Neuroscience
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Although several randomized controlled trials of surgically menopausal women have provided evidence that estrogen protects aspects of memory, many cross-sectional and longitudinal studies, including those from the Women's Health Initiative Memory Study, have failed to confirm these findings. One critical difference between studies that found a protective effect of estrogen on memory and those that did not is that, in the former studies, treatment with estrogen began at the time of menopause and in the latter studies, it was first administered many years after the menopause had occurred. Recent evidence from rodent, nonhuman primate, and human studies consistently suggests that the timing of the initiation of estrogen treatment with regard to the menopause may be critical to our understanding of the estrogenic effect on memory. Results of these animal and human studies indicate that the initiation of estrogen treatment at the time of menopause, or soon after ovariectomy, provides a window of opportunity for the protection of memory in females whereas the administration of the hormone following a considerable delay in time after ovariectomy or following a natural menopause has little or no beneficial effect on cognition.
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The aging process is known to coincide with a decline in circulating sex hormone levels in both men and women. Due to an increase in the average lifespan, a growing number of post-menopausal women are now receiving hormone therapy for extended periods of time. Recent findings of the Women's Health Initiative, however, have called into question the benefits of long-term hormone therapy for treating symptoms of menopause. ⋯ This review focuses on emerging information that estradiol can also activate a repertoire of membrane-initiated signaling pathways and that these rapid signaling events lead to functional changes at the cellular level. The various types of cells in the brain can respond differently to estradiol treatment based on the signaling properties of the cell, as well as which receptor, estrogen receptor alpha and/or estrogen receptor beta, is expressed. Taken together, these findings suggest that the estradiol-induced activation of membrane-initiated signaling pathways occurs in a cell-type specific manner and can differentially influence how the cells respond to various insults.
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Progestins mediate the onset and duration of lordosis, the mating posture of female rodents, through actions in the hypothalamus and ventral tegmental area. In the hypothalamus, progesterone has traditional, "genomic" actions via intracellular progestin receptors. ⋯ Data are reviewed that support the notion that: 1) effects of 3alpha-hydroxy-5alpha-pregnan-20-one in the midbrain ventral tegmental area facilitate lordosis and other reproductively-relevant behaviors. 2) 3alpha-Hydroxy-5alpha-pregnan-20-one, formed in the ventral tegmental area from metabolism of progestins, produced peripherally by endocrine glands, or centrally from biosynthesis in glial cells mediates socio-sexual behaviors. 3) 3alpha-Hydroxy-5alpha-pregnan-20-one's actions at GABA(A)/benzodiazepine receptors, NMDA type glutamate receptors, and dopamine receptors in the ventral tegmental area are important for lordosis; however, effects at these substrates on socio-sexual behaviors have not been elucidated. Given 3alpha-hydroxy-5alpha-pregnan-20-one's involvement in stress responses, its putative role as a homeostatic regulator and in the pathophysiology and treatment of neuropsychiatric disorders is discussed.
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Estrogen has the potential to influence brain processes implicated in Alzheimer's disease pathogenesis. With the loss of ovarian estrogen production after menopause, estrogen-containing hormone therapy might be expected to influence the risk of Alzheimer's disease. Observational data link use of hormone therapy to reductions in Alzheimer risk, but experimental evidence from the Women's Health Initiative Memory Study trial demonstrates that oral estrogen, with or without a progestin, increases the incidence of dementia for postmenopausal women age 65 years or older. ⋯ Finally, Women's Health Initiative Memory Study findings may not generalize to estrogen use by relatively young women during the menopausal transition or early postmenopause, a class of women who were ineligible for the Women's Health Initiative Memory Study trial. In observational studies, hormone therapy exposure often included use by younger women for menopausal vasomotor symptoms. Although there is no clinical trial evidence that hormone therapy at any age protects against Alzheimer's disease, it remains to be determined whether the age at which hormone exposure occurs or the timing of hormone therapy initiation in relation to the menopause (the critical window hypothesis) modifies treatment outcomes on dementia risk.
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Glutamate is a primary excitatory neurotransmitter in the mammalian CNS. Glutamate released from presynaptic neurons is cleared from the synaptic cleft passively by diffusion and actively by glutamate transporters. In this study, the role of glutamate transporters in sensory processing in the spinal cord has been investigated in behavioral, in vivo and in vitro experiments. ⋯ Whole cell recordings made from superficial dorsal horn neurons in an isolated whole spinal cord from newborn rats (2-3 weeks old) revealed that bath-applied L-trans-pyrrolidine-2,4-dicarboxylic acid (100 microM) produced partial membrane depolarization, increased spontaneous action potentials with decreased neuronal membrane resistance and time constant, but without significant changes of capacitance. Finally, the amplitude and duration of primary afferent evoked-excitatory postsynaptic currents recorded from neurons in the substantia gelatinosa in the spinal slices from young adult rats (6-8 weeks old) were increased in the presence of L-trans-pyrrolidine-2,4-dicarboxylic acid (100 microM). This study indicates that glutamate transporters regulate baseline excitability and responses of dorsal horn neurons to peripheral stimulation, and suggests that dysfunction of glutamate transporters may contribute to certain types of pathological pain.