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The Journal of Neuroscience, August 15, 2001, 21(16):6292-6297
Sex Differences and Opposite Effects of Stress on Dendritic Spine
Density in the Male Versus Female Hippocampus
Tracey J.
Shors,
Chadrick
Chua, and
Jacqueline
Falduto
Department of Psychology and Center for Collaborative Neuroscience,
Rutgers University, Piscataway, New Jersey 08854
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ABSTRACT |
Dendritic spines are postsynaptic sites of excitatory input in the
mammalian nervous system. Despite much information about their
structure, their functional significance remains unknown. It has been
reported that females in proestrus, when estrogen levels are elevated,
have a greater density of apical dendritic spines on pyramidal neurons
in area CA1 of the hippocampus than females in other stages of estrous
(Woolley et al., 1990 ). Here we replicate these findings and in
addition, show that females in proestrus have a greater density of
spines in area CA1 of the hippocampus than males. Moreover, this sex
difference in spine density is affected in opposite directions by
stressful experience. In response to one acute stressful event of
intermittent tailshocks, spine density was enhanced in the male
hippocampus but reduced in the female hippocampus. The decrease in the
female was observed for those that were stressed during diestrus 2 and
perfused 24 hr later during proestrus. The opposing effects of stress
were not evident immediately after the stressor but rather occurred within 24 hr and were evident on apical and to a lesser extent on basal
dendrites of pyramidal cells in area CA1. Neither sex nor stress
affected spine density on pyramidal neurons in somatosensory cortex.
Sex differences in hippocampal spine density correlated with sex
hormones, estradiol and testosterone, whereas stress effects on spine
density were not directly associated with differences in the stress
hormones, glucocorticoids. In summary, males and females have different
levels of dendritic spine density in the hippocampus under unstressed
conditions, and their neuronal anatomy can respond in opposite
directions to the same stressful event.
Key words:
estrogen; learning; fear; glutamate; corticosterone; testosterone; synapse; memory
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INTRODUCTION |
It is well accepted that males and
females can behave differently, but how much of that difference is
attributable to environmental versus biological factors is a matter of
debate. Under some circumstances, males and females respond in opposite
directions to the same experience. For example, in response to one
acute stressful experience, male rats acquire an associative learning
task faster and emit more conditioned responses (Shors et al., 1992;
Shors, 2001), whereas female rats exposed to the same stimulus are
learning impaired, emitting fewer conditioned responses (Wood and
Shors, 1998; Shors et al., 1998;Wood et al., 2001). Because there are
no environmental or sociocultural factors to consider, these
differences must be attributable to biological differences between the
male and female. Indeed, it has been shown that the enhanced
conditioning in males after exposure to the acute stressor is dependent
on the presence of stress hormones glucocorticoids, whereas the
impaired conditioning in females is dependent on the presence of the
sex hormone estrogen (Wood and Shors, 1998; Wood et al., 2001).
Dendritic spines are potential sources of contact between many if not
most excitatory neurons in the mammalian brain (Engert and Bonhoeffer,
1999; Kirov and Harris, 1999;Vanderklish et al., 2000). The number of
actual synapses is vast, with one CA3 neuron making as many as 20,000 synapses on a CA1 pyramidal cell (Shephard and Harris, 1998). Because
spines provide a means whereby neurons could become associated after
sensory stimulation or other experience, it has been suggested that
they may play a role in the formation of associative memories. Indeed,
there are data to suggest that learning or training can affect the
density of dendritic spines in several brain regions such as the
cerebral cortex (Jones et al., 1997). There are also data to suggest
that learning alters spine density in the hippocampus (Moser et al.,
1994, 1997; Jones et al., 1997; O'Malley et al., 2000), a brain region
critical for the formation of some types of memories (Solomon et al.,
1986; Clark and Squire, 1998; Riedel et al., 1999; Weiss et al., 1999), including those differentially affected by stress in males versus females (Beylin and Shors, 1998; Wood et al., 2001).
