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Biol Psychiatry. Author manuscript; available in PMC Jan 15, 2011.
Published in final edited form as:
PMCID: PMC2794927
NIHMSID: NIHMS150846

Effects of Estradiol on Learned Helplessness and Associated Remodeling of Hippocampal Spine Synapses in Female Rats

Abstract

Background

Despite the fact that women are twice as likely to develop depression as men, our understanding of depression neurobiology in females is limited. We have recently reported in male rats that development of helpless behavior is associated with a severe loss of hippocampal spine synapses, which is reversed by treatment with the antidepressant, desipramine. Considering the fact that estradiol has a hippocampal synaptogenic effect similar to those of antidepressants, the presence of estradiol during the female reproductive life may influence behavioral and synaptic responses to stress and depression.

Methods

Using electron microscopic stereology, we analyzed hippocampal spine synapses in association with helpless behavior in ovariectomized female rats (n=70), under different conditions of estradiol exposure.

Results

Stress induced an acute and persistent loss of hippocampal spine synapses, while subchronic treatment with desipramine reversed the stress-induced synaptic loss. Estradiol supplementation given either prior to stress or prior to escape testing of nonstressed animals both increased the number of hippocampal spine synapses. Correlation analysis demonstrated a statistically significant negative correlation between the severity of helpless behavior and hippocampal spine synapse numbers.

Conclusions

These findings suggest that hippocampal spine synapse remodeling may be a critical factor underlying learned helplessness and, possibly, the neurobiology of depression.

Keywords: depression, stress, synaptic plasticity, desipramine, estrogen, stereology

Introduction

Major depressive disorder is a devastating illness (1) with an estimated lifetime prevalence of 17% in the United States (2). Despite intensive research on depression neurobiology and antidepressant mechanisms, current clinical management of the disease remains limited (3). Evidence for hippocampal atrophy in depressed patients (4-6), as well as derailment of many hippocampus-related functions in depression (7-9) indicates that the hippocampus is critically involved in the disease (10). Based on considerable evidence (11-17), it has been postulated for many years that stress and depression are associated with the loss of hippocampal dendritic spines and spine synapses (18-20), contributing to hippocampal dysfunction, although there are many reports that do not support this hypothesis (21-23). We have recently demonstrated that the number of spine synapses, determined by electron microscopy, in certain hippocampal areas is a valuable neuroanatomical marker for helpless behavior (24). We have found in male rats that helpless behavior is associated with a severe loss of these synapses across the hippocampal circuitry, which is reversed in animals that respond to antidepressant treatment with decreased helplessness (24). This acute stress-induced spine synapse remodeling does not occur in cortical areas that are not related to stress/depression, such as the motor cortex (24).

It has been reported that contrary to males, females are resistant to the shrinkage of CA3 apical dendrites in response to chronic stress or corticosterone administration (16; 25; 26), suggesting that spine synapse remodeling induced by stress/helplessness may be different in the hippocampus of females vs. males. In addition, the principal ovarian estrogen, estradiol, has a hippocampal synaptogenic effect similar to those of antidepressants (17; 27). As a result, the presence of estradiol during the female reproductive life may, to a large extent, influence behavioral and synaptic responses to stress and depression. Indeed, clinical studies have shown that women are twice as likely to develop depression as men (28); and sex differences have also been observed in various animal models of depression (29; 30). Unfortunately, there is much less known about synaptic remodeling in female stress/depression models; and studies at the ultrastructural level, in particular, are currently not available in the female. Therefore, to investigate potential interactions between the synaptic effects of estradiol and helpless behavior, we used electron microscopic stereology to analyze spine synapses in the female rat hippocampus in association with behavioral changes in the learned helplessness (LH) model of depression and antidepressant response, under different conditions of estradiol exposure.

