* Neurotoxicology Division, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina; Department of Psychology, University of North Carolina, Chapel Hill, North Carolina;
Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; and
Center for Neural Recovery & Rehabilitation Research, Helen Hayes Hospital, West Haverstraw, New York
1 To whom correspondence should be addressed at Neurotoxicology Division (MD B10505), National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711. Fax: (919) 541-4849. E-mail: gilbert.mary{at}epa.gov.
Received February 3, 2005; accepted March 18, 2005
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Key Words: dentate gyrus; adult neurogenesis; lead; Pb; in vivo, hippocampus; rat; neurotoxicity; learning and memory; spatial learning; Morris water maze.
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
In addition to a propensity for LTP, the hippocampus has received considerable attention recently for another form of plasticity, namely, neurogenesis in the mature brain. This phenomenon, initially reported by Altman and Das (1965), refers to the birth of new neurons in the dentate gyrus that occurs throughout the lifetime of the animal. Neural stem cells are abundant in the subgranular zone of the dentate gyrus of the hippocampal formation of the adult and are capable of dividing and differentiating into neurons. These cells migrate into the granule cell layer, express neuronal phenotypes, receive synaptic contacts, make functional synaptic connections, and exhibit activity-dependent LTP (van Praag et al., 2002
; Wang et al., 2000
). It has been purported that dynamic changes in neural stem cells may contribute to underlying substrates of learning and memory (Gould et al., 1999
; Shors et al., 2001
, 2002
). The presence of stem cells in adult brain may also serve as a reserve of neural cells to replace cells that die as the result of various injuries and diseases throughout the lifetime of the animal.
A number of factors have been identified that influence neurogenesis in the adult hippocampus. Genetics and prenatal viral infections can reduce the capacity for neurogenesis in the adult (Sharma et al., 2002; Kempermann et al., 1997
). The birth and survival of new cells in the dentate gyrus is increased by environmental enrichment, reduced caloric intake, physical activity, hippocampal-dependent learning, and either physiological activation (e.g., neuronal activity) or pathological insult (e.g., seizure, stroke) (Derrick et al., 2000
; Gould et al., 1999
; Kempermann et al., 1998
, 2002
; Leuner et al., 2000
; Liu et al., 1998
; Mattson, 2000
; Parent et al., 1997
; Scharfman et al., 2000
; Shors et al., 2001
). The birth of new cells is decreased by stress, age, and chronic exposure to drugs of abuse including opiates and alcohol (Eisch et al., 2000
; Gould et al., 1997
; Herrera et al., 2003
; Kempermann et al., 2002
; Kuhn et al., 1996
; Nixon and Crews, 2002
). To date, little information is available about the impact of exposure to environmental contaminants on this phenomenon. Given the deleterious effects of developmental Pb exposure on synaptic plasticity in the form of LTP, we sought to determine the impact of chronic exposure to Pb on this form of structural plasticity, so prominent in the hippocampus. We also examined the performance of Pb-exposed animals on spatial learning in a task believed to be dependent on the hippocampus. We report no effect of developmental Pb exposure on spatial learning in a Morris water maze or on neural cell proliferation. However, a reduced capacity for survival of newly generated granule cells in the dentate gyrus of adult rats was observed in rats chronically exposed to Pb.
![]() |
METHODS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
BrdU dosing.
Beginning on PN 75, all animals were administered 50 mg/kg BrdU (Sigma, St Louis, MO) ip twice daily at 12-h intervals for 12 consecutive days. A variety of regimens of BrdU administration have been reported with a wide range of dosing parameters. There are proponents of low doses to avoid BrdU-induced damage or higher doses to maximize visualization of dividing cells. The number of cells labeled by a given injection of BrdU is limited by the bioavailability of BrdU (half-life 2 h) and the number of cells in the S phase of the cell cycle during this brief period. Typically, studies designed to identify changes in neurogenesis due to age, lifestyle (e.g., exercise), or long-lasting treatment manipulations (e.g., chronic ethanol exposure, environmental housing, epilepsy, viral infection) have adopted dosing regimens that span several days (Cameron and McKay, 2001
; Herrera et al., 2003
; Kempermann et al., 1998
; Scharfman et al., 2000
; Sharma et al., 2002
). Following the rationale of Kempermann et al. (1998)
and Herrera et al. (2003)
, we selected a BrdU regime that allowed us to reliably detect an adequate number of cells that underwent division without inducing damage.
