Postnatal Handling Increases the Expression of cAMP-Inducible Transcription Factors in the Rat Hippocampus: The Effects of Thyroid Hormones and Serotonin
Open accessAbstract
Postnatal handling increases glucocorticoid receptor expression in the rat hippocampus, thus altering the regulation of hypothalamic synthesis of corticotropin-releasing hormone and the hypothalamic–pituitary–adrenal response to stress. The effect on glucocorticoid receptor gene expression represents one mechanism by which the early environment can exert a long-term effect on neural development. The handling effect on hippocampal glucocorticoid receptor expression is dependent on peripheral thyroid hormone release and the activation of ascending serotonergic pathways. In primary hippocampal cell cultures, serotonin (5-HT) increases glucocorticoid receptor expression, and this effect appears to be mediated by increased cAMP levels. In the current studies we examined the in vivo effects of handling on hippocampal cAMP–protein kinase A (PKA) activity. In 7-d-old rat pups, we found that (1) postnatal handling increased adenylyl cyclase activity and hippocampal cAMP levels, (2) the effect of handling on cAMP levels was completely blocked by treatment with either propylthiouracil (PTU), a thyroid hormone synthesis inhibitor, or the 5-HT receptor antagonist, ketanserin, and (3) handling also increased hippocampal PKA activity. We then examined the effects of handling on cAMP-inducible transcription factors. Handling rapidly increased levels of the mRNAs for nerve growth factor-inducible factor A (NGFI-A) (zif 268,krox 24) and activator protein-2 (AP-2) as well as for NGFI-A and AP-2 immunoreactivity throughout the hippocampus. Finally, we found that the effects of handling on NGFI-A and AP-2 expression were significantly reduced by concurrent treatment with either PTU or ketanserin, effects that paralleled those on cAMP formation. NGFI-A and AP-2 have been implicated in the regulation of glucocorticoid receptor expression during development. Thus, these findings suggest that postnatal handling might alter glucocorticoid receptor gene expression via cAMP–PKA pathways involving the activation of NGFI-A and AP-2.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Maternal effects on hippocampal GR expression are mediated by increases in hippocampal serotonin turnover and expression of the NGFI-A transcription factor.
“In vivo studies with rat pups or in vitro studies using cultured hippocampal neurons suggest that maternal effects on hippocampal GR expression are mediated by increases in hippocampal serotonin (5-HT) turnover and the expression of the nerve-growth factor-inducible factor-A (NGFI-A) transcription factor.78-82”
From Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function (2014) · cites this paper as [78]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Liu, D., Diorio, J., Tannenbaum, B., Caldji, C., Francis, D., Freedman, A., Sharma, S., Pearson, D., Plotsky, P. M., & Meaney, M. J. (1997) · Science · doi:10.1126/science.277.5332.1659 · Cited by 3,170 · see citing works
Self-citationNongenomic Transmission Across Generations of Maternal Behavior and Stress Responses in the Rat
Francis, D., Diorio, J., Liu, D., & Meaney, M. J. (1999) · Science · doi:10.1126/science.286.5442.1155 · Cited by 1,965 · see citing works
Self-citationPlotsky, P. M., & Meaney, M. J. (1993) · Molecular Brain Research · doi:10.1016/0169-328x(93)90189-v · Cited by 1,638 · see citing works
Self-citationEffect of Neonatal Handling on Age-Related Impairments Associated with the Hippocampus
Meaney, M. J., Aitken, D. H., van Berkel, C., Bhatnagar, S., & Sapolsky, R. M. (1988) · Science · doi:10.1126/science.3340858 · Cited by 1,074 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Epigenetic programming by maternal behavior
Weaver, I. C. G., Cervoni, N., Champagne, F. A., D'Alessio, A. C., Sharma, S., Seckl, J. R., Dymov, S., Szyf, M., & Meaney, M. J. (2004) · Nature Neuroscience · doi:10.1038/nn1276 · Cited by 6,177 · see citing works
Self-citationHeim, C., & Nemeroff, C. B. (2001) · Biological Psychiatry · doi:10.1016/s0006-3223(01)01157-x · Cited by 2,791 · see citing works
Stress Effects on Neuronal Structure: Hippocampus, Amygdala, and Prefrontal Cortex
McEwen, B. S., Nasca, C., & Gray, J. D. (2016) · Neuropsychopharmacology · doi:10.1038/npp.2015.171 · Cited by 1,574 · see citing works
Meaney, M. J., & Szyf, M. (2005) · Dialogues in Clinical Neuroscience · doi:10.31887/dcns.2005.7.2/mmeaney · Cited by 958 · see citing works
Self-citationBDNF and 5-HT: a dynamic duo in age-related neuronal plasticity and neurodegenerative disorders
Mattson, M. P., Maudsley, S., & Martin, B. (2004) · Trends in Neurosciences · doi:10.1016/j.tins.2004.08.001 · Cited by 942 · see citing works
Prenatal glucocorticoids and long-term programming
Seckl (2004) · European Journal of Endocrinology · doi:10.1530/eje.0.151u049 · Cited by 825 · see citing works
Maternal care as a model for experience-dependent chromatin plasticity?