The most robust modulator of spine density so far established is the
sex hormone estrogen. It has been shown that exposure to estrogen
either exogenously or endogenously during proestrus (P) greatly
enhances spine density in area CA1 of the hippocampus (Gould et al.,
1990; Woolley et al., 1990; Woolley and McEwen, 1992, 1993). Over the
5 d estrous cycle of the rat, spine density can fluctuate as much
as 30%. It has not been determined whether there are sex differences
in dendritic spine density in the hippocampus or elsewhere, but given
the robust effects of estrogen on spine density, sex differences are
likely. Here, we tested whether there are sex differences in dendritic
spine density in area CA1 of the hippocampus and somatosensory cortex.
Because exposure to acute stress has opposite effects on memory
formation in males versus females (Shors et al., 2000) and dendritic
spines have been implicated in learning processes, we also tested
whether exposure to a stressful experience would have opposite effects on dendritic spine density in these same regions.
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MATERIALS AND METHODS |
Subjects and determination of stage of estrous.
Sprague Dawley male and female rats (250-350 gm; ~2-3 months) were
housed individually, and sexes were housed in separate rooms. Each
morning (10:00-11:00 A.M.) vaginal smears were taken from virgin
females for at least 2 consecutive estrous cycles, and only those with normal 4-5 d cycles, including proestrus, estrus (E), diestrus 1 (D1),
and diestrus 2 (D2), were used in the study. Sterile
cotton-tipped applicators were immersed in physiological saline
and gently inserted into the vaginal tract to remove loose cells. Cells
were rolled onto a slide (Everett, 1989). Cells were dried and fixed in
95% EtOH, rinsed in distilled H20, stained in
slightly alkaline 1% aqueous filtered Toluidine blue, and rinsed in
70%, and then 90% EtOH. Based on their vaginal cytology, rats were
classified into four stages of estrous as follows: proestrus was
associated with pinkish-purple staining epithelial cells with dark
nuclei, estrus with masses of dark blue staining cornified cells,
diestrus 1 with dark leukocytes and numerous epithelial cells, and
diestrus 2 with a similar morphology but reduced numbers of epithelial cells. Relative to estrus and diestrus 1, proestrus is associated with
relatively high levels of circulating estrogen (Feder, 1981; Shors et
al., 1999).
Stressor procedure. On the day of stressor exposure
(10:00-11:00 A.M.), smears were obtained. Immediately thereafter,
cells were stained, and stage of estrous was determined. As soon as possible (within 1-2 hr), groups of male rats (n = 5)
or females in either diestrus 2 (n = 5) or estrus
(n = 5) were restrained and exposed to 30 1 sec, 1 mA,
60 Hz shocks to the tail. Within minutes of stressor cessation (the 0 hr stress condition in Fig. 1A), these groups of
stressed rats were killed with unstressed groups of males
(n = 7) or females in diestrus 2 (n = 5) and estrus (n = 6) (Fig. 1A).
Additional groups of males (n = 6) and females in
diestrus 2 (n = 7) and estrus (n = 6)
were exposed to the restraint and tail shock stressor and returned to
their home cages. Twenty-four hours later, these stressed groups were
removed from their home cages and killed with a group of unstressed
males (n = 7) and groups of females that were in the
same stage as the stressed females at the time of killing [i.e., P,
n = 7; D2, n = 6] (the 24 hr condition
in Fig. 1B). Thus, groups of females were stressed in
E or D2 and killed either immediately and in the same stage of estrous or 24 hr later in the subsequent stages of D1 and P, respectively.
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Figure 1.
Schematic for design for experiment 1. Males and
females in determined stages of estrous were exposed to the stressor
and either immediately (A) or 24 hr later
(B) were perfused for determination of spine
density at that time point.
