Journal of Behavioral and Brain Science, 2013, 3, 67-73 Published Online February 2013 (
Effects of 17β-Estradiol on Cognitive Performance of
Ovariectomized Female Rats Exposed to Space Radiation
Bernard M. Rabin1*, Kirsty L. Carrihill-Knoll1, Lauren V. Long1,
Steven C. Pitts1, Barbara Shukitt-Hale2
1Department of Psychology, University of Maryland, Baltimore County, Baltimore, USA
2Human Nutrition Research Center on Aging, USDA-ARS, Tufts University, Boston, USA
Email: *
Received December 14, 2012; revised January 15, 2013; accepted January 22, 2013
On exploratory class missions to other planets astronauts will be exposed to types and doses of radiation that are not
experienced in low earth orbit. While it is likely that the crew will consist of both male and female astronauts, there has
been little research on the effects of exposure to space radiation on central nervous system function and cognitive per-
formance in female subjects. Because estrogen can function as a neuroprotectant, the present experiments were de-
signed to evaluate whether or not the presence or absence of estrogen at the time of irradiation would affect the suscep-
tibility to the neurocognitive effects of exposure to 56Fe particles in female rats. Capsules containing 17β-estradiol or
vehicle were implanted in ovariectomized rats three days prior to exposure 56Fe particles (50 - 200 cGy, 1000 MeV/n).
Cognitive performance was evaluated using novel object recognition memory to measure learning and memory and
operant responding on an ascending fix ed-ratio schedule to measure ch anges in motivation and in the responsiveness to
environmental contingencies. The results indicated th e estrogen does not function as a neuroprotectant to minimize the
cognitive effects of exposure to 56Fe particles. However, the presence/absence of estrogen at the time of irradiation
could modulate the responsiveness of the subject to the disruptive effects of exposure to HZE particles on the perform-
ance of specific cognitive tasks.
Keywords: Cosmic Rays; Behavior; Sex Differences; Estrogen
1. Introduction
On exploratory class missions to other planets astronauts
will be exposed to types and do ses of radiation, including
particles of high energy and charge (HZE particles) such
as 56Fe, that are not experienced in low earth orbit [1-3]
where there International Space Station and space shuttle
operate. While it is likely that the crew will consist of
both male and female astronauts, there has been little
research on the effects of exposure to HZE particles on
central nervous system function and cognitive perform-
ance in female subjects. Both exposure to HZE particles
[4-9] and the gonadal hormone environment [10-15] can
affect neuronal function and cognitive performance. As
such, it is possible that males and females may respond
to HZE particle irradiation differently.
Estrogen has been reported to provide protection
against the development of neurodegenerative diseases,
delaying the onset and progression of Alzheimer’s and
Parkinson’s diseases and schizophrenia [16-19]. In addi-
tion, estrogen protects against experimental ischemic
stroke [16,19], chronic inflammatory diseases [20] and
dopaminergic system dysfunction following the admini-
stration of a variety of neurotoxins [21,22], including
kainic acid and 6-hydroxydopamine.
The mechanisms underlying the neuroprotective ef-
fects of estrogen are not certain. It has been suggested
that estrogen may function to activate free radical scav-
enging systems [23], reducing oxidative stress and mini-
mizing neuroinflammatory processes in the brain [24,25].
Alternatively, the neuroprotective effects of estrogen may
possibly be mediated by actions on microglia [23-26],
where estrogen can affect both apoptotic [27] and kinase
signaling proce ss es [ 28,29].
Because exposure to HZE particles produces many of
the same changes in neuronal function that characterize
neurodegenerative diseases, including oxidative stress [7,
30], inflammation [31], and changes in dopaminergic
function [32-34], it is possible that estrogen may serve
similar neuroprotective functions following exposure to
HZE particles as it does for neurodegenerative diseases.
The present experiments were designed to evaluate whe-
ther or not the presence or absence of estrogen at the time
*Corresponding a uthor.
opyright © 2013 SciRes. JBBS
of irradiation would affect susceptibility to the neuro-
cognitive effects of exposure to 56Fe particles in female
2. Experimental Procedure
2.1. Subjects
The subjects were 100 ovariectomized (OVX) female
Sprague-Dawley rats weighing 175 - 200 g obtained from
Taconic Farms. All procedures were approved by the
IACUCs of Brookhaven National Laboratory (BNL) and
University of Maryland Baltimore County (UMBC).
