Behavioral effects of estradiol therapy in ovariectomized rats depend on the age when the treatment is initiated (original) (raw)
Related papers
Psychoneuroendocrinology, 2009
Decline in the ovarian steroid, estradiol (E 2), with the menopause transition may influence cognitive and affective processing of older women and there is evidence that hormone replacement therapies (HRTs) with E 2-mimetics may provide benefit in some, but not all, women. The parameters that play a role in determining whether the response to HRTs is positive are of interest. It may be that the likelihood for positive responses is related to the timing of E 2-replacement following E 2 decline. As such, in the present study an animal model was utilized to investigate this. We investigated the effects of long-vs. short-term E 2 replacement by examining cognitive (object placement task), anxiety (open field, mirror maze, light-dark transition task), and depression (forced swim task) behavior of female rats that were ovariectomized (OVX) at middle-age (14 months) or older (19 months) and implanted with E 2-filled implants at the time of surgery or after a delay of 5 months, or OVX at 14 months of age and never replaced with E 2. Rats were tested at 20 months of age. The hypothesis that was tested was that rats would have reduced anxiety and depression behavior and improved cognitive performance with E 2-replacement at ovarian cessation, compared to with a delay in E 2-replacement. Performance in the object placement task was improved in rats that were OVX and then received continuous E 2-replacement, compared to those that were OVX and continuously administered placebo vehicle. In the open field and forced swim task, there was an increase in anti-anxiety and anti-depressive behavior, respectively, among rats that were OVX and then received continuous E 2-replacement, compared to OVX rats administered vehicle or those that experienced a delay in E 2 replacement. In the mirror maze and light-dark transition task, E 2-replacement at OVX, or after a delay, reduced anxiety-like behavior. Thus, E 2 replacement reduced anxiety and depression behavior and improved cognitive performance of aged female rats; however, delay in E 2 treatment influenced whether there were favorable effects of E 2 in some tasks.
Brain Research, 2013
Whether hormone treatment alters brain structure or has beneficial effects on cognition during aging has recently become a topic of debate. Although previous research has indicated that hormone treatment benefits memory in menopausal women, several newer studies have shown no effect or detrimental effects. These inconsistencies emphasize the need to evaluate the role of hormones in protecting against age-related cognitive decline in an animal model. Importantly, many studies investigating the effects of estrogen and progesterone on cognition and related brain regions have used young adult animals, which respond differently than aged animals. However, when only the studies that have examined the effects of hormone treatment in an aging model are reviewed, there are still varied behavioral and neural outcomes. This article reviews some of the important factors that can influence the behavioral and neural outcomes of hormone treatment including the type of estrogen administered, whether or not estrogen is combined with progesterone and if so, the type of progesterone used, as well as the route, mode, and length of treatment. How these factors influence cognitive outcomes highlights the importance of study design and avoiding generalizations from a small number of studies.
Interaction of age and chronic estradiol replacement on memory and markers of brain aging
Neurobiology of Aging, 2003
The current study examined effects of chronic estradiol replacement on cognition and biomarkers of aging. Young, middle-aged, and aged rats were ovariectomized and implanted with blank capsules, or capsules containing high or low doses of estradiol benzoate (EB). Three weeks later, animals were tested on inhibitory avoidance and cue and spatial discrimination on the Morris water maze. High plasma estradiol levels were associated with slower swim speed and impaired retention of inhibitory avoidance. No effect of EB treatment was observed for acquisition of the spatial discrimination task, however, a dose by age interaction was observed for retention of spatial discrimination such that higher retention scores were observed for young, middle-aged and aged animals under blank, low and high dose conditions, respectively. EB treatment reversed several hippocampal markers of age-related memory impairment, blocking induction of long-term depression and decreasing cytosolic calcineurin activity. Results indicate that the level of chronic hormone replacement interacts with age to influence hippocampal function.
