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Prenatal stress produces learning deficits associated with an inhibition of neurogenesis in the hippocampus
Open accessAbstract
Early experiences such as prenatal stress significantly influence the development of the brain and the organization of behavior. In particular, prenatal stress impairs memory processes but the mechanism for this effect is not known. Hippocampal granule neurons are generated throughout life and are involved in hippocampal-dependent learning. Here, we report that prenatal stress in rats induced lifespan reduction of neurogenesis in the dentate gyrus and produced impairment in hippocampal-related spatial tasks. Prenatal stress blocked the increase of learning-induced neurogenesis. These data strengthen pathophysiological hypotheses that propose an early neurodevelopmental origin for psychopathological vulnerabilities in aging.
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“Impaired neurogenesis and associated cognitive impairment have been repeatedly reported in prenatally stressed animals (Lemaire et al., 2000; Fujioka et al., 2006; Lemaire et al., 2006).”
From High pregnancy anxiety during mid-gestation is associated with decreased gray matter density in 6-9-year-old children. (2010) · cites this paper as Lemaire et al., 2000
In the citing paper
“Several lines of evidence from studies in rodents indicate that the cytoarchitecture of the rat hippocampus is altered as a consequence of prenatal stress (Hayashi et al., 1998; Gould & Tanapat, 1999; Lemaire et al., 2000).”
From High pregnancy anxiety during mid-gestation is associated with decreased gray matter density in 6-9-year-old children. (2010) · cites this paper as Lemaire et al., 2000
In the citing paper
“Several studies (Braun, Lange, Metzger, & Poeggel, 1999; Kinnunen, Keonig, & Bilbe, 2003; Lemaire, Koehl, Le Moal, & Abrous, 2000; Liu, Diorio, Day, Frances, & Meaney, 2000) have demonstrated that chronic early stress alters neural functioning and connectivity within and between limbic structures, notably the amygdala and hippocampus, associated with emotion, rapid contextually and temporally boun”
From Stress and the development of self-regulation in context (2010) · cites this paper as Lemaire, Koehl, Le Moal, & Abrous, 2000
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“Prenatal stress produces learning deficits associated with inhibition of hippocampal neurogenesis [23, 24 ].”
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“Recently, PS has also been shown to be able to reduce the formation of new neurons, i.e. neurogenesis, within the hippocampal dentate gyrus (DG) of adult rats [Lemaire et al., 2000; Koo et al., 2003] and juvenile nonhuman primates [Coe et al., 2003].”
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“Also glucocorticoid surges deteriorate the neuronal complexity in CA1 and CA3 (109, 110) and have been shown to increases the number of microglia in DG.”
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“early life Maternal care ↑ [180] NA Prenatal stress ↑ [181–183] Maternal care ↑ [180] Prenatal stress ↓ [181, 183] Maternal care = [184] Maternal deprivation ↓ [141] Maternal deprivation ↓ [141] Prenatal stress ↓ [182]& = [181] Maternal care ↑ [184] Maternal deprivation = [141]”
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“Recently, Lemaire et al. (2000) showed that maternal stress resulted in smaller hippocampi and spatial learning deficits due to impairment in neurogenesis in the offspring.”
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“neurogenesis, as it was shown in several different species using various stress paradigms (Figure 2) (38-48).”
Lateral amygdaloid nucleus expansion in adult rats is associated with exposure to prenatal stress
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“To our knowledge, there has been no prior stereological examination in the prefrontal cortex of prenatally stressed offspring, however Lemaire et al. (2000) also found decreased neuron volume in the hippocampus of prenatally stressed rodents.”
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“As summarized in Table 1, perinatal stress in male rats was generally found to suppress neurogenesis (17, 63).”
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BackgroundHotter nests produce smarter young lizards
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Prenatal stress causes gender‐dependent neuronal loss and oxidative stress in rat hippocampus
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“Prenatal stress (PNS) is shown to cause significant structural, endocrinological, neurochemical, and behavioral changes in the brain of offspring (Hayashi et al., 1998; Poland et al., 1999; Lemaire et al., 2000; Reznikov et al., 2001).”
