We have found that the density of synapses in the stratum radiatum of the hippocampal CA1 region in the adult female rat is sensitive to estradiol manipulation and fluctuates naturally as the levels of ovarian steroids vary during the 5 d estrous cycle. In both cases, low levels of estradiol are correlated with lower synapse density, while high estradiol levels are correlated with a higher density of synapses. These synaptic changes occur very rapidly in that within approximately 24 hr between the proestrus and estrus stages of the estrous cycle, we observe a 32% decrease in the density of hippocampal synapses. Synapse density then appears to cycle back to proestrus values over a period of several days. To our knowledge, this is the first demonstration of such short-term steroid-mediated synaptic plasticity occurring naturally in the adult mammalian brain.Plasticity in the adult nervous system has historically been thought to result from changes in the physiology and/or biochemistry of neuronal circuitry, the physical structure of which has been established during early development (for review, see Arnold and Breedlove, 1985; Gould et al., 199 1). Recent evidence, however, has indicated that adult neuronal circuits are much more structurally plastic than previously thought. Several laboratories have observed naturally occurring morphologic changes in the dendrites of adult neurons that suggest ongoing modification in patterns of synaptic communication between these cells and their afferents (Meyer et al., 1978; Brandon and Goss, 1982; Burgess and Goss, 1983;Purves et al., 1986;Forger and Breedlove, 1987;Woolley et al., 1990). In this report, we present direct evidence for such synaptic plasticity in that we demonstrate naturally occurring, steroid-mediated fluctuation in the density of synapses on hippocampal pyramidal neurons in the adult mammalian brain. Our laboratory has recently shown that, in the adult female rat, the density of apical dendritic spines on CA1 hippocampal pyramidal neurons is positively correlated with circulating levels of estradiol and progesterone. We first observed changes in dendritic spine density with experimental manipulation of these hormones , and subsequently at different stages of the 5 d estrous cycle when estradiol and progesterone

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The hippocampus of the rat loses neurons with age, a loss which may eventuate in some of the functional impairments typical of senescence. Cumulative exposure to corticosterone (CORT) over the lifespan may be a cause of this neuronal loss, as it is prevented by adrenalectomy at mid-age. In this study, we demonstrate that prolonged exposure to CORT accelerates the process of cell loss. Rats were injected daily with sufficient CORT to produce prolonged elevations of circulating titers within the high physiological range. Animals treated for 3 months (chronic subjects) resembled aged rats in a number of ways. First, both groups had extensive and persistent depletions of CORT receptors in the hippocampus; in the case of chronic rats, no recovery of receptor concentrations occurred 4 months after the end of steroid treatment. Second, autoradiographic analysis revealed that the receptor depletion was due, in part, to a loss of CORT-concentrating cells, especially in the CA3 cell field. Remaining cells bound significantly less [3H]corticosterone than did those of control rats. Finally, analysis of size distributions of hippocampal cell bodies indicated that chronic subjects lost neurons of the same size as those lost in the aged hippocampus. Furthermore, chronic subjects also had increased numbers of small, darkly staining cells of CA3; these corresponded in size to the dark glia whose numbers increase in the aged hippocampus, and which are thought to infiltrate in response to neuronal damage or destruction. Thus, this study supports the hypothesis that cumulative exposure to CORT over the lifespan may contribute to age-related loss of neurons in the hippocampus, and that prolonged stress or exposure to CORT accelerates this process.

We have utilized a method to minimize cytosol progestin receptor loss during freezing in order to localize and quantify estrogen-inducible progestin receptors in individual nuclei of the female rat brain.Ovariectomized females received estradiol benzoate (20 pg for 3 days) or vehicle prior to sacrifice. All animals were perfused with cold distilled Hz0 containing the cryoprotective compound, dimethyl sulfoxide (DMSO; 10% (v/v)). Thirty-one nuclei or brain regions were removed from frozen sections (300 pm) according to the method of Palkovits (Palkovits, M. (1973) Brain Res. 59: 449-450) and were assayed in vitro using a synthetic radioligand, r3H]R5020.In ovariectomized animals perfused with DMSO, a basal level (1 to 8 fmol/mg of protein) of progestin receptors was observed in a variety of preoptic, hypothalamic, and limbic structures. Moreover, estrogen treatment induced high levels (24 to 49 fmol/mg of protein) of progestin receptors in regions of the preoptic area of hypothalamus which contain high levels of estrogen receptors. These regions included the medial, periventricular, and superchiasmatic nuclei of the preoptic area, the periventricular anterior hypothalamus, the ventromedial nucleus, and the arcuatemedian eminence. Moderate levels (2 to 8 fmol/mg of protein) of progestin receptors were induced by estrogen in other hypothalamic and limbic structures, including the anterior and lateral hypothalamus, the bed nucleus of the stria terminalis, the cingulate cortex, the medial amygdaloid nucleus, and the CA, subfield of the hippocampus. By contrast, some areas, such .as the caudateputamen and the supraoptic nucleus, were devoid of both estrogen-inducible and uninduced progestin receptors.These results support the hypothesis that progesterone action in the central nervous system is mediated by cytosol receptors in discrete brain regions and provide the first quantitative map of progestin binding in a vertebrate brain.Progesterone (P) and estradiol (E2) synergize to activate feminine reproductive behavior and to induce gonadotropin secretion in a number of vertebrate species, including the rat and guinea pig. Previous studies which have employed [3H]progesterone as a radioligand usually have failed to identify specific progestin-binding components which could mediate the central actions of P in the vertebrate brain (for references, see Feder and Marrone, 1978;McEwen, 1978).

Estrogens were found to exert a biphasic effect on the density of serotonin receptors in the female rat brain: an acute reduction in serotonin receptor density throughout the brain is followed 48 to 72 hr later by a selective increase in those brain regions known to contain estrogen receptors--hypothalamus, preoptic area, and amygdala. The acute reduction in serotonin receptor density can be mimicked by estradiol in vitro. We conclude that estradiol may have a fast, direct effect on brain membranes to modify serotonin receptor availability, while exerting a slow effect on the same receptors through an interaction with intracellular estrogen receptors in those brain regions that contain them. The observation that female sex hormones are involved in the regulation of serotonin receptors may have important implications in the understanding of female sexual behavior in the female rat and in the understanding of hormone-linked emotional disturbances in women.