One male from each litter was perfusion-fixed through the aorta with 4% paraformaldehyde 24 h after the last dose of BrdU (n = 5/treatment group). The remaining male from each litter was perfusion fixed 27 days later (n = 5/ treatment group) such that each group had only a single representative from any litter. Figure 1 outlines the timing of Pb and BrdU exposure conditions.
|
In preparation for BrdU immunocytochemistry, free-floating coronal sections were initially incubated in 50% formamide dissolved in 2x SSC (0.3 M NaCl, 0.03M sodium citrate) followed by 2 N HCl to denature the DNA (Parent et al., 1997). Immunocytochemical staining was performed according to the methods of Goodman and Sloviter (1993)
. Briefly, the sections were washed in Tris buffer (pH 7.6) followed by incubation in 1% hydrogen peroxide to remove endogenous peroxidase activity. Sections were then washed sequentially in Tris followed by Tris A (0.1 M Tris plus 0.1% Triton X-100) and then Tris B (0.1 M Tris, 0.1% Triton X-100, 0.05% bovine serum albumin [BSA]). The sections were then incubated in anti-BrdU antiserum (1:1000 dilution, monoclonal, Boehringer Mannheim, Indianapolis, IN) at 4°C for 48 h. On the second day of processing the sections were incubated in biotinylated secondary antiserum (horse antimouse, dilution 1:400, Vector Labs, Burlingame, CA) followed by avidin-biotin complex (ABC Elite-Vector, 1:1000 dilution), and visualized with diaminobenzidine as the chromogen, which was enhanced with NiCl. Stained sections were mounted on glass slides, dehydrated, and coverslipped.
To indirectly ascertain the phenotype of newly born cells, BrdU-stained sections were double-labeled with an antibody recognizing glial fibrillary acidic protein (GFAP), a protein selectively localized in glial cells. Free-floating BrdU-stained sections, processed as described above, were incubated in anti-GFAP antiserum (1:1000 dilution, monoclonal, Boehringer Mannheim, Indianapolis, IN) at 4°C for 48 h and visualized with Vector NovaRed (Vector Labs, Burlingame, CA) as the chromogen.
Cell counting.
BrdU-stained sections through the dorsal hippocampus were examined from each animal and BrdU-labeled cells from both the upper and lower blades of the dentate gyrus of both hippocampi were counted in a blinded fashion. Serial sections at 200-µm intervals falling between Plates 31 and 37 from Paxinos and Watson (1998) were included, and counts generated from 35 sections were averaged for each animal. When labeled cells were found in clusters, the focal plane was changed to maximize the ability to distinguish individual cells. Granule cells are born at the base of the granule cell layer, and they migrate toward the molecular layer as they mature (Cameron et al., 1993
). Therefore, only BrdU profiles directly in the granule cell layer or touching the granule cell layer were included in the counts, to the exclusion of BrdU-stained cells residing in the dentate hilus and the molecular layer. While this practice should increase the likelihood that only newly born granule cell neurons were counted, some of the BrdU-labeled cells could be glial in origin. This possibility was assessed by double labeling BrdU-stain sections with the glial cell marker GFAP, as described above.
Behavioral testing.
Behavioral testing was performed in two independent cohorts of animals beginning on PN 110. In the first group, litters were exposed to 0 (n = 8) or 0.2% (n = 8) Pb in a similar fashion to that described above and removed from Pb water on PN 21. A second group of control (n = 8) and Pb-exposed (n = 8) litters were exposed developmentally as described and maintained on Pb throughout life. One male from each litter and exposure condition (Control, Pb-Wean, and Control, Pb-Life) was tested for performance in a Morris water maze. Animals were placed in a quiet holding room adjacent to the test room for a minimum of 30 min prior to testing. The water maze consisted of a white circular galvanized tank with a diameter of 165 cm, filled with tap water adjusted to 27°C and made opaque by the addition of powdered white non-toxic tempera paint. Four locations around the edge of the pool were defined as start points, and these divided the pool into four equal quadrants. A circular acrylic escape platform 10 cm in diameter was placed 2 cm below the surface of the water in the middle of one of the four quadrants of the pool. The pool was placed in a 2.5 x 2.5 m square room containing invariant spatial stimuli. A video camera suspended from the ceiling above the middle of the tank permitted the observer to monitor the animal's behavior on a monitor placed in one corner of the room. Animals were tested on two daily trials, each trial separated by approximately 35 min, for 15 consecutive days. Animals were placed into the tank, facing the wall of the pool, and were allowed to circumnavigate the pool in search of the escape platform for a maximum of 60 s. On each day the start points used for each trial varied in a pseudo-random sequence such that no two trials on the same day commenced from the same start point. Latency to reach the escape platform was recorded, and the animals were permitted 15 s to rest on the platform before removal from the tank. If an animal failed to locate the platform within 60 s, it was guided to the platform by the experimenter, placed on it for 15 s, and assigned a latency score of 60 s for that trial. A series of probe trials was inserted on the first trial on test days 3, 6, 9, 12, and 15 in which the platform was removed and animals were allowed to swim freely for 60 s. The platform was reinserted at the end of this period to avoid extinction of the response, and animals were permitted to rest on it for 15 s. The percentage of time animals spent in each quadrant of the pool was recorded for each probe trial. Escape latencies on probe trial days were based on data from the second trial only. Cue testing was conducted on the final trial of day 15. Under this condition, the platform was visible, resting above the water level, and a glove identical to that worn by the experimenter was suspended above the platform. Animals were placed in the pool as on previous trials and latency to reach the visible platform was recorded.