BackgroundInteraction between Neurogenesis and Hippocampal Memory System: New VistasPreprint
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“Stress exerted during prenatal neuronal development inhibits adult neurogenesis in the hippocampus (Lemaire et al., 2000; Coe et al., 2003).”
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“In agreement with this hypothesis, numerous correlative studies have shown that hippocampal neurogenesis can be modulated by learning and behavioural experience [24-27], and that a loss in hippocampal neurogenic function can adversely affect memory formation [20,28-31].”
BackgroundMoreno, J. L., Kurita, M., Holloway, T. D., López, J., Cadagan, R., Martínez‐Sobrido, L., García‐Sastre, A., & González‐Maeso, J. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.4230-10.2011 · Cited by 123
“In rodents, prenatal stress has been shown to induce learning deficits (Lemaire et al., 2000), as well as alterations in the immune system (Vanbesien-Mailliot et al.”
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“Also, prenatal stress in the last week of pregnancy in rats induced lifespan reduction in neurogenesis in the dentate gyrus, accompanied with learning deficits [37].”
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Drapeau, E., Montaron, M., Aguerre, S., & Abrous, D. N. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.1031-07.2007 · Cited by 119
“Conditions increasing memory performances also enhance neurogenesis whereas situations reducing neurogenesis induce cognitive impairments (Kempermann et al., 1997; van Praag et al., 1999; Lemaire et al., 2000; Shors et al., 2001).”
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“function, as suggested by learning deficits associated with a marked reduction in hippocampal neurogenesis (Lemaire et al., 2000; Coe et al., 2003).”
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“Glucocorticoids are known to influence developmental processes (Gass et al., 2001; de Kloet et al., 2005), and early exposure to stress has persistent effects on learning abilities and behavior (Lemaire et al., 2000).”
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“…cognitive and sexual behaviours and neuroendocrine hyper-responsiveness to acute stress in adulthood (Ward, 1972; Fride et al., 1986; Weinstock et al., 1992; Henry et al., 1994; McCormick et al., 1995; Lordi et al., 1997; Vallée et al., 1997, 1999; Lemaire et al., 2000; Szuran et al., 2000).”
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“Prenatal stress in rats and rhesus monkeys induced a life span reduction in neurogenesis in the dentate gyrus (Kramer et al., 2000; Lemaire et al., 2000).”
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Radiation Response of Neural Precursor Cells
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“Interestingly, it has been suggested that chronic stressful experiences during brain development may permanently modify hippocampal neurogenesis (Lemaire et al., 2000; Mirescu et al., 2004).”
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“This might have longlasting effects on hippocampal function because prenatal stress reduces hippocampal neurogenesis to old age (Lemaire et al., 2000).”
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“…and impacts the fetus in utero, damages the brain development of littermates during its fetal phase and changes behavior in later adult life by causing lifespan reduction of neurogenesis in the dentate gyrus and by blocking learning-induced neurogenesis in this brain area (Lemaire et al., 2000).”
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“[44] V.”
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“In this model, the increased immobility time in the forced swim test, disturbances in sleep and cognitive functions, decreases in sexual behavior, neurogenesis inhibition in the dentate gyrus of the hippocampus, enhanced corticosterone concentration in light-dark cycle and after stress have been observed (Koehl et al.…”
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“increased level of GCs, as induced by prenatal stress, are long lasting, resulting in reduced neurogenesis in later life in rodents and non-human primates.(9,15) In previous studies, we observed that prenatal exposure to high levels of synthetic GC dexamethasone (Dex) induces long-lasting alterations in rat neuronal c…”
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“…morphology (Xu et al., 2006; Odaci et al., 2008) due to the fact that the hippocampus is the part of the brain that controls important behavioral and cognitive functions, including spatial learning and working memory (Eichenbaum et al., 1992; McEwen, 1994; Lemaire et al., 2000; Eyre et al., 2003).”
BackgroundMethodSerotonin and neurogenesis in the hippocampal dentate gyrus of adult mammals
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“Life-long reduction of the DG neurogenesis in rats due to prenatal stress produced learning deficits (Lemaire et al. 2000).”
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Neurogenin 2 has an essential role in development of the dentate gyrus
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“Maintenance of neurogenesis in the adult DG has been suggested to play a role in the acquisition of new memories (Aimone et al., 2006; Gould et al., 1999b; Lemaire et al., 2000).”
