Assessment of estradiol influence on spatial tasks and hippocampal CA1 spines: Evidence that the duration of hormone deprivation after ovariectomy compromises 17β-estradiol effectiveness in altering CA1 spines

McLaughlin, Katie J.; Bimonte‐Nelson, Heather A.; Neisewander, Janet L.; Conrad, Cheryl D.

doi:10.1016/j.yhbeh.2008.04.010

Cited by 92 publications

(95 citation statements)

References 95 publications

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“…A recent study by Snyder et al (27) confirms our original finding that E2 increases synaptic NR2B-mediated current, and because these authors did not find an increase in NR2B expression, they suggested that the increase in current was due to lateral movement of NR2B-containing receptors into the synapse. However, in contrast to our findings and those of Snyder et al (27), Adams et al (38) reported no increase in NR2B-containing receptors in synapses of young animals treated with E2. Other studies have found no increase in axospinous synapse or dendritic spine densities in E2-treated aged animals (39,40).…”

Section: Discussioncontrasting

confidence: 99%

“…This increase in NR2B current is consistent with results from 23-to 24-mo-old rats, in which E2 was found to stimulate lateral movement of NR2B-containing NMDARs into the synapse (38). A recent study by Snyder et al (27) confirms our original finding that E2 increases synaptic NR2B-mediated current, and because these authors did not find an increase in NR2B expression, they suggested that the increase in current was due to lateral movement of NR2B-containing receptors into the synapse.…”

Section: Discussionsupporting

confidence: 91%

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Duration of estrogen deprivation, not chronological age, prevents estrogen's ability to enhance hippocampal synaptic physiology

Smith

Vedder

Nelson

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Whether estrogen replacement is beneficial to cognitive health is controversial. Some studies have shown that estrogen replacement therapy (ERT) relieves memory impairment associated with menopause in women, whereas others suggest that estrogen not only is incapable of providing a benefit, but actually can be detrimental. One possible explanation for this discrepancy in study findings could be the varying time after menopause at which ERT is initiated. It has been proposed that a critical period exists during which ERT must be administered to enhance cognitive function. This idea has yet to be tested directly using functional synaptic studies, however. Here we investigated whether prolonged hormone deprivation caused by ovariectomy (OVX) in young adult rats prevents the ability of estrogen replacement to increase synaptic function in the hippocampus to a degree necessary for estrogen-induced improvement in learning and memory. Remarkably, estrogen replacement was found to increase long-term potentiation, the current mediated by NR2B-containing NMDA receptors, and the dendritic spine density at CA3-CA1 synapses up to 15 months post-OVX. However, by 19 months post-OVX, the same estrogen replacement was unable to induce these changes. Importantly, this loss of estrogen's effectiveness was seen to be a consequence of the duration of deprivation. In female rats aged with their ovaries intact and examined at the same chronological age as the 19-month post-OVX group, estrogen replacement significantly increased synaptic function and spine density. These data clearly demonstrate that a critical period exists during which ERT must be administered, and that once this period passes, the beneficial effects are lost.C ognitive function fluctuates across the menstrual cycle in women, with increased learning occurring when plasma estrogen levels are highest (1, 2). As such, loss of endogenous estrogen production after menopause, a consequence of normal aging, has been correlated with cognitive deficits (3). Treatment with estrogen replacement therapy (ERT) is not always successful in alleviating this hormone-related cognitive decline (4, 5). This lack of benefit of ERT may be explained by the critical period hypothesis, which proposes that there is a critical period after reproductive senescence during which estrogen is capable of increasing hippocampal function to a sufficient degree to enhance memory processing. After this period, ERT might be ineffective and possibly even detrimental (6, 7).Hippocampal learning is increased during proestrus in cycling rats, and this effect can be mimicked in young adult ovariectomized (OVX) rats treated with the ovarian estrogen 17β-estradiol (E2) (8-11). Similar to women, rats that experience long-term ovarian hormone deprivation no longer benefit from E2's effects on enhancing hippocampal learning (12-15). The role of ovarian hormone senescence in the effectiveness of E2 replacement in enhancing learning is difficult to distinguish from normal aging processes, given that aging alone is kn...