Materials and Methods

Adult female Sprague-Dawley rats (n=70, 200-250 g; Charles River Laboratories, Wilmington, MA) were kept under standard laboratory conditions. The animals were group housed, maintained on a 12/12-h light/dark cycle, with tap water and rodent chow available ad libitum. The animal protocol was approved by the Institutional Animal Care and Use Committee of Yale University School of Medicine. All rats were ovariectomized a week before stress exposure. Ovariectomy prevents the cyclic change of serum estradiol levels and the resultant fluctuation in the number of hippocampal spine synapses (27). Moreover, the ovariectomized rat is an excellent subject for our studies, because stress and depression are associated with sexual dysfunction (31), ovarian dysfunction (32), and decreased fertility (33).

Learned helplessness

A standard LH paradigm was used as previously described (24). Briefly, testing was conducted in commercial shuttle boxes (Med Associates, St. Albans, VT). Inescapable footshock (IES) was administered in one side of shuttle boxes (60 scrambled footshocks, 0.85 mA intensity, 15 s average duration, 60 s average inter-shock interval). This schedule of IES presentation has been shown to be effective in inducing helpless behavior in rats (24; 34). Nonstressed (NS) control animals were exposed to the chambers but did not receive footshock. Helpless behavior was evaluated by analyzing performance in an active escape paradigm, consisting of 30 trials of escapable footshock (0.65 mA intensity, 35 s maximum duration, 90 s average inter-trial interval). An initial five fixed ratio 1 trials, during which one shuttle crossing terminated the shock, was followed by 25 trials, when two shuttle crossings were required to terminate shock (fixed ratio 2 trials). Shock was terminated automatically if the response requirement was not met within 35 s. Escape latencies were recorded automatically for each trial by a computer. Escape latency represented the time it took for animals to escape shock; while in the case of escape failures, escape latency was set at 35 s. IES administration and active escape testing was conducted in a dimly lit room between 1000-1600 h.

Electron microscopic stereology

The number of spine synapses in CA1 stratum radiatum (CA1sr), CA3 stratum lucidum and radiatum (CA3sl/sr), and dentate gyrus stratum moleculare (DGsm) was calculated as previously described (24). Spine synapses in these areas represent important “relay stations” along the hippocampal trisynaptic loop and, therefore, they critically influence hippocampal signal flow and cellular activity. For more detailed rationale of selecting these areas for analysis, please see our previous paper (24). Briefly, animals were perfusion fixed through the ascending aorta with a mixture of 4% paraformaldehyde and 0.1% glutaraldehyde dissolved in phosphate buffer. Brains were dissected out and postfixed overnight in the same fixative without glutaraldehyde. Throughout the hippocampus, 100-μm thick serial sections were cut in the coronal plane using a vibratome and systematically sorted into ten groups. One randomly selected group of sections was embedded in Durcupan (Electron Microscopy Sciences, Fort Washington, PA) between slides and coverslips. Using these embedded sections, the volume of sampling areas (CA1sr, CA3sl/sr, and DGsm) was estimated utilizing the Cavalieri Estimator module of the Stereo Investigator® system (MicroBrightField, Villiston, VT) mounted on a Zeiss Axioplan 2 light microscope. Thereafter, 20 sampling sites for electron microscopic analysis were localized in each sampling area using a systematic-random approach, as previously described (24). At each sampling site, digitized electron micrographs (Figure 1) were taken for the physical disector in a Tecnai-12 transmission electron microscope (FEI Company, Hillsboro, OR) furnished with a Hamamatsu digital camera system (Hamamatsu Photonics, Hamamatsu, Japan), at a final magnification of 11,000×. This sampling technique provided 20 disectors for each of CA1sr, CA3sl/sr, and DGsm, i.e., 60 disectors per brain altogether. Prior to spine synapse counting, the pictures were coded for blind analysis. Asymmetric spine synapses were counted according to the rules of the disector technique (35). Synapsing spines were identified by the presence of postsynaptic densities, as well as by the absence of mitochondria, microtubules, and synaptic vesicles. The average volumetric density of spine synapses (synapse/μm3) within each sampling area was then determined. Finally, the volumetric density of spine synapses was multiplied by the volume of the sampling area, determined earlier, to arrive at the total number of spine synapses. For more details of this technique, please see our previous paper (24).