Statistical analysis.
The mean number of cells/hippocampus was calculated, and group differences in the mean number of BrdU-positive cells at the 24-h (cell proliferation) and 28-day sacrifice (survival) times were evaluated using analysis of variance (ANOVA). Mean contrast tests were performed when significant effects were observed (Tukey honestly significant difference (HSD) test, p < 0.05). For behavioral assessments, no differences were observed in control groups from the Pb-Wean versus the Pb-Life cohorts, so control data were combined to facilitate comparison across groups. One animal in the Pb-Wean condition developed an abscess on the back of the head and was removed from further testing. Repeated measures ANOVA was used to assess mean latency across days and probe trial percentage scores. One-way ANOVAs were used to assess cue learning latencies and swim speeds.
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Neurogenesis
A large number of darkly stained BrdU-positive cells were evident in the cell body layer of the dentate gyrus in all three groups of animals sacrificed 24 h after the last of 24 BrdU injections (Fig. 2a2c). The mean number of BrdU-positive profiles present in the dentate gyrus was comparable across all groups in animals sacrificed 24 h after the last BrdU treatment (Fig. 2d), indicating that Pb exposure did not alter the proliferation of progenitor cells. As such, it is unlikely that the presence of Pb in the tissue interfered with the incorporation of BrdU into the nucleus. In contrast, chronic Pb exposure did reduce the number of labeled cells present in animals sacrificed 28 days after the last administration of BrdU (Fig. 3c) compared to controls (Fig. 3a). A small, but nonsignificant reduction was also seen following a more restricted period of Pb exposure that terminated at weaning (Fig. 3d). Analysis of variance revealed a significant effect of Treatment [F(2,12) = 10.7, p < 0.0021] that was limited to the chronic Pb exposure group (Life, Tukey's, p < 0.05). These data indicate the chronic Pb exposure reduced the survival of newly generated cells in the adult dentate gyrus.
|
|
|
|
|
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
A number of organismal, experiential, and environmental factors have been shown to influence the process of adult neurogenesis. It is unlikely that age, diet, or level of physical activity differentially affected neurogenesis in control and Pb-exposed animals in the present study. Neuronal activation, by stimulation to induce LTP or seizure activity, augments neurogenesis and cell survival (Derrick et al., 2000; Parent et al., 1997
; Scharfman et al., 2000
). Blockade of NMDA receptor activation increases cell proliferation (Gould et al., 1997
; Nacher et al., 2003
). Pb-exposed animals have higher thresholds for induction and a reduced capacity to support LTP (Gilbert et al., 1996
, 1999a
, 1999b
). The maintenance phase of LTP in the dentate gyrus of the intact animal that occurs over days and weeks post-induction is also significantly reduced in Pb-exposed animals (Gilbert and Mack, 1998
). Deficits in LTP are correlated with reductions in calcium-dependent glutamate release within the hippocampus (Lasley et al., 1999
; Lasley and Gilbert, 2002
), as well as with enhanced binding of the NMDA antagonist MK-801 (Lasley et al., 2001
). Alterations in NMDA receptor density as a function of chronic Pb exposure may reflect an upregulation of NMDA receptors in response to reduced glutamate release (Lasley and Gilbert, 2000
; Lasley et al., 2001
). Additionally, alterations in mRNA expression of glutamate receptors have been reported to accompany developmental Pb exposure (Guilarte et al., 2000
; Nihei and Guilarte, 2002
). Thus, the effects of Pb exposure on LTP and survival of newly generated granule cells in the adult hippocampus may derive in part from the actions of Pb on neuronal activation and glutamate-mediated synaptic transmission.