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“Prenatal stress diminished number of immature neurons (doublecortin expressing) in adolescent male and female rats (Rayen et al., 2011) and decreased neurogenesis in adult male rodents (Lemaire et al., 2000; Belnoue et al., 2013).”
BackgroundInfluentialIntensity matters: brain, behaviour and the epigenome of prenatally stressed rats
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“There is an abundance of evidence illustrating the negative consequences associated with stress early in life (McCormick et al., 1995; Lemaire et al., 2000; Huizink et al., 2003; Patin et al., 2004; Lee et al., 2007).”
BackgroundAdult hippocampal neurogenesis and its impairment in Alzheimer’s disease
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“Interestingly, perinatal stress in rodents affects critical periods of brain development and alters structural (including neurogenesis), emotional, and neuroendocrine parameters in adult offspring in a specific and persisting manner that depends very much on the type and timing of stress (Lemaire et al., 2000; Bredy e…”
Long-term effects of early life stress exposure: Role of epigenetic mechanisms
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“Several hippocampal alterations have been described to be induced by PS including decreased neurogenesis [122], reduction of long term potentiation (LTP) accompanied by a decline of NR1 and NR2B subunits of the NMDA type glutamate receptor in the post-sinapsis [123], a decrease in the number of GABA and serotonin 5-HT…”
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Dubreucq, S., Koehl, M., Abrous, D. N., Marsicano, G., & Chaouloff, F. (2010) · Experimental Neurology · doi:10.1016/j.expneurol.2010.01.017 · Cited by 103
“Immunoperoxidase labelling of doublecortin (DCX) was performed on one-in-ten free-floating sections as previously described (Lemaire et al., 2000; Koehl et al., 2008) using a rabbit polyclonal anti-DCX (1:6000; Sigma D9818).”
MethodSelf-citationAge-Related Decline in Oligodendrogenesis Retards White Matter Repair in Mice
Miyamoto, N., Pham, L. D., Hayakawa, K., Matsuzaki, T., Seo, J. H., Magnain, C. V., Ayata, C., Kim, K., Boas, D. A., Lo, E. H., et al. (2013) · Stroke · doi:10.1161/strokeaha.113.001530 · Cited by 104
Age-related effects on hippocampal precursor cell subpopulations and neurogenesis
Walter, J., Keiner, S., Witte, O. W., & Redecker, C. (2009) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2009.11.011 · Cited by 106
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“memory impairment [18,19].”
Chapter 5 Development of Neural Circuits in the Adult Hippocampus
Li, Y., Mu, Y., & Gage, F. H. (2009) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/s0070-2153(09)01205-8 · Cited by 105
Age-dependent susceptibility of adult hippocampal cell proliferation to chronic psychosocial stress
Simon, M., Czéh, B., & Fuchs, E. (2005) · Brain Research · doi:10.1016/j.brainres.2005.05.006 · Cited by 101
Wu, J., Song, T., Li, Y.-J., He, K.-S., Ge, L., & Wang, L. (2007) · Brain Research · doi:10.1016/j.brainres.2007.01.024 · Cited by 99
“…brain development and learning performance in offspring (Fujioka et al., 1999, 2001), most studies on prenatal stress of long duration during the late pregnancy have revealed changes in brain morphology and impaired learning and memory of offspring (Lemaire et al., 2000; Coe et al., 2003).”
BackgroundAdult Neurogenesis and Hippocampal Memory Function: New Cells, More Plasticity, New Memories?
Kitabatake, Y., Sailor, K. A., Ming, G., & Song, H. (2007) · Neurosurgery Clinics of North America · doi:10.1016/j.nec.2006.10.008 · Cited by 101
“Strain Water maze Positive correlation Kempermann and Gage [53] Running þ Water maze Improved van Praag, et al [58] Enriched environment þ Water maze Improved Nilsson, et al [37] Stress Water maze Impaired Lemaire, et al [82] Irradiation Water maze nc Madsen, et al [64] Object recognition task nc Place recognition tas…”
BackgroundFox, H. C., Jackson, E. D., & Sinha, R. (2009) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2009.03.007 · Cited by 99
“, 2005) have all been shown to induce decreases in hippocampal cell proliferation and cell survival in rats, resulting in deleterious effects on learning (Lemaire et al., 2000).”
