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*
Department of Neuroscience and Anatomy, The Pennsylvania State University College of Medicine, Hershey Medical Center, Hershey, Pennsylvania 17033;
Department of Biobehavioral Health, College of Health and Human Development, The Pennsylvania State University, University Park, Pennsylvania 16802- 6508 and
**
Graduate Program in Nutrition, The Pennsylvania State University, University Park, Pennsylvania 16814
2To whom correspondence should be addressed at Nutrition Department, S125 Henderson Building, University Park 16802. E-mail: its{at}psu.edu
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • iron deficiency • iron excess • rats • behavior • habituation • physical activity
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, Oski et al. 1983
) and later studies
(reviewed in Idjradinata and Pollitt 1993
, Lozoff 1989
, Lozoff and Brittenham 1986
, Pollitt 1993
, Walter 1993
), remarkably similar results
are reported. The biological basis of ID-related cognitive and
behavioral alterations is unclear; however, a conceptual model of
contributing factors must include environmental as well as biological
conditions. Moreover, these mechanisms are not mutually exclusive
(Lozoff 1998
, Lozoff et al. 1998
). The
first group of variables includes disadvantaged environment, poor
feeding practices, maternal depression and limited support for child
development, among others. The biological variables are all related to
the decrease in brain iron associated with ID and likely include
hypomyelination, impaired dopaminergic function and delayed
neuromaturation (Lozoff 1998
). For example, studies in
animals have demonstrated a negative impact of ID on myelination
(Larkin and Rao 1990
, Yu et al. 1986
). In
measuring auditory brainstem-evoked responses in 6-mo-old ID
infants during spontaneous naps, researchers found that absolute and
interpeak latency values were longer among ID infants at several
stimulus conditions, which in turn is related to delayed
neuromaturation (Roncagliolo et al. 1998
). At
follow-up at 12 and 18 mo, after iron therapy, central conduction
times were even greater, indicating probable irreparable damage.
Other studies document increased levels of catecholamines in urine in
ID subjects that normalize with the recovery of iron nutritional status
(Beard 1987
, Oski et al. 1983
). Several
neurotransmitters, including catecholamines, are known to modulate the
capacity for early and late processing of information, affecting
arousal and activation (Izquierdo 1989
). Among limbic
system structures, the amygdala, septum and hippocampus seem to be the
most important structures involved (Izquierdo and Medina 1991
). Therefore, iron may exert a role on cognition and
behavior through its actions in the synthesis and function of
neurotransmitters in limbic structures.
It is important to note that the effects of iron on
neurological functioning in rodents are associated with the levels of
iron in the brain, not with the anemia per se.
Phenylhydrazine-induced anemia does not affect the brain nonheme
iron content, the dopamine (DA) D2 receptor
numbers or apomorphine-related behaviors (Ashkenazi et al. 1982
, Ben-Shachar et al. 1985
, Nelson et al. 1997
). Induction of ID in postweaning rats results in
decreased densities of DA D2 receptors
(Ashkenazi et al. 1982
, Youdim et al. 1983
). More recently, our laboratory demonstrated
ID-related increased extracellular DA and blunted DA reuptake in
vivo, using microdialysis in rats (Beard et al. 1994
,
Chen et al. 1995
, Nelson et al. 1997
).
These effects disappeared when the animals were iron repleted
(Nelson et al. 1997
); lending evidence that in
postweaning rats, the process is reversible. Although it is clear that
the neuromaturation delays observed in human infants are more clearly
observed in anemic deficient subjects (Lozoff et al. 1998),
other studies demonstrate cognitive effects of ID with nonanemic
subjects (Bruner et al. 1996
).
The neural mechanisms that govern exploratory behavior in animals are
very complex, and dopaminergic systems mediate many forms of motivated
behavior and motor function (Izquierdo 1992
,
Robbins and Everitt 1982
). It is then to be expected
that ID-related changes in DA metabolism would result in
alterations in exploratory behavior in animals. Some experiments with
rats have shown that ID animals are less active than control (CN)
animals (Youdim et al. 1980
and 1981
). When placed into
a novel environment, ID rats evinced less exploration than CN rats
(Weinberg et al. 1980
). Repletion of these rats with
iron for 6 wk failed to correct this deficit in their exploratory
behavior compared with CN rats. Stereotypy, a putative index of central
DA activity, was reduced in ID rats that were treated with DA agonists
(Youdim et al. 1980
). Youdim et al. (1981
) reported a reversal in the diurnal activity pattern of
ID rats; however, iron repletion normalized their activity patterns
within 2 wk. Hunt et al. (1994
) reported decreased motor
activity and exploratory behavior in ID rats but could not replicate
the reversed activity cycle phenomenon noted by Youdim’s group.