Figure 1
High power representative electron micrograph taken from the CA1 stratum radiatum of a stressed rat. Arrowheads point to examples of spine synapses established between dendritic spines (s) and axonal boutons (b). The asterisk indicates a stubby spine ...

Treatment group sizes for synapse counting

Because electron microscopic stereology is a time-consuming and labor-intensive method, we performed careful statistical power calculations to minimize the number of animals to be analyzed. In our earlier studies (17; 24), standard deviation for spine synapse counts has consistently been in the range of 5-10% of the mean. Thus, assuming 10% standard deviation and n=4 animals per group in the experimental design described below, ANOVA can detect about 25% change in the number of spine synapses with the desired 80% power at α=0.05. Because our initial observations (17; 24) suggest that modifications in the number of spine synapses will potentially be larger than 25%, we set initial treatment group sizes at n=4.

Experimental design and statistics

Six experimental groups were designed to examine the effects of acute stress on hippocampal spine synapses, and whether it is affected by treatments with the antidepressant, desipramine (DMI), or the estrogen, estradiol benzoate (EB) (Table 1). Animals ovariectomized for a week were exposed to the shuttle boxes either with (4 groups) or without (2 groups) receiving footshock stress. A week after stress exposure, four females were randomly selected from each group for electron microscopic stereology and sacrificed when the remaining rats underwent active escape testing. As a result, our synapse counts represent the number of spine synapses at the beginning of active escape testing. Animals in the IES/DMI group received antidepressant treatment for six days, from stress exposure until escape testing (10 mg/kg DMI dissolved in distilled water; given i.p, twice daily, in a volume of 1 ml/kg). We have used the same DMI treatment schedule in our previous male study for successfully reversing both helpless behavior and hippocampal spine synapse loss (24). Estradiol supplementation was given either prior to footshock stress (EB/IES group) or prior to escape testing of nonstressed females (NS/EB group) in the form of two s.c. injections 24 h apart (each injection contained 40 μg/kg EB dissolved in sesame oil, given in a volume of 1 ml/kg). Testing of escape performance was performed 48 h (NS/EB group) or 9 days (EB/IES group) following the second hormone dose. This estradiol supplementation schedule for ovariectomized rats has been utilized in several past studies to simulate normal proestrus levels of estradiol, and has also been demonstrated to reproduce the number of CA1 spine synapses observed during proestrus (27).

Table 1
Schedule of Treatments and Tests

Data from individual animals were used to determine group means (± S.E.M. for escape latency and ± S.D. for spine synapses). Escape latency measurements were examined by two-way repeated measures ANOVA (treatment as between factor × time as within factor); while spine synapse counts were analyzed by two-way ANOVA (treatment × sampling area). We used the conservative Tukey post-hoc test for individual comparison of spine synapse counts. However, because behavior naturally shows greater variability, the less conservative Holm-Sidak post-hoc test was applied in the case of escape latency. Correlation between escape latencies and number of spine synapses was analyzed with the Pearson product moment test. A criterion for statistical confidence of p<0.05 was adopted.