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionsupporting

confidence: 91%

Duration of estrogen deprivation, not chronological age, prevents estrogen's ability to enhance hippocampal synaptic physiology

Smith

Vedder

Nelson

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…The open field and object location/recognition procedures for this experiment were implemented as previously described (McLaughlin et al 2008). For the open field, rats were placed in the arena and allowed to explore for 10 min.…”

Section: Methodsmentioning

confidence: 99%

“…We hypothesized that PFCX and sex will influence acquisition, extinction, and recall of extinction in fear conditioning. Given the dearth of studies using females and to further characterize the effects of PFCX on behavior, we then tested sham and PFCX male and female rats on several other tasks that have been used in past studies following chronic stress and may be influenced, in part, by PFC function, including the Y-maze (Conrad et al 2004;McLaughlin et al 2007), object location (Beck and Luine 2002;McLaughlin et al 2008), and object recognition (Beck and Luine 2002). Figure 1 illustrates the time line leading up to brain processing.…”

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confidence: 99%

Prefrontal cortex lesions and sex differences in fear extinction and perseveration

Baran¹,

Armstrong²,

Niren³

et al. 2010

Learn. Mem.

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Electrolytic lesions of the medial prefrontal cortex (PFCX) were examined using fear conditioning to assess the recall of fear extinction and performance in the Y-maze, open field, and object location/recognition in male and female Sprague-Dawley rats. Rats were conditioned to seven tone/footshocks, followed by extinction after 1-h and 24-h delays, revealing PFCX effects and sex differences during all phases of fear conditioning. In male rats, PFCX impaired 24-h recall of fear extinction to tone, which required the 1-h delay extinction and was not attributed to nonassociative factors. In contrast, sham and PFCX females increased freezing to tone following a 24-h delay, whether or not 1-h delay tone extinction was presented. Moreover, PFCX females failed to extinguish to tone, contrasting to the robust extinction to tone that was observed for sham females, PFCX, and sham males. Also, sex differences were found during acquisition, with sham females acquiring fear conditioning slower than PFCX females. By the last tone-shock presentation, sham and PFCX females showed a slight but significant reduction in freezing to tone relative to those of sham and PFCX males. Of the other behavioral measures, PFCX females maintained exploration of a novel object during object recognition when sham females habituated. PFCX did not influence other behaviors in the remaining tasks. These findings show important sex differences in PFC function, with the PFC influencing the recall of fear extinction in males and contributing to the acquisition and maintenance of fear extinction memory in females, perhaps through altering perseveration.

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“…Published November 12, 2010. Estrogen receptors affect several neurotransmission systems in many areas, including the catecholaminergic, serotoninergic and gabaergic ones, interfering with cognitive functioning. One of the actions of estrogen is to enhance the density of the dendritic spines in the neurons of the CA1 area in the hippocampus (1). Progesterone contributes to the same action within 6-8 h of ingestion, and returns to basal levels rapidly (2).…”

Section: Introductionmentioning

confidence: 99%

Effects of isoflavone on the learning and memory of women in menopause: a double-blind placebo-controlled study

Santos-Galduróz

Galduróz

Facco

et al. 2010

Braz J Med Biol Res

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Assessment of estradiol influence on spatial tasks and hippocampal CA1 spines: Evidence that the duration of hormone deprivation after ovariectomy compromises 17β-estradiol effectiveness in altering CA1 spines

Cited by 92 publications

References 95 publications

Duration of estrogen deprivation, not chronological age, prevents estrogen's ability to enhance hippocampal synaptic physiology

Duration of estrogen deprivation, not chronological age, prevents estrogen's ability to enhance hippocampal synaptic physiology

Prefrontal cortex lesions and sex differences in fear extinction and perseveration

Effects of isoflavone on the learning and memory of women in menopause: a double-blind placebo-controlled study

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