The reduction in survival of newly generated cells in the dentate gyrus was limited to chronically exposed animals maintained on Pb throughout life. Bromodeoxyuridine-positive cells were slightly (20%) but not significantly reduced in number in animals receiving a more limited exposure to Pb. This suggests that the continued presence of Pb may be necessary for the effects on neurogenesis. In studies examining Pb effects on LTP and neurotransmitter release, chronic exposure produced the largest impairments, whether exposure began in late gestation or at weaning (Gilbert et al., 1999a
; Lasley et al., 1999
). Animals exposed only until weaning and tested as adults when Pb in blood and brain had returned to background levels revealed a deficit in LTP that was smaller in magnitude and limited to the excitatory postsynaptic potential (EPSP) component of the compound field potential. Similarly, Pb-induced reductions in calcium-dependent glutamate release in hippocampus were of lower magnitude in animals whose Pb exposure was limited to the preweaning period, relative to those maintained on Pb throughout life (Lasley et al., 1999
). These data suggest that if the Pb-induced impairments in glutamate synaptic transmission are responsible for reduced neurogenesis, additional studies with larger sample sizes yielding greater statistical power may also reveal deficiencies in neurogenesis in Pb exposures limited to the perinatal period.
Environmental conditions can dramatically affect adult neurogenesis (Kempermann et al., 1998; Rochefort et al., 2002
). Isolated rearing and impoverished housing reduce the proliferation and survival of newly generated neurons, whereas dietary restriction and voluntary exercise enhance cell survival (Farmer et al., 2004
; Lee et al., 2002
; Mattson, 2000
). During embryonic development, brain-derived neurotrophic factor (BDNF) plays a major role in neuronal survival and differentiation. BONF also promotes survival of neural stem cells isolated from hippocampus postnatally (Shetty and Turner, 1998
). Augmented survival of newly generated granule cells in the adult brain induced by manipulations of diet and exercise is associated with increases in BDNF mRNA, and antibodies that block BDNF significantly attenuate the protective effects offered by dietary restriction (Farmer et al., 2004
; Mattson, 2000
; Lee et al., 2002
). Furthermore, increases in BDNF mRNA induced by wheel running in mice are selective for the dentate gyrus of the hippocampal formation and are accompanied by an enhanced capacity for induction and expression of dentate gyrus LTP (Farmer et al., 2004
). These findings strongly implicate a role for BDNF in the plasticity in the brain of adult rats. Schneider et al. (2001)
reported that animals chronically exposed to Pb display a reduction in mRNA expression of a number of trophic factors, including BDNF, and these effects were partially reversed by environmental enrichment. In a similar experiment, Guilarte et al. (2002)
failed to demonstrate a reduction in BDNF expression by Pb, but did report a housing-induced increase in BDNF mRNA expression in Pb-exposed animals. Although BDNF protein measures were not included in these two studies, the alterations observed in mRNA are suggestive of a role for BDNF in compromised cell survival in hippocampus of Pb-exposed animals.
Considerable debate remains concerning the functional implications of adult neurogenesis. Several laboratories have proposed that survival of newly born granule cells in the adult dentate gyrus is enhanced by learning and LTP (Derrick et al., 2000; Gould et al., 1999
; Leuner et al., 2000
; Shors et al., 2001
) and that neurogenesis may be necessary for some forms of long-term memory (Shors et al., 2002
; Snyder et al., 2005
). Developmental exposure to Pb induces learning deficits in children (Bellinger et al., 1991
; Chiodo et al., 2004
), in animal models of cognition (Alber and Strupp, 1996
; Cory-Slechta, 1995
; Hilson and Strupp, 1997
), and in physiological measures of synaptic plasticity presumed to underlie learning (Gilbert et al., 1999a
, 1999b
; Ruan et al., 1998
). Results of experiments designed to assess performance of Pb-exposed animals on hippocampal-dependent tasks, however, have been equivocal. In two standard tests of spatial learning, the radial arm maze and the Morris water maze, some studies reported deficits in acquisition (Kuhlmann et al., 1997
; Nihei and Guilarte, 2002
; Zhou and Suszkiw, 2004
), whereas others failed to detect significant impairment (e.g., Driscoll et al., 1998
; Elliot and Militec, 1997
; Guilarte et al., 2002
; Jett et al., 1997
; Levin et al., 2004
; Ma et al., 1999
; Munoz et al., 1988
; Newman et al., 2002
; Schneider et al., 2001
; Yang et al., 2003
). Although a number of parameters vary from study to study, disparities are evident even from reports generated from the same laboratory (e.g., Guilarte et al., 2002
; Jett et al., 1997
; Kuhlmann et al., 1997
; Nihei and Guilarte, 2000). In the present study, in which a standard Morris water maze procedure was used for testing, developmental Pb exposure did not affect acquisition of spatial learning. Thus, detecting the subtle alterations in learning associated with developmental Pb exposure may require more complex and demanding cognitive tasks and more sophisticated behavioral analyses (see Alber and Strupp, 1996
; Cory-Slechta, 1995
; Hilson and Strupp, 1997
). The same may be true for identifying the function of hippocampal neurogenesis in learning and memory. Our data are consistent with recent findings reported by Shors et al. (2002)
, where neurogenesis in the adult dentate gyrus was found to be essential for some types of hippocampus-dependent learning (i.e., trace fear conditioning), but not spatial learning in the Morris water maze. It is clear that the role in hippocampal function played by compromised neurogenesis in the adult, as well as its relationship to neurological sequelae of Pb-induced neurotoxicity, requires further study.
