Among its various neural actions, estradiol exhibits growth- or neurite-promoting properties for neurons of the developing brain. Toran-Allerand (1-4) first demonstrated that estrogen elicits the selective enhancement of axon and dendrite (neurite) growth and differentiation in developing estrogen target regions of the hypothalamus, preoptic area, and cerebral cortex (1,2,6-8) (Fig. 1). This neurite-promoting property of estradiol is expressed only during development and never in the adult brain that is normally exposed to estrogen. However, following damage in the adult to estrogen target brain regions, as

Fig. 1. (B) Exogenous estradiol (50 ng/mL) added to the culture medium. There is a significant enhancement of neurite growth from the same region of the homologous explant half, with extensive arborization of neurites in the outgrowth. (Adapted with permission from ref. 2.)

a result of loss of trophic support, whether through axotomy, deafferentation, or steroid deprivation, responsiveness to estrogen returns and estrogen can again be shown to influence the regrowth and differentiation of neurite-derived structures such as axons, dendrites and their spines, and synapses (9,10). In this respect, therefore, estrogen should be added to the growing list of important growth- or neurite-promoting molecules such as growth factors, including the members of the neurotrophin family of peptides (e.g., nerve growth factor [NGF], brain-derived neurotrophic factor [BDNF], neurotrophin-3 [NT-3], neurotrophin-4/5 [NT-4/5], and neurotrophin-6 [NT-6]).

Overlapping regions of the male and female forebrain that subserve cognitive functions, such as the basal forebrain, cerebral cortex, and hippocampus, are not only targets of estrogen and the neurotrophins, but sites of estrogen and neurotrophin synthesis as well. Such an association directs attention to the possible importance of steroid/ neurotrophin interactions for their neurons. In neurons of the developing and adult fore-brain, for example, ERs are widely co-expressed with the neurotrophins and their cognate receptors (11-13). This association has led us to question whether the neurotrophic aspects of estrogen's actions in the developing CNS may be mediated, at least in part, by interactions of estrogen with the neurotrophin ligands or their receptors (14,15).

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