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Induction of PGE2 by estradiol mediates developmental masculinization of sex behavior

Abstract

Adult male sexual behavior in mammals requires the neuronal organizing effects of gonadal steroids during a sensitive perinatal period. During development, estradiol differentiates the rat preoptic area (POA), an essential brain region in the male copulatory circuit. Here we report that increases in prostaglandin-E2 (PGE2), resulting from changes in cyclooxygenase-2 (COX-2) regulation induced by perinatal exposure to estradiol, are necessary and sufficient to organize the crucial neural substrate that mediates male sexual behavior. Briefly preventing prostaglandin synthesis in newborn males with the COX inhibitor indomethacin permanently downregulates markers of dendritic spines in the POA and severely impairs male sexual behavior. Developmental exposure to the COX inhibitor aspirin results in mild impairment of sexual behavior. Conversely, administration of PGE2 to newborn females masculinizes the POA and leads to male sex behavior in adults, thereby highlighting the pathway of steroid-independent brain masculinization. Our findings show that PGE2 functions as a downstream effector of estradiol to permanently masculinize the brain.

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Figure 1: Early exposure to PGE2 determines adult sex behavior.
Figure 2: Neonatal administration of PGE2 or indomethacin alters spinophilin content in the developing and adult POA.
Figure 3: Estradiol and PGE2 increase dendritic spine density in the developing POA.
Figure 4: Estradiol upregulates COX-2 mRNA and protein in the developing POA.
Figure 5: Early exposure to aspirin impairs adult male copulatory behavior.

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Acknowledgements

We thank J.J. Alt for assistance with culture preparation and Golgi-Cox impregnation; J.M. Jones for the quantitative real-time PCR experiment; J.A. Mong for technical guidance in the Golgi experiment; and G.F. Ball, A.Z. Murphy and B.J. Todd for comments on the manuscript. This work was supported by a predoctoral National Research Service Award to S.K.A. (MH12862); a grant from the National Institutes of Mental Health to M.M.M. (MH52716); and by the National Institute of Child Health and Human Development (NICHD) and NIH through cooperative agreement (U54 HD28934) as part of the Specialized Cooperative Centers Program in Reproductive Research.

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Correspondence to Stuart K Amateau.

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Amateau, S., McCarthy, M. Induction of PGE2 by estradiol mediates developmental masculinization of sex behavior. Nat Neurosci 7, 643–650 (2004). https://doi.org/10.1038/nn1254

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