The involvement of excess iron in neurological disease has received increased attention in recent years, especially in reference to the increased iron content in the brains of Alzheimer’s disease and Parkinson’s disease patients. Still, there are no studies on the effects of excess dietary iron during early development on the behavior and activity of rats. This experiment was designed to investigate the behavioral effects of early ID and excess iron and to determine whether ID during lactation produces behavioral changes not reversible with subsequent iron repletion.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The data presented here represent part of a large experiment that
evaluated the changes in brain iron metabolism (see Piñero et al. 2000
). We designed a longitudinal intervention study to
examine the effects of ID and iron supplementation during
mid-lactation, after weaning and throughout mid-lactation and
weaning.
Animals and dietary treatment.
Male and female Sprague-Dawley rats weighing 250–270 g and
150–170 g, respectively, were purchased from Harlan Sprague-Dawley
(Indianapolis, IN). On arrival, the female rats were fed a powdered,
iron-adequate diet (see below), and the males were fed a
commercial, pelleted diet (Laboratory Rodent Diet; PMI Nutrition
International, Brentwood, MO). At 200–220 g of body weight, the
females were placed with a male for 5 d (two females and one male)
or until pregnant. Pregnancies were determined by the appearance of
vaginal plugs, and the pregnant dams were housed individually. At
approximately d 10 of pregnancy, some pregnant dams were randomly
assigned to an ID or an iron-supplemented (SU) diet. This date was
selected to allow the dams fed the ID diet to become iron deficient by
d 10 postpartum and to be used as foster dams for ID-destined pups.
The first morning that pups appeared in the cage was considered
postnatal day (PND) 1. At PND 4, the litters were reduced to eight pups
and, if possible, four males and four females. At PND 10, all pups from
CN dams (normal neonatal iron status) were randomly assigned to an ID,
SU or another CN dam for the duration of lactation. Hence, at PND 21
there were three groups of rats: CN, ID and SU, all of which had normal
intrauterine iron status. At PND 21, the rats were randomly assigned to
be weaned to a CN, an ID or an SU diet or to be killed; except for the
SU group, which would be only assigned to an SU diet or killed (see
Fig. 1
). As a result, at PND 35, when the remainder of the rats were killed,
the following groups were generated:
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) but with
cornstarch used as the sole source of carbohydrate in the mixture. As
reported previously (Piñero et al. 2000
), the iron
concentration of the diets was 39.7 ± 0.8 mg/kg for the CN diet,
3.04 ± 0.4 mg/kg for the ID diet and 420 ± 8.1 mg/kg for
the SU diet (mean ± SEM). All the rats were housed individually under controlled environmental conditions (0600–1800 h light cycle and 25°C) and were provided free access to food and water. Food intake and body weights were recorded every other day. The Pennsylvania State University Animal Care and Use Committee approved all animal procedures.
The dams’ iron status was closely followed by measuring hemoglobin (Hb) and hematocrit (Hct) before mating and at mid-pregnancy, delivery, mid-lactation and weaning. The pups’ Hb and Hct were determined at PND 10, 14, 17, 20, 27 and 35. The blood samples were collected via tail puncture.
Hematology and liver nonheme iron.
Hemoglobin was measured colorimetrically with the cyanmethemoglobin method (procedure no. 525; Sigma Chemical Co., St. Louis, MO), and Hct was determined through centrifugation of blood collected into heparinized microcapillary tubes.
Liver nonheme iron was determined according to the standard colorimetric technique described by Cook (1980b) with ferrozine as the color reagent.
Behavioral testing.
All behavioral data were collected with a Digiscan Animal Activity Monitor [model RXYZCM(8); Omnitech Electronics, Columbus, OH), which consists of a set of four 40 x 40 x 30.5-cm Plexiglas boxes with vertical and horizontal infrared sensors. The flooring is an elevated acrylic platform with equally spaced holes (4 x 4 x 1.5 cm in diameter). The rats were tested on PND 14, 17, 20, 27 and 34, in a dark, isolated room between 1100 and 1300 h. The rats were placed in the center of the box for 20 min, and data were aggregated in four 5-min intervals. The rats were returned to their cages on completion of the test. Behavior measures included total distance traveled, number of repeated movements (stereotypy) and rate of habituation in distance traveled. One measure of reactivity is the rate of habituation to a novel environment. Thus, during prolonged exposure to a new environment, animals typically spend progressively less time in movement and exploration. To quantify this measure of reactivity, we performed a regression analysis: distance traveled versus time for the first 20 min. The index used was the slope (in cm/min) or rate at which the rats diminished their total movement. We calculated slopes for all rats in treatment groups for the 21- and 35-d experiments.