Chronic Estradiol Treatment Improves Brain Homeostasis during Aging in Female Rats
Endocrinology, 2008
Aging is associated with a reduction in metabolic function, insulin resistance, increased incidence of neurodegenerative diseases, and memory or cognitive dysfunction. In aging females, loss of gonadal function determines the beginning of the period of reduced metabolic function. Estrogens have neuroprotective effects, but the mechanisms by which they exert these effects remain unclear. The effects of estradiol treatment on the activation of the insulin receptor substrate (IRS)-1 signaling pathway, the interactions between estrogen receptor (ER)-␣ and IRS-1 and the p85␣ subunit of phosphatidylinositol-3 kinase, together with the possible effects of estradiol treatment on glucose transporter-3 and -4 levels, were investigated in female rats. The level of expression of each glucose transporter was greater in control and estradioltreated groups than in the ovariectomized group. Interactions of ER␣46-IRS-1, ER␣46-p85␣, and p85␣-IRS-1, as well as IRS-1 phosphorylation, appeared to increase with estradiol treatment. The results indicate that estradiol treatment improves some aspects of neuronal homeostasis that are affected by aging; this may indicate that estradiol has neuroprotective effects in female rats. Additional animal studies are required to clarify the neuroprotective role of estradiol in relation to other important molecules involved in the IRS-1-phosphatidylinositol-3 kinase signaling pathway. (Endocrinology 149: 57-72, 2008)
Behavioral Neuroscience, 2012
Studies have shown that ovarian hormones protect against some of the cognitive deficits associated with aging. Although much of the literature in rodents has focused on hippocampal dependent tasks, studies suggest that tasks dependent on the prefrontal cortex are also influenced by ovarian hormones. The present study investigated the effects of ovarian hormone treatment during aging on a delayed alternation t-maze. Female Long Evans hooded rats were ovariectomized at middle age (11-12 months) and placed in one of 5 treatment groups: no replacement, chronic estradiol (E 2 ), cyclic E 2 , chronic E 2 and progesterone, or chronic E 2 and medroxyprogesterone acetate (MPA). Following six months of hormone treatment, animals were trained to alternate in a t-maze. After reaching criterion, a series of delays from 5 to 90 seconds were introduced in random order. Rats receiving E 2 with MPA reached criterion significantly faster than animals not receiving treatment and those who received chronic or cyclic E 2 only. There was a nonsignificant trend for animals receiving E 2 and progesterone to reach criterion in fewer sessions than animals receiving E 2 only. Mode of administration, cyclic or chronic, did not affect performance. Hormones did not affect performance on the delayed alternation. This study, in combination with previous research, indicates that hormone effects cannot be generalized across tasks, age or duration, and long-term estrogen in combination with MPA can be beneficial for some tasks.
Endocrinology, 2012
Menopausal women often initiate hormone treatment to alleviate the symptoms of menopause. Research suggests that these treatments also affect cognition, and studies in young animals indicate that hormone treatment can alter several neuroanatomical measures. However, very little is known about the effects of long-term hormone treatment on the aging female brain. This study investigated the effects of hormone treatment on neuron number and tyrosine hydroxylase (TH) in the rat medial prefrontal cortex (mPFC). Female Long Evans rats were ovariectomized at middle age (12-13 months) and placed in one of four groups: no replacement (NR) (n ϭ 12), 17-estradiol (E 2 ) (n ϭ 12), E 2 and progesterone (n ϭ 7), or E 2 and medroxyprogesterone acetate (MPA) (n ϭ 10). Animals were euthanized at 20 months, and the brains were Nissl stained; a subset was immunostained for TH [NR (n ϭ 5); E 2 (n ϭ 6); E 2 ϩ MPA (n ϭ 4); E 2 ϩ progesterone (n ϭ 6)]. E 2 was administered through the drinking water, and progestagens were administered via pellets inserted at the nape of the neck. Neuron number and TH fiber density were quantified in the mPFC. Hormone treatment did not alter neuron number. Treatment with E 2 and MPA resulted in greater TH densities than NR in layer 1 (P Ͻ 0.05). In layers 2/3, animals receiving E 2 had greater TH densities than NR animals (P Ͻ 0.01). These results indicate that long-term hormone treatments alter dopaminergic fibers and potentially the functioning of the aging mPFC. (Endocrinology 153: 4874 -4882, 2012)
Effects of long-term ovariectomy and estrogen treatment on maze learning in aged mice
Experimental Gerontology, 2004
Spatial memory deficits occur earlier in female than male rodents as the animals age, and the cessation of estrous cycle has been suggested to play a role in this phenomenon. We examined the effects of long-term ovariectomy (OVX) and estrogen replacement therapy (ERT) with subcutaneous 17b-estradiol minipellets on maze learning in aged (24-month-old) female C57BL/6J mice using a win-stay task (1/8 arms baited) in the radial arm maze (RAM) and a position discrimination task in the T-maze. ERT was started 40 days before the behavioral tests both in gonadally intact (sham-operated) and OVX mice. The effect of early OVX on RAM performance was investigated using three different age groups (7, 11 and 24 months) with different OVX durations (4, 8 and 19 months, respectively). ERT reduced the number of reference memory errors in RAM in aged sham-operated and OVX mice, but unlike in young mice (Heikkinen et al., 2002) it had no effect on working memory errors. Furthermore, OVX impaired the performance of aged mice in the T-maze. Comparison across the three age groups and three OVX durations indicated that the memory impairment induced by an early age OVX attenuates as the mice get close to their estropausal age.