2.2. Implantation of Estradiol/Vehicle
Implantation of estradiol or vehicle was performed at
BNL. The procedure was adapted from the one detailed
by Strom and colleagues [35]. Thirty mm segments of
silastic laboratory tubing (Inner/outer diameter: 1.575/
3.175 mm, Dow Corning, VWR International, Buffalo
Grove, IL) were filled with a solution of 180 pg l7β-es-
tradiol/mL sesame oil or sesame oil alone (vehicle). The
ends of the tubing were sealed with 5 mm pieces of woo-
den applicator sticks, resulting in a vehicle- or 17β-estra-
diol-filled column 20 mm in length. Before use, the cap-
sules were stored overnight in a vial containing sesame
oil with the same concentration of 17β-estradiol or vehi-
cle as inside the capsules.
To implant the capsules the rats were anesthetized
with sodium pentobarbital (35 mg/kg, i.p.). A 5 mm inci-
sion was made in the loose skin of the rat’s neck, and a
pocket bluntly dissected caudally in which the silastic
capsule was gently installed using forceps. The capsules
were implanted subcutaneously in the neck because of its
abundance of loose skin, and to minimize the risk of
mechanical stress on the capsule. The incision was closed
by a suture. Following surgery th e rats were monitored to
make certain that they recovered from the anesthesia.
Strom et al. [35] have used radioimmunoassay proce-
dures to evaluate the levels of estradiol in serum follow-
ing implantation of silastic capsules containing 17β-es-
tradiol as detailed above. They reported that this proce-
dure resulted in a relatively stable, physiolog ical level of
estradiol in serum from the time of implantation and last-
ing for 4 - 5 w eeks followin g implant a tion.
2.3. Radiation
Because serum estradiol concentrations attained with the
use of silastic capsule implants are relatively constant
immediately following implantation [35] the rats were
irradiated after a 48 hr recovery period. The rats were
exposed to 56Fe particles at the NASA Space Radiation
Laboratory (NSRL) at BNL. Dosimetry was provided by
the staff of the NSRL using ionization chambers. The
doses to which the rats were exposed were 50 (n = 20),
100 (n = 24), 150 (n = 24) and 200 (n = 20) cGy at a
nominal dose rate of 25-100 cGy/min. The co ntrol rats (0
cGy, n = 22) were taken to the NSRL but were not irra-
diated. Half the rats at each dose were implanted with
silastic tubing containing 17β-estradiol and half were im-
planted with tubing containing vehicle.
For irradiation, the rats were placed in well-ventilated
plastic tubes which were placed perpendicular to the
beam. The animal was positioned with the center of its
head in the beam. As such, some of the neck of the ani-
mal was also exposed. Following irradiation the rats were
shipped to UMBC for behavioral testing.
2.4. Behavioral Testing
At UMBC the rats were given 7 - 10 days to recover
from the effects of shipping before beginning behavioral
testing. The behavioral procedures have been detailed in
previous publications, so they will only be briefly de-
scribed her e.
2.4.1. Object Reco gn ition [ 36]
Subjects were tested in a dimly lit op en field (93 cm × 93
cm). The stimulus objects (which are no smaller than the
size of the rat and no larger than two and a half times its
size) vary in shape and color. After habituation to the
apparatus, two identical (familiar) stimulus objects are
placed in symmetrical locations in the open field. The rat
is allowed to explore the stimuli until it accumulates 30
sec total object exploration (i.e., exploration of either ob-
ject) or until 20 min have passed. After 24 hr delay, the
rat is placed back in the field with one familiar and one
novel object and allowed to explore both stimuli until it
has accumulated 30 sec of object exploration on either
object or until 20 min have passed. Normally rats will
spend more time exploring the novel object; old rats and
rats that have impaired recognition memory spend equal
amounts of time with both the familiar and novel object.
2.4.2. Operant Responding [37]
Food-deprived rats (maintained at 90% base weight) are
first trained to press a lever on a continuous reinforce-
ment schedule using an autoshaping procedure in which
they are placed in an operant chamber for 12 hours. Most
rats learn the response within a single session. The rats
are then trained to respond on a fixed-ratio (FR) schedule
by placing them in the chamber for 30 min and reward-
ing them on FR-1, FR-5 ( every fifth response reward ed),
FR-10, and FR-20 reinforcement schedules. For testing
they are then given 30-min sessions in which they are
rewarded on FR-1, FR-5, FR-10, FR-15, FR-20, FR-25,
FR-30 and FR-35 reinforcement schedules on consecu-
tive days. This task is a measure of an organism’s moti-
Copyright © 2013 SciRes. JBBS
vation to work for reinforcement and its ability to re-
spond to changes in env ironmental contingencies. Perfor-
mance on this task is dependent on the dopaminergic sys-
tem [38] and may be related to the activational aspects of
motivation and the effort put into obtaining reinforce-
ment and is dependent upon the integrity of the striatum
2.5. Statistics
The initial data analyses were performed using 2-way or
3-way analyses of variance. Comparisons between groups
exposed to different doses of 56Fe particles were made
using Fisher’s protected-T.