Results

Two-way repeated measures ANOVA found significant treatment (F5,40=12.950, p<0.001), time (F5,200=115.858, p<0.001), and treatment × time interaction effects (F25,200=2.494, p<0.001) on escape latencies. When compared with nonstressed, oil-treated controls, acute stress exposure significantly increased mean escape latency in oil-treated animals at both 24 h (IES1d vs. NS/OIL group) and a week (OIL/IES vs. NS/OIL group) after stress. The escape performance of IES1d and OIL/IES females was similar, indicating that escape deficits develop acutely, within 24 h of stress exposure, and that rats do not show any signs of behavioral recovery within the first week. Estradiol supplementation of nonstressed animals significantly decreased mean escape latency (NS/EB vs. NS/OIL group). Administering estradiol prior to stress exposure also significantly decreased mean escape latency (EB/IES vs. OIL/IES group), as the escape performance of stressed, estradiol-treated females (EB/IES group) was identical with that of nonstressed, oil-treated controls (NS/OIL group). A six-day treatment of stressed, oil-treated rats with the tricyclic antidepressant, desipramine, significantly decreased mean escape latency (IES/DMI vs. OIL/IES group), bringing escape latency levels of DMI-treated animals (IES/DMI group) to that of nonstressed, estradiol-supplemented females (NS/EB group). Escape latency measurements and their statistical analysis are summarized in Figure 2a.

Figure 2
Effects of footshock stress, estradiol supplementation, and antidepressant treatment on escape latency (panel a) and number of hippocampal spine synapses (panel b). Panel a and insert: This chart traces the change of escape latencies during active escape ...

Two-way ANOVA revealed significant treatment (F5,54=262.940, p<0.001), sampling area (F2,54=142.455, p<0.001), and treatment × sampling area interaction effects (F10,54=9.923, p<0.001) on the number of hippocampal spine synapses. In general, significant decreases in escape latency were associated with significant increases in the number of spine synapses in all hippocampal areas analyzed. The only exception was the DGsm area, where spine synapse numbers a week after of stress exposure (in the OIL/IES group) were at the level of nonstressed, oil-treated controls (NS/OIL group), in contrast to the significantly better escape performance of NS/OIL females. Because acute stress exposure uniformly decreased the number of spine synapses across hippocampal areas 24 h following stress (in the IES1d group), spine synapse growth in DGsm a week later (in the OIL/IES group) is likely the initial sign of spontaneous synaptic recovery. Spine synapse counts and their statistical analysis are summarized in Figure 2b.

Mean escape latencies and hippocampal spine synapse numbers across all three areas analyzed showed a significant negative linear correlation (r = -0.973, p=0.001, Figure 3a), suggesting that escape latency decreases as the number of hippocampal spine synapses increases. The strongest correlations were in CA1sr (r = -0.985, p<0.001, Figure 3b) and CA3sl/sr (r = -0.992, p<0.001, Figure 3c), becoming weaker but still statistically significant in DGsm (r = -0.899, p=0.015, Figure 3d). The weaker correlation in DGsm results primarily from the spontaneous recovery of spine synapses following stress exposure, which did not occur in the other two areas. The recovery of DGsm spine synapses does not seem to be reflected in escape performance, perhaps because it represents a relatively small contribution to the combined number of spine synapses from all analyzed hippocampal areas.

Figure 3
Scatter plots of mean escape latencies as functions of spine synapse numbers in all three analyzed hippocampal areas combined (panel a), in CA1 stratum radiatum (CA1sr, panel b), CA3 stratum lucidum and radiatum (CA3sl/sr, panel c), and dentate gyrus ...

Discussion

These observations provide strong ultrastructural evidence for remodeling of hippocampal spine synapses in association with behavioral changes in the female LH model of depression. These synaptic changes are similar to what we have observed in the male LH model (24). Footshock stress induces an acute and persistent loss of hippocampal spine synapses, except for the DGsm area in untreated females, where spine synapses spontaneously recover to pre-stress levels within a week of stress exposure. By contrast, we have not observed this spontaneous spine synapse recovery in the male LH model (24), In line with our previous demonstration of synaptogenic effects of fluoxetine in the nonstressed female hippocampus (17), subchronic treatment with the tricyclic antidepressant, desipramine, reverses the stress-induced synaptic loss.