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Golgi method. Rats were deeply anesthetized with an overdose
of Nembutal (sodium pentobarbitol) and transcardially perfused with
120-180 cc of 4.0% paraformaldehyde in 0.1 M
phosphate buffer with 1.5% (v/v) picric acid. Brains were post-fixed
and stored overnight. A modified version of the single-section Golgi
impregnation procedure was used to process the brains (Gabbott and
Somogyi, 1984). Coronal sections (100 µm) were cut and immersed in
baths of 3.0% potassium dichromate solution and incubated overnight. Brain sections were rinsed, mounted, coverslipped on ungelatinized glass slides with a small drop of Krazy Glue (Elmer's Products Inc.,
Columbus, OH) on each of the four corners, and left overnight in
1.5% silver nitrate solution. Slides were then dismantled and sections
were rinsed and dehydrated with ethanol (95%, then 100%), cleared
with xylene and reassembled, coverslipped with Permount, and dried.
Methods for experiment 2. In a second experiment, we
replicated the opposing effects of stress on spine density 24 hr later in males versus females that were stressed in diestrus 2 and killed in
proestrus. We extended the observation of apical spines on CA1
pyramidal cells to include basal spines on the same neurons, as well as
apical spines on pyramidal cells in the somatosensory cortex. In
addition, we measured levels of the stress hormone corticosterone
(CORT) and sex hormones estradiol and testosterone. Groups of
male (stress = 6; no stress = 6) and female rats in diestrus
2 (stress = 4) were exposed to the stressor and killed 24 hr later
with groups of unstressed males (n = 6) and unstressed females in proestrus (n = 4). Trunk blood was collected
for radioimmunoassay of hormones. Golgi impregnation was conducted as
before, and the analysis was conducted blind to the experimental conditions.
Radioimmunoassay of hormone levels. As indicated, cardiac
blood was collected before perfusion. Samples were immediately added to
test tubes containing 0.1 ml heparin and promptly centrifuged for 20 min at 3000 rpm. Plasma aliquots were stored at  80°C and thawed
before analysis. Circulating levels of CORT, estradiol, and
testosterone were measured using a solid-phase radioimmunoassay (RIA)
system (Coat-A-Count; Diagnostic Products). Assay sensitivity for CORT,
estradiol, and testosterone were 5.7 ng/ml, 8 pg/ml, and 4 ng/dl.
Spine analysis. To be selected for quantitative analysis,
the tissue had to be stained dark with Golgi impregnation that was uniform throughout the section. For an animal to be counted, it would
have at least six Golgi-impregnated pyramidal neurons: (1) located
within the CA1 subregion of the dorsal hippocampal formation, (2)
stained and impregnated without breaks in staining along its dendrites,
and (3) discernible from neighboring impregnated cells. Several
guidelines were met before counting commenced on a selected neuron: (1)
measurement occurred >50 µm away from the soma (a range of 50-150
µm total distance from the soma), (2) secondary and tertiary branches
of apical and basal primary dendrites were located, and segments were
analyzed in 10 µm segments, and (3) five segments of 10 µm each in
the same plane of focus were chosen. In some cases, the segments were
from the same branch. Counting required focusing in and out with the
fine adjustment of the microscope using 1000× and oil immersion. Only
those spines that were distinct from the dendritic branch were counted.
For analysis of cortical neurons, at least three neurons that were: (1)
located in somatosensory trunk regions and parietal association
cortices (3.3-3.8 mm posterior to bregma; 2-3 mm lateral) (Paxinos
and Watson, 1986), (2) stained and impregnated, and (3) easily
distinguished from neighboring cells. For each cortical cell, five
segments of 10 µm each in the same plane of focus were chosen, and
counting commenced at least 25 µm from the soma on secondary and
tertiary branches of apical dendrites. Spine density values are
underestimates because the method does not account for spines
protruding beneath or above the segment. We did not analyze for
possible changes in dendritic diameter in response to either sex or
stress, which could alter the appearance of spines without changing
their number.
