Critical Period Abstracts 2

© 2010

Hippocampal dependent learning ability correlates with N-methyl-D-aspartate (NMDA) receptor levels in CA3 neurons of young and aged rats

            (Adams, Smith et al. 2001) Download

Hippocampal N-methyl-D-Aspartate (NMDA) receptors mediate mechanisms of cellular plasticity critical for spatial learning in rats. The present study examined the relationship between spatial learning and NMDA receptor expression in discrete neuronal populations, as well as the degree to which putative age-related changes in NMDA receptors are coupled to the effects of normal aging on spatial learning. Young and aged Long-Evans rats were tested in a Morris water maze task that depends on the integrity of the hippocampus. Levels of NR1, the obligatory subunit for a functional NMDA receptor, were subsequently quantified both biochemically by Western blot in whole homogenized hippocampus, and immunocytochemically by using a high-resolution confocal laser scanning microscopy method. The latter approach allowed comprehensive, regional analysis of discrete elements of excitatory hippocampal circuitry. Neither method revealed global changes, nor were there region-specific differences in hippocampal NR1 levels between young and aged animals. However, across all subjects, individual differences in spatial learning ability correlated with NR1 immunofluorescence levels selectively in CA3 neurons of the hippocampus. Parallel confocal microscopic analysis of the GluR2 subunit of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) receptor failed to reveal reliable differences as a function of age or spatial learning ability. This analysis linking age, performance, and NR1 levels demonstrates that although dendritic NR1 is generally preserved in the aged rat hippocampus, levels of this receptor subunit in selective elements of hippocampal circuitry are linked to spatial learning. These findings suggest that NMDA receptor abundance in CA3 bears a critical relationship to learning mediated by the hippocampus throughout the life span.

Estrogen therapy and Alzheimer's dementia

            (Craig and Murphy 2010) Download

Previous studies in postmenopausal women have reported that estrogen treatment (ET) modulates the risk for developing Alzheimer's disease (AD). It has recently been hypothesized that there may be a "critical period" around the time of menopause during which the prescription of ET may reduce the risk of developing AD in later life. This effect may be most significant in women under 49 years old. Furthermore, prescription of ET after this point may have a neutral or negative effect, particularly when initiated in women over 60-65 years old. In this paper, we review recent studies that use in vivo techniques to analyze the neurobiological mechanisms that might underpin estrogen's effects on the brain postmenopause. Consistent with the "critical period" hypothesis, these studies suggest that the positive effects of estrogen are most robust in young women and in older women who had initiated ET around the time of menopause.

Long-term treatment with estrogen and progesterone enhances acquisition of a spatial memory task by ovariectomized aged rats

            (Gibbs 2000) Download

Female Sprague-Dawley rats were ovariectomized at 13 months of age. Four groups received different regimens of estrogen or estrogen plus progesterone replacement beginning either immediately, 3 months, or 10 months after ovariectomy and were compared with non-hormone-treated controls. Eight to twelve months after ovariectomy, animals were trained on a delayed matching-to-position (DMP) spatial memory task. Long-term treatment with estrogen or estrogen plus progesterone significantly enhanced acquisition of the DMP task by aged animals after long-term loss of ovarian function. Weekly administration of estrogen and progesterone was at least as effective as, if not more effective than, continuous treatment with estrogen alone. In addition, treatment initiated 3 months, but not 10 months, after ovariectomy was as effective at enhancing DMP acquisition as continuous estrogen treatment initiated immediately after ovariectomy, suggesting a window of opportunity after the loss of ovarian function during which hormone replacement can effectively prevent the effects of aging and hormone deprivation on cognitive function. These findings suggest that repeated treatment with estrogen and progesterone initiated within a specific period of time after the loss of ovarian function may be effective at preventing specific negative effects of hormone deprivation on brain aging and cognitive decline.

Surgical versus natural menopause: cognitive issues

            (Henderson and Sherwin 2007) Download

OBJECTIVE: Women who undergo both natural and surgical menopause experience the loss of cyclic ovarian production of estrogen, but hormonal and demographic differences distinguish these two groups of women. Our objective was to review published evidence on whether the premature cessation of endogenous estrogen production in women who underwent a surgical menopause has deleterious consequences for cognitive aging and to determine whether consequences differ for women if they undergo natural menopause. Studies of estrogen-containing hormone therapy are relevant to this issue. DESIGN: We reviewed evidence-based research, including the systematic identification of randomized clinical trials of hormone therapy with cognitive outcomes that included an objective measure of episodic memory. RESULTS: As inferred from very small, short-term, randomized, controlled trials of high-dose estrogen treatment, surgical menopause may be accompanied by cognitive impairment that primarily affects verbal episodic memory. Observational evidence suggests that the natural menopausal transition is not accompanied by substantial changes in cognitive abilities. For initiation of hormone therapy during perimenopause or early postmenopause when the ovaries are intact, limited clinical trial data provide no consistent evidence of short-term benefit or harm. There is stronger clinical trial evidence that initiation of hormone therapy in late postmenopause does not benefit episodic memory or other cognitive skills. CONCLUSIONS: Further research is needed on the long-term cognitive consequences of surgical menopause and long-term cognitive consequences of hormone therapy initiated near the time of surgical or natural menopause. A potential short-term cognitive benefit might be weighed when a premenopausal woman considers initiation of estrogen therapy at the time of, or soon after, hysterectomy and oophorectomy for benign conditions, although data are still quite limited and estrogen is not approved for this indication. Older postmenopausal women should not initiate hormone therapy to improve or maintain cognitive skills.

