OVARIAN-STEROIDS AND THE BRAIN - IMPLICATIONS FOR COGNITION AND AGING

Ovarian steroids have many effects on the brain throughout the lifespa n, beginning during gestation and continuing into senescence. These ho rmones affect areas of the brain that are not primarily involved in re production, such as the basal forebrain, hippocampus, caudate putamen, midbrain raphe, and brainstem locus coeruleus. Here we discuss three effects of estrogens and progestins that are especially relevant to me mory processes and identify hormonal alterations associated with aging and neurodegenerative diseases. First, estrogens and progestins regul ate synaptogenesis in the CA1 region of the hippocampus during the 4- to 5-day estrous cycle of the female rat. Formation of new excitatory synapses is induced by estradiol and involves N-methyl-D-aspartate (NM DA) receptors, whereas synaptic downregulation involves intracellular progestin receptors. Second, there are developmentally programmed sex differences in the hippocampal structure that may help to explain why male and female rats use different strategies to solve spatial navigat ion problems. During the period of development when testosterone is el evated in the male, aromatase and estrogen receptors are transiently e xpressed in the hippocampus. Recent data on behavior and synapse induc tion strongly suggest that. this pathway is involved in the masculiniz ation or defeminization of hippocampal structure and function. Third, ovarian steroids have effects throughout the brain, including effects on brainstem and midbrain catecholaminergic neurons, midbrain serotone rgic pathways, and the basal forebrain cholinergic system. Regulation of the serotonergic system appears to be linked to the presence of est rogen- and progestin-sensitive neurons in the midbrain raphe, whereas the ovarian steroid influence on cholinergic function involves inducti on of choline acetyltransferase and acetylcholinesterase according to a sexually dimorphic pattern. Because of these widespread influences o n these various neuronal systems, it is not surprising that ovarian st eroids produce measurable cognitive effects after ovariectomy and duri ng aging.