Estrogen receptor alpha (ERα) mediates estrogen (E 2 ) actions in the brain and is critical for normal reproductive function and behavior. In the classical pathway, ERα binds to estrogen response elements (EREs) to regulate gene transcription. ERα can also participate in several non-classical pathways, including ERE-independent gene transcription via protein-protein interactions with transcription factors and rapid, non-genotropic pathways. To distinguish between ERE-dependent and ERE-independent mechanisms of E 2 action in vivo, we have created ERα null mice that possess an ER knock-in mutation (E207A/G208A; "AA"), in which the mutant ERα cannot bind to DNA but retains activity in ERE-independent pathways (ERα −/AA mice). Understanding the molecular mechanisms of ERα action will be helpful in developing pharmacological therapies that differentiate between ERE-dependent and -independent processes. This review focuses on how the ERα −/AA model has contributed to our knowledge of ERα signaling mechanisms in estrogen regulation of the reproductive axis and sexual behavior. Keywordsestrogen receptor alpha; estrogen response element; non-classical signaling; negative feedback; sexual behaviorThe biological effects of estrogens are mediated through at least two distinct nuclear receptors, ERα and ERβ, which belong to the nuclear hormone receptor superfamily (Mangelsdorf et al., 1995). In the classical pathway of estrogen action, E 2 binds to ER, inducing conformational changes within the receptor that promote dimerization and interaction with coactivator and corepressor molecules. The ligand-receptor complex binds with high affinity to specific estrogen response elements (EREs) in the regulatory regions of target genes to either activate or repress gene expression (Glass, 1994;McKenna et al

Summary In most species, females time reproduction to coincide with fertility. Thus, identifying factors that signal fertility to the brain can provide access to neural circuits that control sexual behaviors. In vertebrates, levels of key signaling molecules rise at the time of fertility to prime the brain for reproductive behavior [1–11], but how and where they regulate neural circuits is not known [12, 13]. Specifically, 17α,20β-dihydroxyprogesterone (DHP) and prostaglandin F2α (PGF2α) levels rise in teleost fish around the time of ovulation [10, 14, 15]. In an African cichlid fish, Astatotilapia burtoni, fertile females select a mate and perform a stereotyped spawning routine, offering quantifiable behavioral outputs of neural circuits. We show that within minutes, PGF2α injection activates a naturalistic pattern of sexual behavior in female A. burtoni. We also identify cells in the brain that transduce a prostaglandin signal to mate, and show that the gonadal steroid DHP modulates mRNA levels of the putative receptor for PGF2α (Ptgfr). We use CRISPR/Cas9 to generate the first targeted gene mutation in A. burtoni, and show that Ptgfr is necessary for the initiation of sexual behavior, uncoupling sexual behavior from reproductive status. Our findings are consistent with a model in which PGF2α communicates fertility status via Ptgfr to circuits in the brain that drive female sexual behavior. Our targeted genome modification in a cichlid fish shows that dissection of gene function can reveal basic control mechanisms for behaviors in this large family of species with diverse and fascinating social systems [16, 17].

The results indicate that sildenafil may improve learning by modulating NO-cGMP signal transduction, a pathway implicated in age-related cognitive decline and neurodegenerative disease.

No abstract