The role of estradiol

Estradiol supplementation in nonstressed animals and estradiol treatment prior to acute stress exposure both increase hippocampal spine synapse numbers and improves escape performance (see Figure 2). However, judging the true influence of estradiol given prior to stress is limited due to the 9-day delay between estradiol treatment and escape testing. It is conceivable that hippocampal spine synapse numbers in estradiol-treated, stressed females (EB/IES group) are higher initially, but then they decline during the 9-day delay to the level of nonstressed, oil-treated controls (NS/OIL group) due to lack of estradiol (27). Despite the limitation, this design led to an important situation, because these two treatment groups (EB/IES and NS/OIL), differing in both stress exposure and estradiol supplementation, displayed identical spine synapse numbers and identical escape performance, suggesting a potentially critical role of hippocampal spine synapse remodeling in helpless behavior. Another factor that may confound the interpretation of our findings is the locomotor-activating effect of estradiol in female rats (36), which probably contributes to the behavioral observations in the nonstressed NS/EB group. On the other hand, the antidepressant-like action of estradiol given prior to footshock stress (EB/IES group) cannot be explained with locomotor activation. First, stress appears to interfere with estradiol's locomotor activating effect (37), mostly negating it, which is further supported by our own recent observation that estradiol given after footshock stress does not improve escape performance (Hajszan T, MacLusky NJ, Leranth C, Duman RS, unpublished observation). Most importantly, the escape performance of EB/IES animals was tested nine days after the last estradiol injection, a period long enough to completely clear injected estradiol from the circulation (38). As a result, at the time of escape testing, EB/IES females were not under the influence of estradiol and hence, the locomotor activating effect could not be present.

Our finding of an antidepressant-like effect from estradiol is in line with the well-documented relevance of decreasing estradiol levels to elevated risks for developing depressive symptoms in both women (39; 40) and laboratory animals (41). It has been reported that gene polymorphisms affecting estradiol synthesis, metabolism, and signaling increase the occurrence of depression in young/midlife women (42; 43). In the postmenopausal period, serum concentrations of estradiol are inversely associated with depressed mood (44; 45). From the therapeutic perspective, women with mood disorders seem to benefit from estradiol administration both in young/midlife (46), and in the peri/postmenopausal period (47; 48). It also has to be mentioned, however, that there are an equally large number of clinical studies reporting that hormone therapy does not affect depression severity (49-51). Furthermore, the increased prevalence of depression in women exists only during the reproductive years, beginning with puberty and lasting until menopause (39; 52). Some recent work with the mouse forced-swim test model (53; 54) also suggests that the presence of ovarian hormones amplifies the risk of mood disorders, seemingly contradicting our findings. (However, the forced-swim test is primarily a screening test for antidepressant efficacy (55) rather than a depression model per se.) In fact, there are two characteristic peaks of depression prevalence in women; the first is postpartum depression, the second is perimenopausal depression (39; 52). Both of these peaks are associated with large drops (postpartum) or excessive fluctuations (perimenopausal) of serum estradiol levels (52), indicating that it is the drop in serum levels rather than the presence of estradiol that increases the risk of depression. It has to be noted, however, that the ovariectomized animals as used in our study are not appropriate to model perimenopausal hormone fluctuations. Nevertheless, the controversy about the role of ovarian hormones in stress/depression remains to be further investigated.

The involvement of estradiol in affective behavior is not surprising considering its impact on many mechanisms thought to be important in depression neurobiology. In addition to its hippocampal synaptogenic effects, estradiol influences neurogenesis (56), expression of brain-derived neurotrophic factor (57; 58), and monoaminergic neurotransmission (59; 60). Apart from hippocampal spine synapse remodeling, however, these estrogen-related mechanisms show questionable correlations to helpless behavior, and even their relevance to depressive symptoms is intensively debated (61-63).