BackgroundInfluentialBaş, O., Odacı, E., Mollaoğlu, H., Üçok, K., & Kaplan, S. (2009) · Toxicology and Industrial Health · doi:10.1177/0748233709106442 · Cited by 98
Prenatal stress and depression associated neuronal development in neonates
Fatima, M., Srivastav, S., & Mondal, A. C. (2017) · International Journal of Developmental Neuroscience · doi:10.1016/j.ijdevneu.2017.04.001 · Cited by 103
“PS also produces learning deficits associated with inhibition of neurogenesis (Lemaire et al., 2000) and expression of PSA-NCAM, a molecule involved in migration of new neurons (Morley-Fletcher et al., in revision).”
BackgroundInfluentialAdult neurogenesis: implications for psychiatry
Eisch, A. J. (2002) · Progress in brain research · doi:10.1016/s0079-6123(02)38085-3 · Cited by 98
“This decrease in newly born cells in the adult SGZ is correlated with impaired performance on behavioral tasks (Lemaire et al., 2000).”
BackgroundNavailles, S., Hof, P. R., & Schmauss, C. (2008) · The Journal of Comparative Neurology · doi:10.1002/cne.21775 · Cited by 99
“…risk factor for developing depression, namely, prenatal, early life, and adult stress, reduces hippocampal neurogenesis (Gould et al., 1998; Lemaire et al., 2000; Mirescu et al., 2004; Thomas et al., 2007), that subjects with recurrent major depression have decreased hippocampal volumes…”
Comparison of neurogenic effects of fluoxetine, duloxetine and running in mice
Marlatt, M. W., Lucassen, P. J., & van Praag, H. (2010) · Brain Research · doi:10.1016/j.brainres.2010.03.086 · Cited by 96
Effects of pyrethroids on brain development and behavior: Deltamethrin
Pitzer, E. M., Williams, M. T., & Vorhees, C. V. (2021) · Neurotoxicology and Teratology · doi:10.1016/j.ntt.2021.106983 · Cited by 99
Parental enrichment and offspring development: Modifications to brain, behavior and the epigenome
Mychasiuk, R., Zahir, S. M., Schmold, N., Ilnytskyy, S., Kovalchuk, O., & Gibb, R. L. (2011) · Behavioural Brain Research · doi:10.1016/j.bbr.2011.11.036 · Cited by 96
“[1,3,6,23,24], but there has been very limited examination of outcomes associated with positive prenatal experiences [12,25,26].”
BackgroundExercise‐induced promotion of hippocampal cell proliferation requires β‐endorphin
Koehl, M., Meerlo, P., Gonzales, D., Rontal, A., Turek, F. W., & Abrous, D. N. (2008) · The FASEB Journal · doi:10.1096/fj.07-099101 · Cited by 95
Self-citationMild Neurotrauma Indicates a Range-Specific Pressure Response to Low Level Shock Wave Exposure
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“Also in rats, maternal stress during the last week of pregnancy affects hippocampal neurogenesis in the pups (Lemaire et al. 2000), but this finding has not been replicated in nonhuman primate infants.”
BackgroundAdult neurogenesis, human after all (again): Classic, optimized, and future approaches
Lucassen, P. J., Fitzsimons, C. P., Salta, E., & Maletić‐Savatić, M. (2019) · Behavioural Brain Research · doi:10.1016/j.bbr.2019.112458 · Cited by 102
“Other studies in rodents have further shown that neurogenesis as well as dentate gyrus structure and function in rodents can be ‘pro-grammed’ by stressful experiences, particularly if they occur early in life [190–197].”
Hippocampal Neurogenesis, Depressive Disorders, and Antidepressant Therapy
Païzanis, E., Hamon, M., & Lanfumey, L. (2007) · Neural Plasticity · doi:10.1155/2007/73754 · Cited by 99
“Prenatal stress also decreases neurogenesis in the adult hippocampus along with increased anxiety-like behavior, hyperactivity of HPA axis, and reduced learning ability in rats [59] and exacerbated emotional behavior in rhesus monkeys [60].”
