Journal of Steroid Biochemistry & Molecular Biology 74 (2000) 365 – 373 Estrogens, brain and behavior: studies in fundamental neurobiology and observations related to women’s health Donald W. Pfaff *, Nandini Vasudevan, H. Kami Kia, Yuan-Shan Zhu, Johnny Chan, Joan Garey, Maria Morgan, Sonoko Ogawa Laboratory of Neurobiology and Behaior, The Rockefeller Uniersity, 1230 York Aenue, New York, NY 10021, USA Abstract Mechanisms and consequences of the effects of estrogen on the brain have been studied both at the fundamental level and with therapeutic applications in mind. Estrogenic hormones binding in particular neurons in a limbic-hypothalamic system and their effects on the electrophysiology and molecular biology of medial hypothalamic neurons were central in establishing the first circuit for a mammalian behavior, the female-typical mating behavior, lordosis. Notably, the ability of estradiol to facilitate transcription from six genes whose products are important for lordosis behavior proved that hormones can turn on genes in specific neurons at specific times, with sensible behavioral consequences. The use of a gene knockout for estrogen receptor  (ER) revealed that homozygous mutant females simply would not do lordosis behavior and instead were extremely aggressive, thus identifying a specific gene as essential for a mammalian social behavior. In dramatic contrast, ER knockout females can exhibit normal lordosis behavior. With the understanding, in considerable mechanistic detail, of how the behavior is produced, now we are also studying brain mechanisms for the biologically adaptive influences which constrain reproductie behaior. With respect to cold temperatures and other environmental or metabolic circumstances which are not consistent with successful reproduction, we are interested in thyroid hormone effects in the brain. Competitive relations between two types of transcription factors — thyroid hormone receptors and estrogen receptors have the potential of subserving the blocking effects of inappropriate environmental circumstances on female reproductive behaviors. TRs can compete with ER both for DNA binding to consensus and physiological EREs and for nuclear coactivators. In the presence of both TRs and ERs, in transfection studies, thyroid hormone coadministration can reduce estrogen-stimulated transcription. These competitive relations apparently have behavioral conse- quences, as thyroid hormones will reduce lordosis, and a TR gene knockout will increase it. In sum, we not only know several genes that participate in the selective control of this sex behavior, but also, for two genes, we know the causal routes. Estrogenic hormones are also the foci of widespread attention for their potential therapeutic effects improving, for example, certain aspects of mood and cognition. The former has an efficient animal analog, demonstrated by the positive effects of estrogen in the Porsolt forced swim test. The latter almost certainly depends upon trophic actions of estrogen on several fundamental features of nerve cell survival and growth. The hypothesis is raised that the synaptic effects of estrogens are secondary to the trophic actions of this type of hormone in the nucleus and nerve cell body. © 2000 Elsevier Science Ltd. All rights reserved. Keywords: Estrogen; Women; Hormone www.elsevier.com/locate/jsbmb 1. Fundamental neurobiology: neuroendocrine mechanisms for a mammalian behavior 1.1. Hormone binding, genes actiated, and neural circuitry for the execution of a behaior 1.1.1. Hormone binding phenomena The initial entry into mechanisms by which hor- mones could facilitate instinctive behaviors was by the examination of radioactive estrogen binding properties expressed by neurons in the forebrain [1]. Viewed from a 1999 perspective, the retention of labeled estrogens revealed the functions of both ER and ER, as well as other neuronal hormone binding components if such exist. Our autoradiographic studies demonstrated a lim- bic-hypothalamic system which included both estrogen- * Corresponding author. Tel.: +1-212-3278666; fax: 1-212- 3278666. E-mail address: pfaff@rockvax.rockefeller.edu (D.W. Pfaff). 0960-0760/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved. PII:S0960-0760(00)00114-X