Acute stress impairs spatial memory in male but not female rats: influence of estrous cycle

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Abstract

We investigated how sex and estrous cycle influenced spatial recognition memory in the Y-maze after exposure to acute restraint stress. In Experiment 1, intact male and female rats were restrained for 1 h and then 2 h after the start of restraint, rats were trained on the Y-maze. After a 4 h delay, hippocampal-dependent spatial recognition memory was assessed. Acute stress produced opposite patterns between the sexes with spatial memory being impaired in males and facilitated in females. Serum corticosterone measures indicated that both sexes showed a robust corticosterone response after restraint and a moderate corticosterone response after Y-maze exposure. Serum corticosterone levels in response to restraint and Y-maze were not statistically different between the sexes. Experiment 2 examined the influence of the estrous cycle on spatial memory ability after acute stress. Acute stress facilitated spatial memory in females compared to controls, regardless of the estrous cycle phase (estrus and proestrus). Moreover, females in proestrus showed higher serum corticosterone levels during restraint compared to females in estrus. No differences in corticosterone levels were observed at baseline or following 2 h of recovery from restraint. These data show important differences in how sex and estrous cycle influence cognitive functions following acute stress.

Introduction

Exposure to both chronic and acute stress has substantial effects on learning and memory Cahill and McGaugh, 1998, Kim and Diamond, 2002, LeDoux, 2000, McEwen and Sapolsky, 1995). Chronic stress generally produces deficits on hippocampal-dependent memory processes in male rats Conrad et al., 1996, Luine et al., 1994, Park et al., 2001, while enhancing these processes in females Bowman et al., 2001, Bowman et al., 2002, Bowman et al., 2003, Conrad et al., 2003. The deficits observed in males may be associated with chronic stress-induced restructuring of the hippocampus Conrad et al., 1999b, Magariños and McEwen, 1995, Sousa et al., 2000, Watanabe et al., 1992, which is not extensive in females (Galea et al., 1997). The effects of acute stress on learning and memory are less consistent. In male rats, acute stress enhances memory performance on highly aversive tasks Blank et al., 2002, Sananbenesi et al., 2003, Shors, 2001, Shors et al., 1992, impairs memory performance on appetitive spatial navigation tasks Diamond et al., 1996, Shors and Dryver, 1992 and object recognition tasks Baker and Kim, 2002, Beck and Luine, 2002, or has no effect Warren et al., 1991, Youngblood et al., 1997. There are many differences across these experiments that might contribute to the diversity of outcomes. These include not only appetitive versus aversive components of the task, but differences in the type of stressor, task difficulty (Diamond et al., 1999), and timing between stress and training (Blank et al., 2002). In addition, acute stress may influence cognitive search strategies, such as cue utilization (Kim and Baxter, 2001). For example, acute restraint and tailshock stress just prior to training biases male rats to use hippocampus-insensitive tactics, such as cued or stimulus–response (S–R) learning (Kim et al., 2001). Moreover, disruption of the amygdala interferes with this stress-induced shift, but leaves the response of the hypothalamic–pituitary–adrenal axis intact (Maroun and Richter-Levin, 2003), suggesting that stress may modulate the interaction between memory systems through amygdala activation and synaptic plasticity (for review, see Conrad, in press).

Sexual dimorphisms in the stress response may be another important contributor to the differential effects of acute stress on learning and memory. Many examples of sexual dimorphisms in the stress response have been reported, including differences in adrenocorticotropin levels (Handa et al., 1994), corticosterone levels Critchlow et al., 1963, Galea et al., 1997, Haleem et al., 1988, Kant et al., 1983, Kitay, 1961, corticosterone binding in the brain MacLusky et al., 1996, Turner, 1992, Turner and Weaver, 1985, and hippocampal activation (Figueiredo et al., 2002). A growing literature in humans and rodents suggests that acute stress also produces sex differences in cognition Shors et al., 2000, Wolf et al., 2001. Shors et al. have shown that acute exposure to restraint and tail shock stress in rats enhances eyeblink delay conditioning in males, but impairs performance in females (Wood and Shors, 1998). However, the literature is limited on the influence of acute stress on learning and memory processes using females.