indicates that it is impacted by age, lifetime experience, and ovarian hormone milieu. One particular domain of cognitive function that is susceptible to age-related decrements is spatial memory. Cognitive practice can affect spatial memory when aged in both males and females, and in females alone ovarian hormones have been found to alter spatial memory via modulating brain microstructure and function in many of the same brain areas affected by aging. The research in this dissertation has implications that promote an understanding of the effects of cognitive practice on aging memory, why males and females respond differently to cognitive practice, and the parameters and mechanisms underlying estrogen's effects on memory. This body of work suggests that cognitive practice can enhance memory when aged and that estrogen is a probable candidate facilitating the observed differences in the effects of cognitive practice depending on sex. This enhancement in cognitive practice effects via estrogen is supported by data demonstrating that estrogen enhances spatial memory and hippocampal synaptic plasticity. The estrogenfacilitated memory enhancements and alterations in hippocampal synaptic plasticity are at least partially facilitated via enhancements in cholinergic signaling from the basal forebrain. Finally, age, dose, and type of estrogen utilized are important factors to consider when evaluating estrogen's ii effects on memory and its underlying mechanisms, since age alters the responsiveness to estrogen treatment and the dose of estrogen needed, and small alterations in the molecular structure of estrogen can have a profound impact on estrogen's efficacy on memory.
Effects of ovariectomy and estrogen treatment on learning and hippocampal neurotransmitters in mice
Hormones and Behavior, 2002
This study examined the effects of long-term estrogen treatment (sc 17β-estradiol minipellets) on learning in C57BL/6J female and male mice using a position discrimination task in the T-maze and a win-stay task (1/8 arms baited) in the radial arm maze (RAM). In addition, hippocampal monoamines and ChAT activity were measured at the end of the study and correlated to task performance. Female sham-operated (gonadally intact) and ovariectomized (OVX) mice were treated with estrogen either for 7 or 40 days before the behavioral tests and intact male mice for 7 days before the behavioral tests. In sham-operated mice the 40-day estrogen treatment improved RAM performance and in OVX mice both the 7- and 40-day estrogen treatments improved the performance in both maze tasks. The estrogen treatment also improved RAM performance in males. The hippocampal ChAT, NA, 5-HIAA, and DOPAC levels were decreased in OVX mice. Furthermore, the effects of estrogen treatment on the levels of hippocampal 5-HT and its metabolite 5-HIAA were different in sham-operated than in OVX mice. We could find no correlation between cognitive measures and neurochemical variables. This study gives new information about the effects of estrogen on learning and hippocampal neurotransmitters in mice.
Estradiol reduces anxiety- and depression-like behavior of aged female mice
Physiology & Behavior, 2010
Beneficial effects of the ovarian steroid, 17β-estradiol (E 2), for affective behavior have been reported in young individuals, but less is known about the effects of E 2 among older individuals, and the capacity of older individuals to respond to E 2 following its decline. In the present study, the effects of acute E 2 administration to aged mice for anxiety-like and depression-like behaviors were investigated. Intact female C57BL/6 mice (N=18) that were approximately 24 months old were administered vehicle (sesame oil, n=9) or E 2 (10 μg, n=9) subcutaneously 1h prior to behavioral testing. Mice were tested for anxiety-like behavior (open field, elevated plus maze, mirror chamber, light-dark transition task, Vogel conflict task) and depression-like behavior (forced swim task). To assess the role of general motor behavior and coordination in these aged mice, performance in an activity monitor and rotarod task, and total entries made in tasks (open field, elevated plus maze, light-dark transition task) were determined. Mice administered E 2 , compared to vehicle, demonstrated anti-anxiety behavior in the open field, mirror chamber, and light-dark transition task, and anti-depressive-like behavior in the forced swim task. E 2 also tended to have anti-anxiety effects in the elevated plus maze and Vogel task compared to vehicle administration, but these effects did not reach statistical significance. E 2 did not alter motor behavior and/or coordination in the activity monitor, open field, or rotarod tasks. Thus, an acute E 2 regimen produced specific anti-anxiety and anti-depressant effects, independent of effects on motor behavior, when administered to aged female C57BL/6 mice.