Because of the constraints of a complex experimental design and the possibility that prior experience in the activity chamber would alter subsequent behavior during testing, only a random subsample of six to eight rats from each treatment group were tested for differences in physical activity at each time point. The data collected for the different tests were aggregated for each session to evaluate total differences by group and by day. To evaluate changes in habituation, we calculated the slope of the corresponding regression line for the collected data for each day and animal, using the four 5-min interval data points. These slopes were used to analyze possible differences between groups by day of test. Some rats that were tested before PND 21 were killed at weaning. These rats were included only in the analyses of the early ID/iron supplementation, although there were no detectable differences in performance in the subgroup that continued up to PND 35 and the subgroup that was killed at PND 21. Only the rats that were tested from PND 14 to PND 34 were included in the analyses of the long-term ID/iron supplementation and repletion effects. Hence, for the effects of early ID/iron supplementation, the analyses were performed between the ID, CN and SU groups. The effects of late ID were evaluated in a comparison of the CNCN and CNID groups; the effects of repletion were evaluated in a comparison of the CNCN, IDCN and IDSU groups; and the CNCN, IDID and SUSU groups were compared to determine the effects of long-term ID/iron supplementation.
Statistical analysis.
Analysis of variance for two between-subject factors (treatment and sex) was performed for biological data, and an additional within-subject factor (day) was added to the model for behavioral data analysis. Subsequent post hoc comparisons were made with the Tukey HSD method, and Dunnett’s t test was used for comparisons between treatment and control.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Early ID and iron supplementation.
The period of early ID refers to the dietary ID induced between PND 10
and PND 21. Hematological indices and liver nonheme iron demonstrate
that profound ID anemia existed in the ID rats at PND 21 (Table 1
). The Hb and Hct values followed the pattern SU > CN > ID,
with the differences between the groups being significant (P
< 0.05).
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Recovery from ID.
For the rats that were iron deficient from PND 10 to PND 21 and
subsequently repleted with iron by weaning them to either the CN or SU
diet, hematological indices rapidly returned to normal (Table 2
). The repletion with the high SU diet clearly provided a faster
recovery than the repletion with the CN diet. At PND 35, the rats
showed a clear recovery from ID, as demonstrated by their final body
weight and liver and brain weights. These findings occurred for both
sexes (data not shown).
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), confirming that the rats were iron deficient at PND 35. By PND 27,
after only 1 wk, Hb and Hct, as well as body weight, were already
significantly lower for the CNID rats than for their iron-adequate
comparison group (CNCN) (data not shown). The final body and liver
weights, but not the brain weight, were significantly smaller than
those of the CNCN group (Table 3)
. When the brain weight was expressed
as a percentage of the body weight, the differences were still present,
and the brains of the CNID rats were significantly larger than those of
the CN rats. Dietary treatment with extra iron in CNSU rats produced
significantly larger rats with greater hematological indices, although
the increases in liver and brain weight of these supplemented rats was
proportional to their increase in body weight (Table 3)
.
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All of the hematological variables, as well as the liver iron levels,
were significantly lower in the ID group than their respective CN rats
(Table 4
). The difference in body weight between the CNCN and IDID groups was
already significant at PND 21 and continued to increase, so that at PND
35, the IDID rats were 45% smaller than the CNCN rats. The livers and
brains of these long-term ID rats were also smaller than their CN
rats (Table 4)
. When the organs of these long-term ID rats were
expressed as a percentage of their body weight, they were still
different from the CN rats. Interestingly, the brains of the IDID rats
were proportionally larger than those of the CNCN rats.
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. Behavioral Measures
Total distance.
This variable is a measure of ambulatory activity, usually associated
with exploratory behavior. The amount of time spent in movement
(movement time) was also measured, but because it is highly correlated
with distance traveled, we present only the former data in this report.