3. Results
3.1. Novel Object Recognition
Exposing OVX female rats, with either estradiol or vehi-
cle implants at the time of irradiation, to 56Fe particles
did not affect the response to the novel object (Figure 1).
All rats spent significantly more time with the novel ob-
ject than with the familiar object. Neither the main effect
for dose, (F[4,75] = 2.40, p > 0.05), for treatment (estra-
diol/vehicle) (F[1,45] = 0.05, p > 0.10), nor the dose by
treatment interaction (F[4,84] = 1.30, p > 0.10) was sig-
3.2. Operant Responding
The effect of exposure to 56Fe particles on operant re-
sponding on an ascending FR schedule in OVX female
rats is shown in Figure 2. A 3-way ANOVA with one
Figure 1. The percentage of time spent exploring the novel
or familiar object in female rats implanted with 17β estra-
diol or vehicle and irradiated with 56Fe particles. Mean ±
standard error of the mean (s.e.m.).
repeated variable (reinforcement schedule) was used for
the initial analysis. The ANOVA indicated that the main
effects for dose, treatment (estradiol or vehicle implant)
and reinforcement schedule were all significant (F[4,90]
= 2.54, p < 0.05; F[1,90] = 4.08, p < 0.05; F[7,630] =
39.70, p < 0.01; respectively). The dose by schedule in-
teraction was significant (F[28,630] = 1.50, p < 0.05) as
was the treatment by schedule interaction (F[7,630] =
2.77, p < 0.01]. Neither the dose by treatment interaction
nor the triple interaction was significant.
To partial out the main effects, two different 2-way
Figure 2. Performance on an ascending fixed-ration operant
task in female rats exposed to 56Fe particles (0 - 200 cGy).
Upper panel: capsules containing vehicle only implanted
prior to irradiation; low er panel: capsules containing estra-
diol 17β implanted. Mean ± s.e.m.
Copyright © 2013 SciRes. JBBS
ANOVAs were run for each of the implant conditions
using the MS error from the 3-way ANOVA [41]. For the
animals given estradiol implants, the main effect for dose
of radiation (F[4,90] = 2.77, p < 0.05) and for reinforce-
ment schedule (F[7,28] = 17.63, p < 0.01) were signifi-
cant. The dose by schedule interaction was also signifi-
cant (F[28,630] = 1.62, p < 0.01) indicating that perfor-
mance deteriorated as a greater number of responses
were needed to produce reinforcement. In contrast, for
the rats given vehicle implants, only the main effect for
reinforcement schedule was significan t. Neither the main
effect of dose nor the dose by schedule interactions was
Because visual inspection of Figure 2 suggests the
possibility that there were differences in responding in
the non-irradiated control animals as a function of estra-
diol or vehicle implants, a final 2-way ANOVA was run
to compare the performance of the non - irradia t e d an i mals
(0 cGy) given either estradiol or vehicle implants. For
both treatment groups (estradiol or vehicle) there was a
significant increase in response rate as the reinforcement
schedule increased (F[7,140] = 6.95, p < 0.01). However,
there were no differences in performance as a function of
treatment condition (F[1,20] = 1.78, p > 0.10), or in the
treatment by schedule interaction (F[7,175] = 0.98, p >
0.10). These results indicate that the differences in re-
sponding between animals given estradiol or vehicle at
the time of radiation could not be due to differences in
hormonal status only, but must reflect an interaction be-
tween hormonal status and exposure to 56Fe particle.
4. Discussion
While the results suggest that estrogen may exert both
organizational and activational effects on cognitive per-
formance following exposure to HZE particles, depend-
ing upon the specific task, overall, the results do not
support the or iginal hypo thesis that estrog en can function
as a neuroprotectant to counteract the effects of exposure
to 56Fe particles on cognitive performance. Rather, the
presence of estrogen at the time of irradiation seems to
be necessary for the particle-induced disruption of oper-
ant responding. In addition, although male subjects were
not run at the present time, comparison with the results of
previous experiments u tilizing male rats [36,37] suggests
that male and female rats may respond differently to ex-
posure to HZE particles, depending upon the specific
In contrast to operant performance none of the OVX
rats, given either estradiol or vehicle at the time of irra-
diation, showed a disruption of recognition memory fol-
lowing exposure to 56Fe particles. All rats, both radiated
and non-irradiated controls, spent more time interacting
with the novel object than with the familiar object. Al-
though the hormonal environment for these rats differed
at the time of irradiation, depending upon whether the
rats were given estradiol or vehicle implants, there were
no differences in the hormonal environment at the time
of testing because the estradiol levels measured in blood
would have returned to normal OVX levels by the time
they were tested on the novel object recognition task
which occurred 4 - 6 weeks following surgery [35]. As
such, these results indicate that the hormonal environ-
ment (presence or absence of estradiol) at the time of ir-
radiation was not a factor influencing the effects of ex-
posure to 56Fe particles on recognition memory in female
rats. These results differ from those obtained using male
subjects which show a disruptio n of recognition memory
following exposure to 56Fe particles [36] such that equal
amounts of time are spent with both novel and familiar
objects. The failure to observe a radiation-induced per-
formance decrement in female rats, compared to male
rats, following exposure to 56Fe particles may reflect dif-
ferences in hormone levels at th e time of testing or in the
organization of the brain as the result of differences in
perinatal hormones [42]. Alternatively, the differences
between males and females may reflect the fact that go-
nadal hormones have can have different effects on cogni-
tive performance in males and female [43-45].
