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 large majority of women receiving hormone therapy initiate therapy early in life for the treatment of menopausal symptoms. However, the Women's Health Initiative Memory Study, the only randomized clinical trial to date on hormone therapy and dementia, was carried out in women age 65 and older. That trial provided important insights into the detrimental effects of hormone therapy on dementia in women initiating later in life. ⋯ To address this important issue, this review focuses on observational trials of hormone therapy and dementia risk, randomized clinical trials of hormone therapy and cognitive function, and basic science studies. These lines of research provide suggestive, but not definitive, evidence that early initiation of hormone therapy may provide cognitive benefits, particularly to verbal memory and other hippocampally mediated functions. Other forms of hormone therapy, other cognitive domains, and cyclic hormone regimens may not conform to this "critical period hypothesis." Further research is needed to test the validity and limits of this hypothesis.
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It is now clear that the study of the effects exerted by steroids on the nervous system may be considered as one of the most interesting and promising topics for biomedical research. Indeed, new effects, mechanisms of action and targets are becoming more and more evident suggesting that steroids are not only important key regulators of nervous system function but they may also represent a new therapeutic tool to combat certain diseases of the nervous system. The present review summarizes recent observations on this topic indicating that while the concept of the nervous system as a target for steroid hormones has been appreciated for decades, a promising new era for the study of these molecules and their actions in the nervous system has been initiated in the last few years.
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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.
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Dopaminergic neurons exhibit a short-latency, phasic response to unexpected, biologically salient stimuli. The midbrain superior colliculus also is sensitive to such stimuli, exhibits sensory responses with latencies reliably less than those of dopaminergic neurons, and, in rat, has been shown to send direct projections to regions of the substantia nigra and ventral tegmental area containing dopaminergic neurons (e.g. pars compacta). Recent electrophysiological and electrochemical evidence also suggests that tectonigral connections may be critical for relaying short-latency (<100 ms) visual information to midbrain dopaminergic neurons. ⋯ Significantly, virtually no retrogradely labeled neurons were found either in the superficial layers of the superior colliculus or among the large tecto-reticulospinal output neurons. Taken in conjunction with recent data in the rat, the results of this study suggest that the tectonigral projection may be a common feature of mammalian midbrain architecture. As such, it may represent an additional route by which short-latency sensory information can influence basal ganglia function.