-Binding Protein

“…The effects of estradiol on CREB phosphorylation are sex specific and occur via a membrane receptor The previous experiments were performed on hippocampal cultures generated solely from female animals, because many of the characterized actions of estradiol in the brain are sex specific (Arnold and Breedlove, 1985;Williams, 1986). Thus, we next investigated whether the bidirectional effects of estradiol observed in female-derived cultures would also occur in those prepared from male rats.…”