Densities of spines on five segments of a cell were averaged for a cell
mean, and the six cells from each animal were averaged for an animal
mean. ANOVA was conducted using the animal means as a dependent
measure and stress and sex and stage of estrous at the time of
perfusion as independent measures. Dependent measures included the
density of apical and basal dendrites in area CA1, density on cortical
neurons, and hormone levels. To evaluate group differences, post
hoc analysis using Newman-Keuls was applied to significant main
effects or interactions.
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RESULTS |
Opposite effects of stress 24 hr later in the male versus
female hippocampus
Results from the experiment addressing the effects of stress on
apical dendrites in the hippocampus 24 hr after its cessation are
presented first (Figs. 1B, 2). There was a
significant two-way interaction between the stress versus no stress
condition and sex including the two stages of estrous in the female
(diestrus 1 and proestrus) (F(2,32) = 50.15; p < 0.000001). Using Newman-Keuls post
hoc analysis, it was determined that stressed males had a greater
density of spines (>25%) when compared with other groups in this
experiment (p < 0.0005), including the
unstressed males (p < 0.0005). Exposure to the
stressor was also associated with changes in spine density in females,
but this effect was dependent on the stage of estrous. Females that
were stressed 24 hr earlier during estrus and perfused during diestrus
1 had a greater density of spines than their stage-matched controls,
the unstressed females that were perfused during diestrus 1 (p = 0.01). Thus, the effect of stress on this
group of females was enhancing and similar to that observed in the
males. In contrast, females that were stressed 24 hr earlier during
diestrus 2 and perfused in proestrus had a reduced spine density
(~20%) when compared with their stage-matched controls unstressed
females that were also perfused during proestrus (p = 0.001). In summary, exposure to the stress
had different effects on spine density that was dependent on sex and
the stage of estrous in the female. There were also sex differences and effects of stage of estrous on spine density in the unstressed groups
of rats. Unstressed females in proestrus had a greater density of
spines than unstressed females in diestrus 1 (~25%; p < 0.0005) and unstressed males (~20%;
p < 0.005).
Stress does not alter spine density immediately after its cessation
in males or females
Next we present data that evaluated the effects of stress on
apical dendritic spine density in area CA1 within minutes of stressor
cessation (Fig. 1A). Using the stress condition
(stress versus no stress) and sex and stage of estrous (male versus
estrus female versus diestrus 2 female) as independent variables, there was no main effect of stress (F(1,28) = 0.95; p = 0.34) and no interaction between stress and
sex versus stages of estrous (F(2,28) = 0.01; p = 0.99). Thus, there was no effect of stress
on dendritic spine density immediately after stressor cessation.
However, there was a main effect of estrous stage and sex differences
(F(2,28) = 5.32; p = 0.01). Females in estrus had a reduced density compared with females in
diestrus 2 (p < 0.01) and males
(p < 0.05). The mean density (+SEM)
was 13/10 ± 0.71 µm for males, 14/10 ± 0.66 µm for
females in diestrus 2, and 11/10 ± 0.58 µm for females in
estrus. Although we did not statistically compare groups across the
first and second parts of experiment 1 (Fig. 1, compare A, B), dendritic spine density was greater for females in diestrus 2 than in diestrus 1 and similar to those in proestrus, suggesting that
estradiol levels had already begun to rise (Woolley and McEwen, 1992).