In summary, we have demonstrated that chronic exposure to low levels of Pb reduces the capacity for structural plasticity in the adult hippocampus. Although no impairment in spatial learning was detected, deficiencies in the restorative capacities of the adult brain may contribute to subtle deficits in cognitive ability associated with chronic Pb exposure. The actions of Pb on glutamatergic transmission, neurotrophin-mediated signaling, and synaptic plasticity in the hippocampus may underlie reductions in the survival of newly generated neurons in the adult dentate gyrus.
![]() |
ACKNOWLEDGMENTS |
---|
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Altmann, L., Weinsberg, F., Sveinsson, K., Lilienthal, H., Wiegand, H., and Winneke, G. (1993). Impairment of long-term potentiation and learning following chronic lead exposure. Toxicol. Lett. 66, 105112.[CrossRef][ISI][Medline]
Altman, J., and Das, D. D. (1965). Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J. Comp. Neurol. 124, 319336.[CrossRef][ISI][Medline]
Bellinger, D., Sloman, J., Leviton, A., Rabinowitz, M., Needlemen, H. L., and Waternaux, C. (1991). Low-level lead exposure and children's cognitive function in the preschool years. Pediatrics 87, 219227.[Abstract]
Cameron, H. A., and McKay, R. D. (2001). Adult neurogenesis produces a large pool of new granule cells in the dentate gyrus. J. Comp. Neurol. 435, 406417.[CrossRef][ISI][Medline]
Cameron, H. A., Woolley, C. S., McEwen, B. S., and Gould, E. (1993). Differentiation of newly born neurons and glia in the dentate gyrus of the adult rat. Neuroscience 56, 337344.[CrossRef][ISI][Medline]
Chiodo, L. M., Jacobson, S. W., and Jacobson, J. L. (2004). Neurodevelopmental effects of postnatal lead exposure at very low levels. Neurotoxicol. Teratol. 26, 359371.[CrossRef][ISI][Medline]
Cory-Slechta, D. A. (1995). Relationships between lead-induced learning impairments and changes in dopaminergic, cholinergic, and glutamatergic neurotransmitter system functions. Annu. Rev. Pharmacol. Toxicol. 35, 391415.[CrossRef][ISI][Medline]
Derrick, B. E., York, A. D., and Martinez, J. L., Jr. (2000). Increased granule cell neurogenesis in the adult dentate gyrus following mossy fiber stimulation sufficient to induce long-term potentiation. Brain Res. 857, 300307.[CrossRef][ISI][Medline]
Driscoll, L. L., Gilbert, M. E., and Strupp, B. J. (1998). Lead-exposed rats are more sensitive than controls to the effect of scopolamine on long-term explicit memory. Neurobehav. Toxicol. Teratol. 20, 363.
Eisch, A. J., Barrot, M., Schad, C. A., Self, D. W., and Nestler, E. J. (2000). Opiates inhibit neurogenesis in the adult rat hippocampus. Proc. Natl. Acad. Sci. U.S.A. 97, 757984.
Elliot, A. Z., and Militec, V. (1997). A disconnection between spatial learning and LTP in young rats chronically exposed to lead. Toxicologist 36, 305.