Relevance of hippocampal synaptic remodeling to stress and depression

The negative correlation between escape latency and hippocampal spine synapse numbers provides strong evidence supporting the hypothesis that depressive behavior is linked to spine synapse remodeling (18-20; 24). It is most impressive and significant that the correlation exists irrespective of several conditions, such as footshock stress exposure, estradiol supplementation and antidepressant treatment, as both stressed and nonstressed, estradiol-supplemented and -nonsupplemented, as well as antidepressant-treated and -nontreated animals can show identical escape performance, (e.g., EB/IES vs. NS/OIL, and NS/EB vs. IES/DMI groups), given that their hippocampal spine synapse numbers are also identical.

Our observations are in line with the earlier study of Shors et al. (22) reporting dendritic spine loss in the female hippocampus in response to acute stress. On the other hand, our results are in conflict with most other studies (16; 25; 26) indicating that females are resistant to the shrinkage of CA3 apical dendrites in response to stress or corticosterone administration. We have already noted in our previous paper (24) that direct, electron microscopic analysis of spine synapses may not reproduce the effects observed via studying dendritic structure or synaptic markers [e.g., (24) c.f. (12; 13)]. Although differences in experimental design may partially explain the varying observations, this is not applicable in the case of our NS/OIL (ovariectomized, oil-treated, nonstressed animals) and NS/EB groups (ovariectomized, estradiol-supplemented, nonstressed females). These two groups received treatments that are well established and have been used in many earlier light microscopic studies that examined the effects of estradiol on hippocampal morphology. Nevertheless, there are striking differences between these earlier light microscopic reports (64; 65) and our present ultrastructural findings. This is an exciting phenomenon suggesting differentiated roles for dendritic, molecular, and synaptic plasticity in mood regulation. Our findings also suggest that remodeling of dendritic spines, synaptic vesicle proteins, and spine synapses is regulated independently from each other. Indeed, earlier evidence indicates that formation of new spine synapses does not necessitate the emergence of new spines and axonal boutons; and spine synapse loss does not necessarily imply the loss of these structures (66; 67).

How could remodeling of hippocampal spine synapses contribute to changes in helpless behavior? The hippocampus is strongly involved in learning and memory (68), regulating the stress response (8; 69; 70), and modulating the mesolimbic dopaminergic system and motivation circuitries (71-73), which all seem to be important contributors to the mechanisms of LH (24; 74; 75). The very synapses that we analyzed in this study represent the vast majority of connections between hippocampal principal cells and as such, they serve as an important morphological correlate of hippocampal activity. Loss of these synapses compromises hippocampal signal flow and activity by decreasing the amount of excitatory input that principal cells receive. Deteriorating hippocampal activity in turn may critically contribute to the joint development of cognitive problems, dysregulation of the stress response, and loss of motivation, common traits in helpless animals and in human depression (18; 74).

In summary, our findings demonstrate that the hippocampal synaptic loss associated with helpless behavior can fully be reversed in female rats by treatment with the antidepressant, desipramine. Although the detailed role of synaptic plasticity in mood regulation remains to be further investigated, the observed strong association of reliable synapse counts with escape performance supports our hypothesis that hippocampal spine synapse remodeling critically contributes to the modulation of helpless behavior. Based on its excellent face, predictive, and construct validity, learned helplessness is considered one of the best animal models of depression and antidepressant response (76; 77). Our findings in this model thus indicate that hippocampal spine synapse remodeling may represent a neuroanatomical marker that predicts the risk of depression and the effectiveness of antidepressant treatment.

Acknowledgments

This work was supported by NIH grants MH074021 (Hajszan), MH025642 (Duman), MH045481 (Duman), and ES014893 (Leranth); a NARSAD Young Investigator Award (Hajszan); a Hungarian Ministry of Health grant ETT476/2006 (Parducz); a Hungarian National Office for Research and Technology grant RET08/2004 (Parducz); a Hungarian Scientific Research Fund grant OTKA75954 (Parducz); and by the Connecticut Mental Health Center and the Veterans Administration Center for Posttraumatic Stress Disorder.

Footnotes

Disclosures: The authors report no biomedical financial interests or potential conflicts of interest.

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