Sex and stress alter dendritic spine density in area CA1 of the
hippocampus but not cortex
In the final experiment, we replicated the results of the first
experiment. There was a significant interaction between the stressor
condition (stress versus no stress) and sex (male versus proestrus
female) on the density of apical spines in area CA1 of the hippocampus
(F(1,16) = 19.05; p < 0.0005) (Fig. 4A). Thus, exposure to the acute
stressful stimulus differentially affected apical spine density in area
CA1 of the hippocampus and interacted with sex. As in the first
experiment, unstressed females in proestrus had a greater density of
apical dendritic spines than unstressed males (p < 0.05). Exposure to the stressor increased apical spine density in
males relative to the unstressed males (p < 0.01) and decreased apical spine density in females that were stressed
in diestrus 2 and perfused 24 hr later in proestrus relative to
unstressed females that were also perfused in proestrus
(p < 0.05). We extended the measurements to
include the basal dendrites on CA1 pyramidal cells. Sex and stress also
differentially affected the density of spines on basal dendrites in
area CA1, as illustrated by the interaction
(F(1,16) = 7.16; p < 0.05) (Fig. 4B). However, post hoc
analysis revealed that only stressed males were different from stressed
females, having a greater density of spines on basal dendrites
(p < 0.05) (Fig. 4B). We also
evaluated the effects of stress and sex on spines on pyramidal neurons
in the somatosensory cortex (Fig. 4C). In contrast to the
hippocampus, neither sex (p = 0.40) nor stress
(p = 0.72) altered spine density on the cortical
neurons, nor was there an interaction between stress and sex on the
cortical spines (p = 0.91).
Relationship between spine density and sex and stress hormones
With respect to corticosterone, females had higher levels than
males (F(1,16) = 18.97;
p < 0.001). Stress did not affect or differentially
affect corticosterone levels in either sex 24 hr after cessation of the
stressor (p = 0.84; p = 0.96, respectively) (Fig. 5A). Males had elevated levels of
testosterone relative to females in proestrus
(F(1,16) = 16.08; p < 0.001), but there was no effect of stress (p = 0.19) nor interaction between sex and stress on testosterone
(p = 0.19) (Fig. 5B). Females had
elevated levels of estradiol relative to males
(F(1,16) = 15.76; p < 0.001), but again, there was no effect of stress
(p = 0.49) nor interaction between stress and
sex on estradiol (p = 0.61) (Fig.
5C). Across groups and conditions, spine density did not
correlate with any of the hormones measured (p > 0.05).
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DISCUSSION |
Previous studies have demonstrated that spine density in area CA1
of the hippocampus fluctuates across the estrous cycle (Woolley et al.,
1990; Woolley and McEwen, 1992; Woolley, 1998). The highest density
occurs during proestrus, a period before ovulation when estradiol
levels peak. We replicate these findings here. In addition, we present
new data indicating that unstressed females in proestrus have a greater
density of spines in area CA1 than unstressed males (Figs.
2,
3C,E). Moreover, we report
that the density of spines in males versus females respond in opposite
directions to the same stimulus. Twenty-four hours after exposure to a
relatively short (30 min) yet fearful event of brief intermittent
tailshocks, the density of spines on apical dendrites in the male
hippocampus increased by as much as 30% (Figs. 2,
3C,D), whereas that of females in proestrus was
reduced (Figs. 2, 3E,F). Although the
effects of stress on spine density in males and proestrus females were evident 24 hr after its cessation, they were not evident within minutes
of stressor cessation. Thus, although spines themselves are dynamic and
motile structures (Desmond and Levy, 1998; Fischer et al., 1998), the
present stress-induced changes in spine density are not rapidly induced
and require some time to accumulate. Once established, stress-induced
changes in spine density are evident for at least 1 d after
cessation of the stressful event.
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Figure 2.
Opposite effects of stress on spine density in
males versus females. Graph illustrates the mean (±SEM) density of
apical dendritic spines on pyramidal cells in area CA1 of the
hippocampus 24 hr after exposure to an acute stressor of brief
inescapable tail stimulation. Significant differences are noted with
asterisks. Under unstressed conditions, females in
proestrus had a greater density of spines than males or females in
diestrus 1. Exposure to the stressor increased synaptic spine density
in males and decreased density in females that were stressed in
diestrus 2 and perfused 24 hr later in proestrus.
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Figure 3.
Golgi impregnation of apical dendrites in area CA1
of the hippocampus. A, A diagram of the hippocampal
formation illustrating the apical and basal dendrites of CA1 pyramidal
cells. B, Golgi-impregnated pyramidal cell, dendrite
from unstressed male (C), stressed male
(D), unstressed female in proestrus
(E), and female stressed during diestrus 2 and
perfused 24 hr later in proestrus (F).
