Elsevier

Hormones and Behavior

Volume 58, Issue 3, August 2010, Pages 415-426
Hormones and Behavior

Acute estrogen treatment facilitates recognition memory consolidation and alters monoamine levels in memory-related brain areas

https://doi.org/10.1016/j.yhbeh.2010.05.013Get rights and content

Abstract

Acute effects of estrogens on mnemonic processes were examined at the behavioral and neurochemical levels. 17β-estradiol and 17α-estradiol influences on memory consolidation were assessed using object placement (OP) and object recognition (OR) tasks. Subjects received treatment immediately after a sample trial (exploring two novel objects), and memory of objects (OR memory) or location of objects (OP memory) was tested 4 h later. Both isomers of estradiol enhanced memory. For spatial memory, 15 and 20 µg/kg of 17β-estradiol facilitated OP, while lower and higher doses were ineffective. 17α-estradiol had a similar pattern, but a lower dose was effective. When treatment was delayed until 45 min after a sample trial, memory was not enhanced. For non-spatial memory, OR was facilitated at 5 µg/kg of 17β-estradiol and at 1 and 2 µg/kg of 17α-estradiol and, similar to OP, lower and higher doses were ineffective. These data demonstrate that beneficial effects of estrogens are dose, time and task dependent, and the dose–response pattern is an inverted U. Because monoamines are known to have contributions to memory, brains were removed 30 min after treatment for measurements of dopamine (DA), norepinephrine (NE), serotonin (5-HT), and metabolites. Estrogen elevated 5HT, NE metabolite MHPG, turnover ratio of NE to MHPG, and DA metabolite DOPAC levels in the prefrontal cortex, while NE and MHPG were decreased in the hippocampus. Thus, acute estrogens exert rapid effects on memory consolidation and neural function, which suggests that its mnemonic effects may involve activation of membrane associated estrogen receptors and subsequent signaling cascades, and that monoamines may contribute to this process.

Introduction

The majority of existing research on cognitive effects of estrogen has focused on chronic and/or sub-chronic treatments and has demonstrated that administration of estradiol (E2) to ovariectomized (OVX) animals enhances performance in some, but not all, memory and learning tasks (see Dohanich, 2002, Luine, 2006, Luine, 2008 for a review). These studies indicate that estrogen has specific, rather than global, effects on memory systems. Moreover, accumulative evidence has revealed that the beneficial effects of estrogen treatments depend on various factors, including demands of memory tasks (Galea et al., 2001, McLaughlin et al., 2008, Zurkovsky et al., 2007), doses (Holmes et al., 2002, Wide et al., 2004), routes of administration (Garza-Meilandt et al., 2006), duration and timing of treatment (Daniel et al., 2006, Gresack and Frick, 2006a), age (see Frick (2009) for a review), sex (Gibbs and Johnson, 2008) stress level of subjects (Bowman et al., 2002, Bowman et al., 2003, Bowman et al., 2009, Luine et al., 2007), environmental enrichment (Gresack et al., 2007a, Gresack et al., 2007b) and extent of daily handling (Bohacek and Daniel, 2007).

In contrast, acute effects of estrogen on memory function are less studied, but recent work has shown that acute treatments can influence memory consolidation processes in rats (Luine et al., 2003, Packard et al., 1996, Packard and Teather, 1997a, Packard and Teather, 1997b, Rhodes and Frye, 2004, Rhodes and Frye, 2006) and mice (Fernandez et al., 2008, Gresack and Frick, 2006b, Harburger et al., 2009, Lewis et al., 2008). Some of these studies demonstrated time-limited effects of acute estrogen on memory consolidation using “post-training treatment paradigms”, in which hormone treatment was given after training or the sampling phase of a memory task. This paradigm minimizes possible non-mnemonic or psychological effects of treatments since drug/hormones are not present when animals encounter new information. Packard and Teather (1997a), for example, trained OVX rats in a Morris water maze and immediately gave intraperitoneal injections of 0.1, 0.2 or 0.4 mg/kg of 17β-estradiol. The intermediate dose (0.2 mg/kg) improved memory for the hidden platform location when tested 24 h later, but the same dose given 2 h after training was ineffective. The results suggested a “critical time and/or dose window” for acute estrogen enhancements of memory consolidation.