Farmer, J., Zhao, X., van Praag, H., Wodtke, K., Gage, F. H., and Christie, B. R. (2004). Effects of voluntary exercise on synaptic plasticity and gene expression in the dentate gyrus of adult male Sprague-Dawley rats in vivo. Neuroscience 124, 7179.[CrossRef][ISI][Medline]
Gilbert, M. E., and Mack, C. M. (1998). Chronic developmental lead exposure accelerated decay of long-term potentiation in rat dentate gyrus in vivo. Brain Res. 789, 139149.[CrossRef][ISI][Medline]
Gilbert, M. E., Mack, C. M., and Lasley, S. M. (1996). Chronic developmental lead (Pb++) exposure increases threshold for long-term potentiation in the rat dentate gyrus in vivo. Brain Res. 736, 118124.[CrossRef][ISI][Medline]
Gilbert, M. E., Mack, C. M., and Lasley, S. M. (1999a). The influence of a developmental period of lead exposure on long-term potentiation in the rat dentate gyrus in vivo. Neurotoxicology 20, 5770.[ISI][Medline]
Gilbert, M. E., Mack, C. M. and Lasley, S. M. (1999b). Developmental lead exposure reduces the magnitude of long-term potentiation: A doseresponse analysis. Neurotoxicology 20, 7182.[ISI][Medline]
Goodman, J. H., and Sloviter, R. S. (1993). Cocaine neurotoxicity and altered neuropeptide Y immunoreactivity in the rat hippocampus; a silver degeneration and immunocytochemical study. Brain Res. 616, 26372.[CrossRef][ISI][Medline]
Gould, E., Beylin, A., Tanapat, P., Reeves, A., and Shors, T. J. (1999). Learning enhances adult neurogenesis in the hippocampal formation. Nat. Neurosci. 2, 260265.[CrossRef][ISI][Medline]
Gould, E., McEwen, B. S., Tanapat, P., Galea, L. A., and Fuchs, E. (1997). Neurogenesis in the dentate gyrus of the adult tree shrew is regulated by psychosocial stress and NMDA receptor activation. J. Neurosci. 17, 24922498.
Goyer, R. (1990). Lead toxicity: From overt to subclinical to subtle health effects. Environ. Health Perspect. 86, 177181.[ISI][Medline]
Guilarte, T. R., McGlothan, J. L., and Nihei, M. K. (2000). Hippocampal expression of N-methyl-D-aspartate receptor (NMDAR1) subunit splice variant mRNA is altered by developmental exposure to Pb(2+). Brain Res. Mol. Brain Res. 76, 299305.[ISI][Medline]
Guilarte, T. R., Toscano, C. D., McGlothan, J. L., and Weaver, S. A. (2002). Environmental enrichment reverses cognitive and molecular deficits induced by developmental lead exposure. Ann. Neurol. 53, 5056.[ISI]
Herrera, D. G, Yague, A. G., Johnsen-Soriano, S., Bosch-Morell, F., Collado-Morente, L., Muriach, M., Romero, F. J., and Garcia-Verdugo, J. M. (2003). Selective impairment of hippocampal neurogenesis by chronic alcoholism: Protective effects of an antioxidant. Proc. Natl. Acad. Sci. U.S.A. 100, 79197924.
Hilson, and Strupp, B. J. (1997). Analyses of response patterns clarify lead effects in olfactory reversal and extradimensional shift tasks: Assessment of inhibitory control, associative ability, and memory. Behav. Neurosci. 111, 532542.[CrossRef][ISI][Medline]
Jett, D. A., Kuhlmann, A. C., Farmer, S. J., and Guilarte, T. R. (1997). Age-dependent effects of developmental lead exposure on performance in the Morris water maze. Pharmacol. Biochem. Behav. 57, 271279.[CrossRef][ISI][Medline]
Kempermann, G., Gast, D., and Gage, F. H. (2002). Neuroplasticity in old age: Sustained fivefold induction of hippocampal neurogenesis by long-term environmental enrichment. Ann. Neurol. 52, 135143.[CrossRef][ISI][Medline]
Kempermann, G., Kuhn, H. G., and Gage, F. H. (1997). Genetic influence on neurogenesis in the dentate gyrus of adult mice. Proc. Natl. Acad. Sci. U.S.A. 94, 1040910414.
Kempermann, G., Kuhn, H. H., and Gage, F. H. (1998). Experience-induced neurogenesis in senescent dentate gyrus. J. Neurosci. 18, 32063212.