The rats that were iron deficient during mid- and late lactation
traveled a shorter distance than the CN rats at PND 20 (Fig. 2
, top). When ID was continued with weaning to an ID diet (IDID), this
difference in exploration became even greater at PND 27 and PND 34
(Fig. 2
, top). The ID rats had a slower rate of short-term
habituation in activity over the 5-min intervals at PND 20 compared
with CN rats (Fig. 3
, top).
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, top). The repletion with either CN or SU diets (IDCN
and IDSU, respectively) failed to return the ambulatory activity
completely to normal at PND 34, despite the normalization of iron
status (Fig. 2
, middle). These iron-replete rats showed the same
habituation for this variable, for the tests at PND 27 and PND 34, as
their CN group (Fig. 3
, bottom).
The rat pups that were provided extra dietary iron from PND 10 to PND
21 and beyond (SUSU) had decreased ambulatory activity by PND 20, and
this difference was also apparent at PND 34 (Fig. 2
, bottom). Their
habituation did not differ from that of the CN rats (Fig. 3)
.
Stereotypy.
The number of stereotypic activities that occurred during the testing
session was not affected by ID before PND 21, but at PND 27, the
long-term ID rats (IDID) showed a marked decreased in stereotypic
movements that persisted at PND 34 (Fig. 4
, top). Postweaning ID (CNID) also greatly reduced the number of
repeated movement of the rats, although not as dramatically as in those
that had experienced ID during lactation and postweaning (Fig. 4
, top).
Habituation was significantly slower in IDID rats only at PND 34 (data
not shown) compared with CN rats.
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, middle). The rat pups that were
provided excess iron during lactation and weaning (SUSU) had fewer
stereotypic behavior episodes than their corresponding CN rats at PND
35 but not at earlier time points (Fig. 4
, bottom). There were no
differences in habituation for this variable for either the repletion
or the supplemented groups. Because stereotypic behavior could be affected by motor activity, an analysis of covariance was performed using motor activity as the covariate and stereotypy as the dependent variable (data not shown). The group differences in stereotypy persisted after this statistical examination, demonstrating an independent effect.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). The growth, hematological data and the concentration of
iron in the livers of these rats all demonstrate an affect of
lactational ID that is similar to that observed previously in
postweaning-induced dietary ID (Borel et al. 1991
,
Erikson et al. 1998). Although ID does not affect the
brain weight of older rats (Chen et al. 1995a
,
Serfass et al. 1988), early ID anemia and long-term
anemia of early onset result in smaller brains that contain less iron
despite normalization of hematological indicators of iron status
(Felt and Lozoff 1996
, Kwik-Uribe et al. 2000
). Postweaning ID did not produce smaller brains, because
the brain has a different growth curve than the whole body
(Dobbing and Sands 1979), and the brain growth spurt was
almost completed by the time the late ID rats of our study became iron
deficient. This is in contrast to the research designs that use
gestational ID (Felt and Lozoff 1996
, Kwik-Uribe et al. 2000
). The repletion of the lactation ID rats with a CN
diet (IDCN) was effective in returning the hematological values and the
liver iron concentration to normal within several weeks, but a larger
amount of dietary iron (IDSU) was necessary to normalize body weight
within that short time frame. We noted previously that this repletion
protocol is also adequate to replete most brain iron regions with iron
within 14 d (Piñero et al. 2000
).
There is a reported effect of early high doses of supplemental iron on
attenuation of brain growth as well (Taylor et al. 1991
). However, the SU group in the current report had larger
brains that the CN rats when normalized to body size. This discrepancy
could arise from the fact that the rats from the study by Taylor et al.
were supplemented with a much larger dose of iron and were provided the
SU diet for a longer time. Felt and Lozoff (1996
), using
a paradigm of late lactational ID in which rats that are comparable to
our early ID group were repleted after weaning and up to 3 mo of age,
found that at 3 mo of age, the brains of these rats were not different
from those of the CN rats. Our results indicate that this recovery is
in fact very fast and occurs during the first 14 d of repletion.
