Estrogen Therapy and Cognition: A Review of the Cholinergic Hypothesis

Gibbs, Robert G.

doi:10.1210/er.2009-0036

Cited by 175 publications

(172 citation statements)

References 295 publications

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“…Collectively, results from previous animal behavioral studies and our synaptic physiology studies demonstrate that a critical window exists during which E2 replacement is beneficial for hippocampal function. However, the duration of the window is variable and depends on the chronological age at the time of OVX as well as the duration of hormone deprivation (32)(33)(34). Thus, precisely defining the duration of the critical period will require investigations that simultaneously combine measures of synaptic physiology, morphology, and behavior within the same cohort of ovariectomized animals at various chronological ages and durations of hormone deprivation.…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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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“…Given that both 8-OH-DPAT and EE confer similar behavioral benefits after TBI and affect corresponding targets, one of which is the cholinergic neurotransmitter system (Barnes and Sharp, 1999;Fujii et al, 1997;Krech et al, 1960;Lazaris et al, 2003;Paban et al, 2005;Park et al, 1992;Segovia et al, 2009). which is involved in learning and memory (Gibbs, 2010;Gold, 2003;Hasselmo, 2006;Sarter et al, 2003), we hypothesized that the combination of therapies would be more efficacious than either alone in attenuating brain trauma-induced choline acetyltransferase-positive (ChAT þ ) cell loss and promoting behavioral recovery.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of a Combined Therapeutic Regimen of 8-OH-DPAT and Environmental Enrichment after Experimental Traumatic Brain Injury

Kline

McAloon²,

Henderson³

et al. 2010

Journal of Neurotrauma

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126

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When provided individually, both the serotonin (5-HT 1A )-receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and environmental enrichment (EE) enhance behavioral outcome and reduce histopathology after experimental traumatic brain injury (TBI). The aim of this study was to determine whether combining these therapies would yield greater benefit than either used alone. Anesthetized adult male rats received a cortical impact or sham injury and then were randomly assigned to enriched or standard (STD) housing, where either 8-OH-DPAT (0.1 mg/kg) or vehicle (1.0 mL/kg) was administered intraperitoneally once daily for 3 weeks. Motor and cognitive assessments were conducted on post-injury days 1-5 and 14-19, respectively. CA1/ CA3 neurons and choline acetyltransferase-positive (ChAT þ ) medial septal cells were quantified at 3 weeks. 8-OH-DPAT and EE attenuated CA3 and ChAT þ cell loss. Both therapies also enhanced motor recovery, acquisition of spatial learning, and memory retention, as verified by reduced times to traverse the beam and to locate an escape platform in the water maze, and a greater percentage of time spent searching in the target quadrant during a probe trial in the TBI þ STD þ 8-OH-DPAT, TBI þ EE þ 8-OH-DPAT, and TBI þ EE þ vehicle groups versus the TBI þ STD þ vehicle group ( p 0.0016). No statistical distinctions were revealed between the TBI þ EE þ 8-OH-DPAT and TBI þ EE þ vehicle groups in functional outcome or CA1/CA3 cell survival, but there were significantly more ChAT þ cells in the former ( p ¼ 0.003). These data suggest that a combined therapeutic regimen of 8-OH-DPAT and EE reduces TBI-induced ChAT þ cell loss, but does not enhance hippocampal cell survival or neurobehavioral performance beyond that of either treatment alone. The findings underscore the complexity of combinational therapies and of elucidating potential targets for TBI.

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“…Nevertheless, it is important that investigators consider the possible effects of sex steroid hormones on neural function and behavior in their experimental designs and data interpretation. However, when thinking about sex differences in brain function or behavior, it is important to note whether differences are due to the activational effects of circulating hormones in adulthood or from organizational effects of hormones in early development, as it has been argued that only the latter can be construed as a true sex difference (McCarthy and Konkle 2005).Numerous recent reviews have discussed the effects of E 2 on learning and memory in females (Korol 2002;Foster 2005;Daniel 2006Daniel , 2013Sherwin and Henry 2008;Barha and Galea 2010;Bimonte-Nelson et al 2010;Gibbs 2010;Kim and Casadesus 2010;Choleris et al 2012;Foster 2012;Frick 2012;Acosta et al 2013;Chisolm and Juraska 2013;Ervin et al 2013;Galea et al 2013;Hogervorst 2013;Luine and Frankfurt 2013;Maki 2013;Bean et al 2014;Luine 2014;Frankfurt and Luine 2015;Tuscher et al 2015). As such, this review will not attempt to provide a comprehensive discussion of all effects of E 2 on learning and memory.…”

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confidence: 99%

Sex steroid hormones matter for learning and memory: estrogenic regulation of hippocampal function in male and female rodents

et al. 2015

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Ample evidence has demonstrated that sex steroid hormones, such as the potent estrogen 17b-estradiol (E 2 ), affect hippocampal morphology, plasticity, and memory in male and female rodents. Yet relatively few investigators who work with male subjects consider the effects of these hormones on learning and memory. This review describes the effects of E 2 on hippocampal spinogenesis, neurogenesis, physiology, and memory, with particular attention paid to the effects of E 2 in male rodents. The estrogen receptors, cell-signaling pathways, and epigenetic processes necessary for E 2 to enhance memory in female rodents are also discussed in detail. Finally, practical considerations for working with female rodents are described for those investigators thinking of adding females to their experimental designs.Hormones have long been known to play key roles in regulating learning and memory. Many hormones, including epinephrine, glucocorticoids, and insulin influence learning and memory via inverted U-shaped dose-response relationships in which memory is enhanced by moderate, but not low or high, hormone levels (Roozendaal 2000;Korol and Gold 2007;McNay and Recknagel 2011). Research from the past two decades has demonstrated that sex steroid hormones, particularly the potent estrogen 17b-estradiol (E 2 ), also regulate learning and memory in male and female rodents via an inverted U-shaped dose-response function that is influenced by estrogen receptor expression (Packard and Teather 1997a;Packard 1998;Foster 2012). Yet E 2 has not gained widespread acceptance as a hormonal modulator of memory in both females and males, perhaps because the majority of this research has been conducted in female rodents. Moreover, the common view of E 2 as a "female" hormone may contribute to the misperception that E 2 is not relevant for cognitive function in males. However, considerable evidence supports a vital role for E 2 in mediating neural function and behavior in male rodents. Therefore, it is important for investigators working with males to understand the ways in which E 2 and other sex steroid hormones (e.g., androgens, progestins, and other estrogens) may influence their brain regions and behaviors of interest.Another reason for investigators to be cognizant of sex steroid hormone-induced regulation of learning and memory is that males and females may respond differently to various treatments and environmental factors. A classic example is that of acute stress, which enhances classical conditioning and increases apical CA1 dendritic spine density in male rats, but impairs classical conditioning and decreases CA1 spine density in female rats (Wood and Shors 1998;Shors et al. 2001). Therefore, investigators hoping to comply with National Institutes of Health policies that encourage the inclusion of females in biomedical research must be aware that adding females to a study is not as simple as adding another group. In some ways, females are fundamentally different from males, the most obvious of which is the presence of reproductive...

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Estrogen Therapy and Cognition: A Review of the Cholinergic Hypothesis

Cited by 175 publications

References 295 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

Evaluation of a Combined Therapeutic Regimen of 8-OH-DPAT and Environmental Enrichment after Experimental Traumatic Brain Injury

Sex steroid hormones matter for learning and memory: estrogenic regulation of hippocampal function in male and female rodents

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