Kuhlmann, A. C., McGlothan, J. L., and Guilarte, T. R. (1997). Developmental lead exposure causes spatial learning deficits in adult rats. Neurosci. Lett. 233, 101104.[CrossRef][ISI][Medline]
Kuhn, H. G., Dickinson-Anson, H., and Gage, F. H. (1996). Neurogenesis in the dentate gyrus of the adult rat: Age-related decrease of neuronal progenitor proliferation. J. Neurosci. 16, 20272033.[Abstract]
Lasley, S. M., and Gilbert, M. E. (1996). Presynaptic glutamatergic function in hippocampal dentate gyrus is diminished by chronic exposure to inorganic lead. Brain Res. 736, 125134.[CrossRef][ISI][Medline]
Lasley, S. M., Green, M. C., and Gilbert, M. E. (1999). Influence of exposure period on in vivo hippocampal glutamate and GABA release in rats chronically exposed to lead. Neurotoxicology 20, 619630.[ISI][Medline]
Lasley, S. M., and Gilbert, M. E. (1999). Lead inhibits the rat N-methyl-D-aspartate receptor channel by binding to a site distinct from the zinc allosteric site. Toxicol. Appl. Pharmacol. 159, 224233.[CrossRef][ISI][Medline]
Lasley, S. M., and Gilbert, M. E. (2000). Glutamatergic components underlying lead-induced impairments in hippocampal synaptic plasticity. Neurotoxicology 21, 10571068.[ISI][Medline]
Lasley, S. M., and Gilbert, M. E. (2002). Rat hippocampal glutamate and GABA release exhibit biphasic effects as a function of chronic lead exposure level. Toxicol. Sci. 66, 139147.
Lasley, S. M., Green, M. C., and Gilbert, M. E. (2001). Rat hippocampal n-methyl-d-aspartate receptor binding as a function of the level of chronic lead exposure. Neurotoxicol. Teratol. 23, 185189.[CrossRef][ISI][Medline]
Lee, J., Duan, W., and Mattson, M. P. (2002). Evidence that brain-derived neurotrophic factor is required for basal neurogenesis and mediates, in part, the enhancement of neurogenesis by dietary restriction in the hippocampus of adult mice. J. Neurochem. 82, 13671375.[CrossRef][ISI][Medline]
Leuner, B., Mendolia-Loffredo, S., Kozorovitskiy, Y., Samburg, D., Gould, E., and Shors, T. J. (2000). Learning enhances the survival of new neurons beyond the time when the hippocampus is required for memory. J. Neurosci. 24, 74777481.[CrossRef]
Levin, E., Sato, K., Freedman, J. H., Skene, J., and Harry, G. (2004). Developmental lead exposure impacts on spatial learning and memory: Cholinergic and glutamatergic involvement. Toxicologist 78, 893.
Liu, J., Solway, K., Messing, R. O., and Sharp, F. R. (1998). Increased neurogenesis in the dentate gyrus after transient global ischemia in gerbils. J. Neurosci. 18, 77687778.
Ma, T., Chen, H. H., and Ho, I. K. (1999). Effects of chronic lead (Pb) exposure on neurobehavioral function and dopaminergic neurotransmitter receptors in rats. Toxicol. Lett. 105, 111121.[CrossRef][ISI][Medline]
Mattson, M. P. (2000). Neuroprotective signaling and the aging brain: Take away my food and let me run. Brain Res. 886, 4753.[CrossRef][ISI][Medline]
Munoz, C., Garbe, K., Lilienthal, H., and Winneke, G. (1988). Significance of hippocampal dysfunction in low level lead exposure of rats. Neurotoxicol. Teratol. 10, 245253.[CrossRef][ISI][Medline]
Nacher, J., Alonso-Llosa, G., Rosell, D. R., and McEwen, B. S. (2003). NMDA receptor antagonist treatment increases the production of new neurons in the aged rat hippocampus. Neurobiol. Aging 24, 273284.[CrossRef][ISI][Medline]
Newman, H. M., Hang, R. S., and Magnusson, K. R. (2002). Effects of developmental exposure to lead, magnesium and zinc mixtures on spatial learning and expression of NMDA receptor subunit mRNA in Fischer 344 rats. Toxicol. Lett. 126, 107119.[CrossRef][ISI][Medline]
Nihei, M. K., and Guilarte, T. R. (2002). Molecular changes in glutamatergic synapses induced by Pb2+: Association with deficits of LTP and spatial learning. Neurotoxicology 22, 635643.[ISI]
Nixon, K., and Crews, F. T. (2002). Binge ethanol exposure decreases neurogenesis in adult rat hippocampus. J. Neurochem. 83, 10871093.[CrossRef][ISI][Medline]
Okano, H. J., Pfaff, D. W., and Gibbs, R. B. (1993). RB and Cdc2 expression in brain: Correlations with 3H-thymidine incorporation and neurogenesis. J. Neurosci. 13, 29302038.[Abstract]
Parent, J. M., Yu, T. W., Leibowitz, R. T., Geschwind, D. H., Sloviter, R. S., and Lowenstein, D. H. (1997). Dentate granule cell neurogenesis is increased by seizures and contributes to aberrant network reorganization in the adult rat hippocampus. J. Neurosci. 17, 37273738.