Although the neurological bases of animal and human behavior are not
yet understood, spontaneously emitted behaviors, like motor activity
patterns, exploration and stereotypy, have been used extensively in
pharmacological studies (Robbins and Everitt 1982
). We
have already alluded to the substantial literature indicating
alterations in the dopaminergic systems and in the myelination of
neural fibers in ID. In the current investigation, we examined
behaviors that are sensitive to alterations in the dopaminergic system,
with its projections to the striatum and the limbic system. Moreover,
it has been shown that spontaneous locomotor activity depends on intact
dopaminergic pathways (Iversen and Koob 1977
) and that
stereotypy is mediated by DA (Ben-Shachar et al. 1988
,
Costall et al. 1977
). In this study, the decrease in
movement time, distance traveled and number of repeated movements in ID
rats is consistent with reduced dopaminergic function (Youdim and Green 1977
). Using postweaning ID, Hunt et al. (1994
) found a decrease in horizontal movement and distance
traveled in older (
12-wk-old) rats fed an ID diet for 8 wk.
Youdim et al. (1980
) reported a reduction in 24-h motor
activity in postweaning ID rats. The current study extends the
developmental time frame into lactational ID and demonstrates a much
more profound effect when ID occurs during lactation and weaning
compared with the effect induced during weaning. We noted previously
that postweaning ID results in alterations in striatum DA levels,
metabolism and expression of DA transporters (Chen et al. 1995
, Erikson et al. 2000
, Nelson et al. 1997
). The sensitivity of DA transporter in ID rats to cocaine,
an inhibitor of functioning of the DA transporter, was significantly
blunted, resulting in less enhancement of movement with administration
of the drug. Although the drug did increase both stereotypy and
movement time and distance, it never did fully normalize these
behaviors in postweaning ID rats (Erikson et al. 2000
).
Thus, ID could be accomplishing its deleterious effects on physical
activity and exploratory behavior via its direct effects on DA
metabolism and, through it, on motivation.
A novel finding of the current report is that early ID anemia produced
a decrease in movement time and distance traveled by PND 21.
Felt and Lozoff (1996
) also observed a decrease in
movement of ID rat pups back to their nest when the nutritional insult
was instituted during gestation and early lactation. Recently,
Kwik-Uribe and colleagues (2000)
used a similar model of
gestational and lactational ID in mice to demonstrate decreased
performance on learning tasks and motor tasks that was resistant to
normalization with dietary iron repletion after weaning. No data were
provided in either of these reports on regional iron concentrations or
neurotransmitter metabolism. These findings indicate effects of
lactational ID on activity patterns that, in rats, coincide with
alterations in DA receptor density. Unpublished data from our
laboratory show that ID during lactation irreversibly changes the
density of the DA transporters in the caudate putamen and nucleus
accumbens. If this finding is replicated with further experimentation,
it would support our contention that there is a functional relationship
between brain DA metabolism and the alterations in behavior noted in
the current report. It is reasonable to assume that other
neurotransmitter systems could be affected in ID. Indeed, a few reports
suggest alterations in the metabolism of 
-aminobutyric acid,
glutamate and serotonin. However, we concentrated our discussion on DA
because of the stronger evidence for alterations in the dopaminergic
system in ID.
We became interested in the potential negative effects of excess
dietary iron when the literature noted that excess iron is associated
with Alzheimer’s disease and Parkinsonian syndromes (Connor 1992
, Sofic et al. 1988
). Although the possible
participation of iron in neurological diseases, especially its role in
oxidative damage, is a very active field of research, there is scarce
evidence regarding the effects of lactational excess of iron on brain
functioning. Iron supplementation of rats, at the levels used in this
study, produced a decrease in motor activity and exploratory and
stereotyped behaviors similar to that of late ID anemia. It also
significantly elevated brain iron concentrations in several regions of
the brain beyond normal concentrations (Piñero et al. 2000
). A recent report (Fredriksson et al. 1999
)
showed that in mice, the oral administration of a large dose of iron
had long-term effects on spontaneous motor behavior, with the
animals showing a lack of habituation at 3 mo of age. Clearly, our
experiments demonstrate the brain is not "immune" to large dietary
doses of iron during lactation or weaning, with resulting attenuation
of functioning. These phenomena could result from neurodegeneration
with a subsequent loss in pathway functioning (Youdim 1980
) or from alterations in the synthesis and metabolism of
neurotransmitters. However, we can only speculate about causal
mechanisms at this time. Clearly, these very new observations warrant
much further exploration and examination, especially because of the
possible implications for unwarranted iron supplementation in
populations not at risk for anemia.
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FOOTNOTES |
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3 Abbreviations used: CN, control; DA, dopamine; Hb, hemoglobin; Hct, hematocrit; ID, iron deficient; SU, iron supplemented; PND, postnatal day.
Manuscript received August 8, 2000. Initial review completed September 21, 2000. Revision accepted October 27, 2000.
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