Brain aging modulates the neuroprotective effects of estrogen on selective aspects of cognition in women: a critical review

            (Sherwin and Henry 2008) Download

Although there is now a substantial literature on the putative neuroprotective effects of estrogen on cognitive functioning in postmenopausal women, it is replete with inconsistencies. The critical period hypothesis, posited several years ago, attempts to account for the discrepancies in this literature by positing that estrogen treatment (ET) will protect aspects of cognition in older women only when treatment is initiated soon after the menopause. Indeed, evidence from basic neuroscience and from the animal and human literature reviewed herein provides compelling support for the critical period hypothesis. Although it is not known with certainty why estrogen does not protect cognition and may even cause harm when administered to women over the age of 65years, it is likely that the events that characterize brain aging, such as a reduction in brain volume and in neuronal size, alterations in neurotransmitter systems, and a decrease in dendritic spine numbers, form an unfavorable background that precludes a neuroprotective effects of exogenous estrogen on the brain. Other factors that have likely contributed to the discrepancies in the estrogen-cognition literature include differences in the estrogen compounds used, their route of administration, cyclic versus continuous regimens, and the concomitant use of progestins. This critical analysis attempts to define conditions under which ET may protect aspects of cognition in aging women while also considering the cost/benefit ratio for the treatment of women aged 50-59years. Suggestions for specific future research questions are also addressed.

Estrogen therapy: is time of initiation critical for neuroprotection?

            (Sherwin 2009) Download

According to the 'critical period' hypothesis, which attempts to explain the observed discrepancies in the studies on estrogen and cognition, estrogen therapy effectively decreases cognitive decline in aging women when it is initiated around the time of menopause but not when it is started decades later. Here, I review studies in which the timing of the initiation of estrogen therapy was provided, to determine whether their findings support the 'critical period' hypothesis. The vast majority of the reviewed studies support the idea that early but not late initiation of estrogen therapy might prevent or delay cognitive decline in aging women. Nevertheless, numerous design issues, such as the specific drugs and doses that were used, the possible effects of progestins on cognition, and the failure to administer neuropsychological tests of specific cognitive domains that are sensitive to estrogen therapy confound the extant literature. In view of the reanalyzes of the Women's Health Initiative's data that show a beneficial effect of estrogen therapy on cardiac and breast diseases in women aged 50-59 years, more definitive evidence is needed to confirm that the early initiation of estrogen therapy that is continued for a few years provides enduring protection against cognitive aging 15-20 years later.

Decreased dendritic spine density on prefrontal cortical and hippocampal pyramidal neurons in postweaning social isolation rats

            (Silva-Gomez, Rojas et al. 2003) Download

The effects of postweaning social isolation (pwSI) on the morphology of the pyramidal neurons from the medial part of the prefrontal cortex (mPFC) and hippocampus were investigated in rats. The animals were weaned on day 21 postnatal (P21) and isolated 8 weeks. After the isolation period, locomotor activity was evaluated through 60 min in the locomotor activity chambers and the animals were sacrificed by overdoses of sodium pentobarbital and perfused intracardially with 0.9% saline solution. The brains were removed, processed by the Golgi-Cox stain and analyzed by the Sholl method. The locomotor activity in the novel environment from the isolated rats was increased with respect to the controls. The dendritic morphology clearly showed that the pwSI animals presented a decrease in dendritic length of pyramidal cells from the CA1 of the hippocampus without changes in the pyramidal neurons of the mPFC. However, the density of dendritic spines was decreased in the pyramidal cells from mPFC and Hippocampus. In addition, the Sholl analyses showed that pwSI produced a decrease in the number of sholl intersections compared with the control group only in the hippocampus region. The present results suggest that pwSI may in part affect the dendritic morphology in the limbic structures such as mPFC and hippocampus that are implicated in schizophrenia.


Adams, M. M., T. D. Smith, et al. (2001). "Hippocampal dependent learning ability correlates with N-methyl-D-aspartate (NMDA) receptor levels in CA3 neurons of young and aged rats." J Comp Neurol 432(2): 230-43.

Craig, M. C. and D. G. Murphy (2010). "Estrogen therapy and Alzheimer's dementia." Ann N Y Acad Sci 1205: 245-53.

Gibbs, R. B. (2000). "Long-term treatment with estrogen and progesterone enhances acquisition of a spatial memory task by ovariectomized aged rats." Neurobiol Aging 21(1): 107-16.

Henderson, V. W. and B. B. Sherwin (2007). "Surgical versus natural menopause: cognitive issues." Menopause 14(3 Pt 2): 572-9.

Sherwin, B. B. (2009). "Estrogen therapy: is time of initiation critical for neuroprotection?" Nat Rev Endocrinol 5(11): 620-7.

Sherwin, B. B. and J. F. Henry (2008). "Brain aging modulates the neuroprotective effects of estrogen on selective aspects of cognition in women: a critical review." Front Neuroendocrinol 29(1): 88-113.

Silva-Gomez, A. B., D. Rojas, et al. (2003). "Decreased dendritic spine density on prefrontal cortical and hippocampal pyramidal neurons in postweaning social isolation rats." Brain Res 983(1-2): 128-36.