Operant responding on an ascending FR schedule, a
measure of the responsiveness of the organism to envi-
ronmental contingencies, showed distinct changes in the
patterns of responding as a function of hormonal status at
the time of irradiation. The ovariectomized females given
vehicle-only implants showed no effect of exposure to
56Fe particles on their response pattern: there were no
differences in response patterns between the non-irradi-
ated control rats and the irradiated rats. However, the
OVX females given estradiol implants showed an effect
of irradiation on cognitive performance following irra-
diation. Compared to the non-irradiated controls, the
OVX rats with estradiol implants at the time of irradia-
tion failed to show a corresponding increase in respond-
ing as the reinforcement schedule increased following
exposure to 150 or 200 cGy of 56Fe particles. In this re-
gard, the performance of the female rats with estradiol
implants at the time of irradiation was similar to that of
male rats which showed a disruption of operan t respond-
ing following exposure to 200 cGy of 56Fe particles [37].
The mechanisms underlying the interaction between
exposure to 56Fe particles and estradiol in OVX rats
which result in the disruption of operant responding are
not certain. Performance on this specific task is depend-
ent upon the integrity of the dopaminergic system [38].
Gender differences have been reported in the functioning
of the dopaminergic system in the striatum, with estrogen
enhancing the release of dopamine in female, but not
male rats [46]. Estrogen has been reported to have dif-
Copyright © 2013 SciRes. JBBS
ferent effects on striatal- and hippocampal-mediated learn-
ing [10], such that estrogen facilitates hippocampal-me-
diated learning while it interferes with striatally- mediated
learning. It has been further suggested that the interaction
between estrogen and dopamine influences the use of
striatally- or hippocampally-mediated strategies in the
performance of a cognitive task [13].
Similar task-dependent sex differences following ex-
posure to HZE particles have been reported by Villasana
et al. [8]. Exposure to 56Fe particles impaired perform-
ance of hippocampal-dependent contextual fear condi-
tioning task in female mice, but led to improved perfor-
mance in male mice. There was no effect of exposure to
56Fe particles in the performance of a cued fear condi-
tioning task, which is not mediated by the hippocampus,
in either male or female mice.
Overall, the results of these experiments indicate that
the relationship between the gonadal hormone environ-
ment and cognitive performance following exposure to
56Fe particles is complex. The effects of gonadal hor-
mones on neuronal function can be classified as “activa-
tional” or “organizational” [42,47]. Activational effects
refer to contemporary correlations between the current
hormonal environment and cognitive performance. Or-
ganizational effects refer to developmental correlations
between the perinatal hormonal environment which in-
fluences the org anization of the brain, and which may, at
some later time, affect cognitive performance. Both types
of effects are observed following exposure to 56Fe parti-
cles. Estradiol- and vehicle-implanted rats showed no
differences in performance on the novel object recogni-
tion task, indicating that the hormonal environment, pre-
sence or absence of estrogen at the time of irradiation,
had no effect on subsequent performance. However, the
observation that neither the estradiol or vehicle implanted
females, in contrast to males [36], spent more time with
the novel object following irradiation suggests that there
may be differences in brain organization which affect
performance on this task. In contrast, activational effects
were observed in the effects of exposure to 56Fe particles
on operant performance.
In summary, the results of these experiments indicate
that estrogen, despite its capacity to function as a neuro-
protectant following a variety of toxic insults [19,21,22]
or neurodegenerative disorders [16,18], may not fulfill
that role following ex posu re to HZE particles. Rather, the
results suggest that the activational effects of estrogen
may be to produce a performance deficit with selected
cognitive tasks, sp ecifically operant responding on an as-
cending fixed ratio reinforcement schedule which is a
measure of the responsiveness of the organism to changes
in environmental contingencies. As such, the presence of
estrogen at the time of irradiation seems to function to
make females respond to exposure to 56Fe particles in a
manner similar to males. The role of testosterone in male
subjects re mains to be establ ished .
5. Acknowledgements
This research was supported by NASA grant NNX08
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