The different effects of stress on memory between male and female rats might reflect the influence of the ovarian steroids across the estrous cycle. Circulating ovarian steroids may predispose females to the impairing action of acute stress on certain tasks because ovariectomy prior to stress attenuates the impairment (Wood et al., 2001). Furthermore, rats at proestrus, when gonadal steroids are high, show significantly fewer conditioned responses following acute stress than rats at estrus and diestrus, when gonadal steroids are low or rising (Shors et al., 1998). Additionally, chronically stressed rats at proestrus show impaired acquisition on the radial arm maze, while rats in estrus and diestrus are unimpaired on acquisition (Bowman et al., 2001). In related work, stress or arousal during performance of a variety of tasks may interact with ovarian hormone status to produce learning and memory deficits when estrogen is high, unless habituation to the task has occurred Frye, 1995, Markus and Zecevic, 1997, Perrot-Sinal et al., 1996. Perhaps, acute stress alters memory ability through enhancing the levels of estradiol (Shors et al., 1999). Together, the results suggest that responses to acute stress exposure are sexually dimorphic and that cyclic changes in circulating ovarian steroids across the estrous cycle will produce different outcomes, with proestrus (high estrogen) impairing performance and estrus (low estrogen) facilitating performance following acute stress.

While acute stress may interact with sex and estrous cycle to define the magnitude and direction of memory effects, demonstrations have included only a few tasks, including the radial arm maze, T-maze, water maze, and Pavolvian conditioning. Determining the effects of acute stress on other tasks is necessary to better characterize the role of sex and related gonadal hormones. This need is especially evident, given that increases in circulating estrogen in nonstressed animals facilitate hippocampal-dependent learning and memory, but are ineffective or impair performance on other tasks, such as those requiring egocentric or cued strategies (Korol and Kolo, 2002; for review, see Dohanich, 2002). Thus, estrous cycle and ovarian hormones may produce different outcomes on hippocampal-dependent tasks between control and stressed females.

The present experiments assess the effects of acute stress on memory for a spatial recognition task previously shown to be sensitive to hippocampal manipulations (Conrad et al., 1996). Experiment 1 tested the hypothesis that acute restraint stress influences spatial recognition memory on a Y-maze differently between the sexes. Based upon prior studies Diamond et al., 1996, Shors and Dryver, 1992, acute restraint was predicted to impair spatial recognition memory in males and this effect may be observed for females. However, the study by Wood and Shors (1998) implies that the sexes may have opposing responses to acute stress and thus, acute stress may facilitate spatial recognition memory in females. The latter finding was observed in the present research with stressed females performing better on the Y-maze than stressed males. Therefore, Experiment 2 was performed to determine whether acute stress influenced spatial recognition memory differently between females in proestrus and estrus, which represents the estrous phases with the highest and lowest estrogen levels, respectively. We predicted that acute stress would facilitate spatial recognition memory in females in estrus compared to females in proestrus.

Section snippets

Subjects

Approximately 2-month-old Sprague–Dawley rats were purchased from Harlan (Madison, WI) and were same sex, pair housed in two temperature-controlled chambers. Males and females that were arbitrarily assigned to the stress group were housed in a separate chamber than the nonstressed controls. Rats were maintained on a 12 h light–dark cycle (lights off at 7:00 a.m.), and had ad libitum access to food (Teklad diet 8604, Harlan) and tap water. Arizona State University's Institutional Animal Care and

Experiment 1: Influence of acute stress and sex on Y-maze performance

Control males and stressed females exhibited better spatial memory performance on the Y-maze compared to stressed males and control females, as indicated by a significant interaction between treatment and sex [F(1,31)=4.66, P<.05] and subsequent LSD tests (Fig. 1A). The results show that the difference scores were significantly more positive for control males and stressed females than stressed males and control females. The main effects for treatment (P=.68) and sex (P=.94) were not

Discussion

The data from Experiment 1 support the hypothesis that acute restraint stress influences spatial recognition memory on the Y-maze differently between the sexes. While 1 h of restraint impaired spatial memory in males, stressed females demonstrated the opposite pattern by exhibiting intact spatial memory. The influence of the estrous cycle and acute stress on spatial memory ability in females was examined in Experiment 2. Acute stress facilitated spatial memory in females during both proestrus

Acknowledgements

This work was funded by MH64727 (Conrad), the Howard Hughes Medical Institute through the Undergraduate Biology Enrichment Program (Jackson, Wieczorek, and Harman), and IBN-0081061 (Korol). The contributions of the following individuals are gratefully acknowledged: Elizabeth Lightner, Katie McLaughlin, Sergey Tsekhanov, and Lisa Wise.

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