Using pre- and post-sampling injection paradigms, we have shown that enhanced memory occurs rapidly, within a few hours after acute estrogen treatment (Luine et al., 2003). Interestingly, 17α-estradiol was more potent than 17β-estradiol for hippocampal dependent spatial memory when treatment was given 30 min before a sample trial and memory tested 4 h later. Affinity of 17α-estradiol for nuclear estrogen receptors, ERα and ERβ, is much lower compared to 17β-estradiol (Kuiper et al., 1997), but recent studies indicate that 17α-estradiol shows greater affinity for some membrane-related estrogen receptors (Toran-Allerand et al., 2002, Toran-Allerand et al., 2005). Thus, rapid memory enhancement by acute estrogen treatment and the greater potency of 17α-estradiol suggest that the responses are, at least in part, mediated via non-genomic pathways. Monoaminergic neurotransmitters are important in rapid membrane associated effects, but few studies have investigated monoamines in relation to rapid effects of estrogen on memory. Non-genomic regulation of monoamine systems following acute estrogen treatment has been reported in some brain areas such as the hypothalamus, an important region for estrogen-regulated sexual behavior, and in the hindbrain, telencephalon, cerebellum (Cornil et al., 2005, Cornil et al., 2006) and the nucleus accumbens (Thompson and Moss, 1994). But whether acute estrogen treatments affect monoamines in relation to memory is not known.

The objective of the present study was to investigate acute effects of estrogens on memory consolidation. To achieve this goal, we tested various doses of 17β- and 17α-estradiol given post-sampling in the spatial memory task, object placement, and the non-spatial memory task, object recognition (Ennaceur et al., 1997). Possible contributions of monoamines to estrogen-induced enhancements of memory consolidation were assessed by measuring DA, NE, 5-HT and metabolites in brain areas known important for memory including the prefrontal cortex, the hippocampus, the vertical limb of the diagonal band and the striatum during the period of memory consolidation. The results obtained provide further support for and novel information on estradiol's ability to rapidly enhance memory consolidation in OVX rats.

Section snippets

Subjects

Thirty eight female Sprague–Dawley rats (Harlan Sprague–Dawley, Inc., Indianapolis, IN), aged 55–60 days upon arrival and ovariectomized (OVX) by the vender, served as subjects. All rats were double-housed in cages, maintained on a 12/12 h light–dark cycle (lights on at 7:00 AM). They had ad libitum access to low phyto-estrogen food (Chow 2016, 16% protein rodent diet, Harlan Teklad Global Diets, Madison, WI) and water for the entire period of the experiments. Rats were allowed to acclimate to the

Acute 17β-estradiol; effects on object placement (OP)

To determine the most effective dose of 17β-estradiol for OP memory consolidation, we first tested 60 μg/kg and 30 μg/kg in separate sessions because previous studies indicated these doses injected immediately before or after T1 significantly enhanced OP (Luine et al., 2003), or increased spine synapse density in the CA1 hippocampus (MacLusky et al., 2005a, MacLusky et al., 2005b). During T1, rats spent similar amounts of time exploring the two identical objects for both sessions (12.91–14.13 s).

Discussion

The current study examined acute effects of estrogen on memory consolidation and determined dose–response characteristics between hormone treatment and OP (spatial memory) and OR (non-spatial memory) tasks. In addition, we compared levels of monoamines and metabolites in vehicle-treated and estrogen treated OVX rats in brain areas involved in memory function. The present data are consistent with previous findings that post-sampling injection of 17β-estradiol facilitates memory consolidation,

Acknowledgments

The authors thank to G. Mohan, K. Monde, and P. Snyder for their assistance in behavior testing, and Dr. Maya Frankfurt for the advice and help. This work was part of the dissertation thesis of T. Inagaki. This research was supported by NIH grant GM60654, RR-TT03037 and CUNY Research Grants for doctoral students.

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