Maternal Deprivation Stress Exacerbates Cognitive Deficits in Immature Rats with Recurrent Seizures
Huang, L., Holmes, G. L., Lai, M., Hung, P., Wang, C., Wang, T., Yang, C., Liou, C., & Yang, S. N. (2002) · Epilepsia · doi:10.1046/j.1528-1157.2002.14602.x · Cited by 94
“In rodent studies, both prenatal stress (37) and postnatal stress (38) result in decreased neurogenesis in the granule cells of the dentate gyrus.”
BackgroundStandard chemoradiation for glioblastoma results in progressive brain volume loss
Prust, M. J., Jafari‐Khouzani, K., Kalpathy–Cramer, J., Polaskova, P., Batchelor, T. T., Gerstner, E. R., & Dietrich, J. (2015) · Neurology · doi:10.1212/wnl.0000000000001861 · Cited by 95
“Furthermore, diminution of hippocampal neurogenesis in mice decreases performance on the hippocampus-dependent Morris Water Maze (Lemaire et al., 2000).”
BackgroundThe influence of complex and threatening environments in early life on brain size and behaviour
DePasquale, C., Neuberger, T., Hirrlinger, A. M., & Braithwaite, V. A. (2016) · Proceedings of the Royal Society B Biological Sciences · doi:10.1098/rspb.2015.2564 · Cited by 94
García‐Cáceres, C., Lagunas, N., Calmarza-Font, I., Azcoitia, Í., Diz-Chaves, Y., García‐Segura, L. M., Baquedano, E., Frago, L. M., Argente, J., & Chowen, J. A. (2010) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2010.05.006 · Cited by 91
“Indeed, behavioral disturbances produced by prenatal stress are associatedwith cellular and synaptic protein alterations in the hippocampus, dentate gyrus and prefrontal cortex of adult offspring (Lemaire et al., 2000; Koo et al., 2003; Van den Hove et al., 2006;Michelsen et al., 2007).”
BackgroundAdult hippocampal neurogenesis and its role in cognition.
Oomen, C. A., Bekinschtein, P., Kent, B. A., Saksida, L. M., & Bussey, T. J. (2014) · WIREs Cognitive Science · doi:10.1002/wcs.1304 · Cited by 93
Targeting the gut microbiota to influence brain development and function in early life
Wang, S., Harvey, L., Martı́n, R., van der Beek, E. M., Knol, J., Cryan, J. F., & Renes, I. B. (2018) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2018.09.002 · Cited by 97
Kaiser, S., Kruijver, F. P. M., Swaab, D. F., & Sachser, N. (2003) · Behavioural Brain Research · doi:10.1016/s0166-4328(03)00077-9 · Cited by 94
Metadata
- Authors
- Lemaire, V., Koehl, M., Le Moal, M., & Abrous, D. N.
- Affiliations
- Université de Bordeaux (FR)
- Laboratoire de Psychobiologie des Comportement Adaptatifs, Institut National de la Santé et de la Recherche Médicale Unit 259, Université de Bordeaux II, Domaine de Carreire, Rue Camille Saint Saëns, 33077 Bordeaux Cedex, France
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2000-09-26
- Volume
- 97
- Issue
- 20
- Pages
- 11032-11037
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC27143
- OpenAlex
- W2142525943
- Cited by
- 1,044
- References
- 48
- Citations by year
- 2026: 18 · 2025: 15 · 2024: 18 · 2023: 23 · 2022: 23 · 2021: 31 · 2020: 25 · 2019: 31 · 2018: 35 · 2017: 46 · 2016: 56 · 2015: 63 · 2014: 55 · 2013: 59 · 2012: 48
- FWCI
- 5.35
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- prenatal stress, hippocampal neurogenesis, dentate gyrus, learning deficits, spatial learning, hippocampal-dependent memory, brain development, aging, psychopathology
- MeSH terms
- Animals, Cell Differentiation, Female, Hippocampus, Learning Disabilities, Neurons, Pregnancy, Prenatal Exposure Delayed Effects, Stress, Psychological, Rats, Sprague-Dawley, Rats
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