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In the second set of studies, we replicated the opposite effects of
stress 24 hr later on apical spine density in males versus females and
extended the observation to include basal dendrites of the same neurons
(Fig. 4B). Although
there was a significant interaction suggesting effects similar to those
observed for the apical dendrites, the differences were not significant
between individual stressed and unstressed groups. Thus, the effect on these dendrites is not as pronounced as that on the apical dendrites. The functional significance of this differential impact is unknown. Axons from CA3 can terminate on the apical dendrite of one neuron in
CA1 and the basal dendrite of another (Amaral and Witter, 1995). However, there is a heavier commissural projection to basal dendrites of stratum oriens than apical dendrites in radiatum (Swanson et al.,
1978), with corresponding differences in plasticity in these two
regions (Kaibara and Leung, 1993; Cavus and Teyler, 2001). With respect
to spines outside the hippocampus, we observed no effect of sex or
stress on pyramidal neurons in the overlying somatosensory cortex (Fig.
4C). These results are consistent with previous reports that
sex did not affect spine density in the adult visual cortex
(Munoz-Cueto et al., 1991). In summary, the effects of sex and stress
on spine density are not pervasive throughout the brain, and they are,
instead, regionally specific.
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Figure 4.
Effects of sex and stress on apical and basal
hippocampal spines and cortical spines. Graph illustrates the mean
(±SEM) density of apical and basal dendritic spines on pyramidal cells
in area CA1 of the hippocampus 24 hr after stressor exposure.
Significant differences are noted with asterisks.
Exposure to the acute stressor differentially affected density of
apical (A) and basal (B)
dendritic spines on pyramidal cells of area CA1 of the male versus
female hippocampus. C, Exposure to the stressor did not
alter spine density in the cortex.
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With regard to sex and stress hormones, estrogen and corticosterone
levels were enhanced in females relative to males, and testosterone was
enhanced in males relative to females (Fig.
5). There was no effect of stress on
corticosterone or estradiol 24 hr after its cessation, after a
stress-induced increase would have returned to baseline (Shors et al.,
1999). These results indicate that the sex differences and opposite
effects of stress on spine density are not determined by any one
hormonal system. We have not yet manipulated sex hormones to evaluate
more thoroughly their role in these effects. In addition to hormonal
modulation, dendritic spine density can be modulated by changes in
neurotransmission and in particular activation of glutamate receptors.
For example, antagonizing NMDA receptors prevents the estrogen-induced
increase in spine density in ovariectomized females (Woolley and
McEwen, 1994). Others have shown that increases in spine density occur in response to AMPA-mediated activity (McKinney et al., 1999). In a
related manner, exposure to the stressor used here greatly enhances
AMPA receptor binding in area CA1 of the male hippocampus (Tocco et
al., 1991), suggesting increases in AMPA activity as a possible
mechanism for enhancing spine density after stress, at least in males.
Others, however, have shown that a reduction in neuronal activity
increases spine density in the hippocampus (Kirov and Harris,
1999).
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Figure 5.
Effects of sex and stress on hormone levels. Blood
levels of corticosterone (A), testosterone
(B), and estradiol (C) in
males versus proestrus females under stressed and unstressed conditions
are presented.
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Contribution of estrogen to reduction in spine density after stress
in proestrus females
As noted, the reducing effect of stress on spine density was
limited to females in proestrus, suggesting that females are especially
sensitive to stressful experience when estrogen levels are high (Fig.
2). Because unstressed females have an enhanced density of spines in
proestrus, the effect of stress in spine density in females can be
interpreted in one of two ways: either exposure to a stressful
experience reduces spine density in the proestrus female or exposure to
the experience prevents the enhancement of spine density that occurs
normally when estrogen levels are high, as during proestrus. In either
case, contributions of estrous cycle to the stress-induced reduction in
spine density in females suggest that the effect is dependent on the
presence of estrogen.