Paxinos, G., and Watson, C. (1998). The Rat Brain in Stereotaxic Coordinates, 4th Edition. Academic Press, San Diego.
Riess, J. A., and Needleman, H. L. (1992). Cognitive, neural, behavioral effects of low-level lead exposure. In The Vulnerable Brain and Environmental Risks (Isaacson, R. L., and Jensen, K. F., Eds.), vol. 2: Toxins in Food., Plenum Press, NY, pp. 111126.
Rochefort, C., Gheusi, G., Vincent, J. D., Lledo, P. M. (2002). Enriched odor exposure increases the number of newborn neurons in the adult olfactory bulb and improves odor memory. J. Neurosci. 22, 26792689.
Ruan, D. Y., Chen, J. T., Zhao, C., Xu, Y. Z., Wang, M., and Zhao, W. F. (1998). Impairment of long-term potentiation and paired-pulse facilitation in rat hippocampal dentate gyrus following developmental lead exposure in vivo. Brain Res. 806, 196201.[CrossRef][ISI][Medline]
Scharfman, H. E., Goodman, J. H., and Sollas, A. L. (2000). Granule-like neurons at the hilar/CA3 border after status epilepticus and their synchrony with area CA3 pyramidal cells: Functional implications of seizure-induced neurogenesis. J. Neurosci. 20, 61446158.
Schneider, J. S., Lee, M. H., Anderson, D. W., Zuck, L., and Lidsky, T. I. (2001). Enriched environment during development is protective against lead-induced neurotoxicity. Brain Res. 896, 4855.[CrossRef][ISI][Medline]
Sharma, A., Valadi, N., Millerm A. H., and Pearce, B. D. (2002). Neonatal viral infection decreases neuronal progenitors and impairs adult neurogenesis in the hippocampus. Neurobiol. Dis. 11, 246256.[CrossRef][ISI][Medline]
Shetty, A. K., and Turner, D. A. (1998). In vitro survival and differentiation of neurons derived from epidermal growth factorresponsive postnatal hippocampal stem cells: Inducing effects of brain-derived neurotrophic factor. J. Neurobiol. 35, 395425.[CrossRef][ISI][Medline]
Shors, T. J., Miesegaes, G., Beylin, A., Zhao, M., Rydel, T., and Gould, E. (2001). Neurogenesis in the adult is involved in the formation of trace memories. Nature 410, 372376.[CrossRef][ISI][Medline]
Shors, T. J., Townsend, D. A., Zhao, M., Kozorovitskiy, Y., and Gould, E. (2002). Neurogenesis may relate to some but not all types of hippocampal-dependent learning. Hippocampus 12, 578584.[CrossRef][ISI][Medline]
Snyder, J. S., Hong, N. S., McDonald, R. J., and Wojtowicz, J. M. (2005). A role for adult neurogenesis in spatial long-term memory. Neuroscience 13, 843852.
van Praag, H., Schinder, A. F., Christie, B. R., Toni, N., Palmer, T. D., and Gage, F. H. (2002). Functional neurogenesis in the adult hippocampus. Nature 415, 10301034.[CrossRef][ISI][Medline]
Wang, S., Scott, B. W., and Wojtowicz, J. M. (2000). Heterogenous properties of dentate granule neurons in the adult rat. J. Neurobiol. 42, 248257.[CrossRef][ISI][Medline]
Yang, Y., Ma, Y., Ni, L., Zhao, S., Li, L., Zhang, J., Fan, M., Liang, C., Cao, J., and Xu, L. (2003). Lead exposure through gestation-only caused long-term learning/memory deficits in young adult offspring. Exp. Neurol. 184, 489495.[CrossRef][ISI][Medline]
Zhou, M., and Suszkiw, J. B. (2004). Nicotine attenuates spatial learning deficits induced in the rat by perinatal lead exposure. Brain Res. 999, 142147.[CrossRef][ISI][Medline]
|