Ovarian steroids have numerous effects on the brain throughout the lifespan, beginning during gestation and continuing on into senescence. These hormones affect areas of the brain that are not primarily involved in reproduction, such as the basal forebrain, hippocampus, caudate-putamen, midbrain raphe and brainstem locus coeruleus. We study four classes of actions of estrogens and progestins that are especially relevant to memory processes and their alterations during aging and neurodegenerative diseases:

First, estrogens and progestins regulate synaptogenesis in the CA1 region of the hippocampus during the 4-5d estrus cycle of the female rat. Formation of new excitatory synapses is induced by estradiol and involves NMDA receptors, whereas down-regulation of these synapses involves intracellular progestin receptors.

Second, there are developmentally-programmed sex differences in hippocampal structure that may help to explain differences in the strategies which male and female rats use to solve spatial navigation problems. During the period of development when testosterone is elevated in the male, aromatase and estrogen receptors are transiently expressed in hippocampus, and recent data on behavior and synapse induction strongly suggest that this pathway is involved in the masculin-ization or defeminization of hippocampal structure and function.

Third, ovarian steroids have widespread effects throughout the brain, including brainstem and midbrain catecholaminergic neurons, midbrain serotonergic pathways and the basal forebrain cholinergic system. Regulation of the serotonergic system appears to be linked to the presence of estrogen and progestin sensitive neurons in the midbrain raphe, whereas the ovarian steroid influence upon cholinergic function involves induction of choline acetyltransferase and acetylcholinesterase according to a sexually dimorphic pattern. Because of the widespread influences of these various neuronal systems, it is not so surprising that ovarian steroids have measurable effects on cognition that are evident after ovariectomy and during aging.

Fourth, ovarian steroids influence repair processes and exert neuroprotective effects on brain cells via the regulation of the production of inflammatory cyokines that are activated in microglial cells in aging and by damage and in diseases such as Alzheimer's

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