Dendritic spines and memory formation
It has long been accepted that new dendritic spines or branches
could form new synapses and thereby reinforce associations between
cells or establish new ones. This capacity for connectivity is one
among several means by which spines could participate in the formation
of new associative memories (Cajal, 1894). Indeed, manipulations that
affect learning can affect branching of dendrites (Wantanabe et al.,
1992; Galea et al., 1997; Jones et al., 1997), and learning itself can
affect their structure (Weiler et al., 1995; Geinisman et al., 2000).
There are only a few studies to suggest that learning affects spine
density, per se, at least in the hippocampus. One study reported a
transient increase in spine density in the dentate gyrus after spatial
learning (O'Malley et al., 2000) whereas another observed increased
density on basal but not apical dendrites of CA1 after a similar
training procedure (Moser et al., 1994, 1997). In an ultrastructural
analysis, Geinisman et al. (2000) reported that trace eyeblink
conditioning did not affect axospinous synapse number in area CA1 of
the hippocampus, although measurements were limited to the apical
dendrites. We are currently investigating the effects of trace
conditioning on dendritic spine density on basal dendrites of those neurons.
An opportunistic role for dendritic spines in the modulation of
learning and memory
From the above discussion, it is apparent that learning can alter
spine density under some conditions, but whether spines are necessary
for the formation of associative memories is unknown. It may be that
differing levels of spine density or the availability of dendritic
spines modulate learning. In fact, the opposite effects of stress on
spine density in males versus proestrus females reported here are very
similar in effect to those of stress on learning in males versus
proestrus females (Wood et al., 2001). Using hippocampal-dependent trace conditioning as a measure of performance, we have shown that
exposure to the acute tailshock stressor greatly facilitates conditioning in the male rat 24 hr later but reduces performance in the
proestrus female (Beylin and Shors, 1998; Shors, 1998, 2001; Shors et
al., 2000; Wood et al., 2001). Moreover, we have shown that unstressed
females in proestrus acquire the conditioned response faster than do
unstressed males. Thus, under these various conditions, memory
formation is positively related to dendritic spine density in area CA1
of the hippocampus. That is, stressed males have a greater density of
spines than unstressed males, and they condition more. Also, unstressed
females in proestrus have a greater density of spines than unstressed
males or females in other stages of estrous and they condition more.
Finally, unstressed females in proestrus have a greater density of
spines than stressed females in proestrus and they condition more,
again when trained 24 hr after the stressor in proestrus. Given these
data, it could be proposed that an increase in spine density (either
endogenously through high levels of estrogen in females or exogenously
via stressor exposure in males) "primes" the nervous system for
efficient learning. The presence of those spines can then be used for a more rapid formation of new memories should the opportunity arise. In
this scenario, the important point is that the presence of spines is
opportunistic rather than deterministic.
In summary, we present data illustrating sex differences in dendritic
spine density in select regions of the brain with females in proestrus
having a greater density than males. In addition, we demonstrate that
dendritic spines are especially sensitive to acute stressful experience
and respond in opposite directions to the same stimulus simply as a
matter of sex differences.
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FOOTNOTES |
Received Jan. 12, 2001; revised May 9, 2001; accepted May 16, 2001.
This work was supported by National Institute of Mental Health Grant
R01-59970, the National Alliance for Research on Schizophrenia and
Depression, and the van Ameringen Foundation (T.J.S.). We thank E. Gould, P. Tanapat, J. Heal, and L. King for technical advice and E. Gould and L. D. Matzel for comments on this manuscript.
Correspondence should be addressed to T. J. Shors, Department of
Psychology, Center for Collaborative Neuroscience, 152 Frelinghuysen Road, Rutgers University, Piscataway, NJ 08854-8020. E-mail:
shors{at}rci.rutgers.edu.
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ABSTRACT
INTRODUCTION
Compound via MeSH