Meaney, M. J., & Szyf, M. (2005) · Trends in Neurosciences · doi:10.1016/j.tins.2005.07.006 · Cited by 658 · see citing works
Self-citationPrenatal stress, glucocorticoids and the programming of the brain
Welberg, L. A. M., & Seckl, J. R. (2001) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2001.00601.x · Cited by 928 · see citing works
Self-citationStress, depression, and anhedonia: caveats concerning animal models
Anisman, H., & Matheson, K. (2005) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2005.03.007 · Cited by 569 · see citing works
Epigenetics and the environmental regulation of the genome and its function
Zhang, T.-Y., & Meaney, M. J. (2010) · Annual Review of Psychology · doi:10.1146/annurev.psych.60.110707.163625 · Cited by 565 · see citing works
Self-citationEarly programming of the hypothalamo–pituitary–adrenal axis
MATTHEWS, S. (2002) · Trends in Endocrinology and Metabolism · doi:10.1016/s1043-2760(02)00690-2 · Cited by 513 · see citing works
Maternal separation as a model of brain-gut axis dysfunction
O’Mahony, S. M., Hyland, N. P., Dinan, T. G., & Cryan, J. F. (2011) · Psychopharmacology · doi:10.1007/s00213-010-2010-9 · Cited by 415 · see citing works
Maternal programming of steroid receptor expression and phenotype through DNA methylation in the rat
Szyf, M., Weaver, I. C. G., Champagne, F. A., Diorio, J., & Meaney, M. J. (2005) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2005.10.002 · Cited by 348 · see citing works
Self-citationGlucocorticoids, developmental ‘programming’ and the risk of affective dysfunction
Seckl, J. R. (2007) · Progress in Brain Research · doi:10.1016/s0079-6123(07)67002-2 · Cited by 245 · see citing works
Self-citationRoth, T. L., & David Sweatt, J. (2011) · Journal of Child Psychology and Psychiatry · doi:10.1111/j.1469-7610.2010.02282.x · Cited by 246 · see citing works
Weaver, I. C. G. (2007) · Epigenetics · doi:10.4161/epi.2.1.3881 · Cited by 239 · see citing works
Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function
Anacker, C., O'Donnell, K. J., & Meaney, M. J. (2014) · Dialogues in Clinical Neuroscience · doi:10.31887/dcns.2014.16.3/canacker · Cited by 237 · see citing works
Self-citationGlucocorticoid “Programming” and PTSD Risk
SECKL, J. R., & MEANEY, M. J. (2006) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1364.027 · Cited by 234 · see citing works
Self-citationEarly life nutrition and neural plasticity
Georgieff, M. K., Brunette, K. E., & Tran, P. V. (2015) · Development and Psychopathology · doi:10.1017/s0954579415000061 · Cited by 177 · see citing works
Epigenetics and the Biological Basis of Gene × Environment Interactions
Bagot, R. C., & Meaney, M. J. (2010) · Journal of the American Academy of Child & Adolescent Psychiatry · doi:10.1016/j.jaac.2010.06.001 · Cited by 177 · see citing works
Self-citationPeripheral and central mechanisms of stress resilience
Pfau, M. L., & Russo, S. J. (2015) · Neurobiology of Stress · doi:10.1016/j.ynstr.2014.09.004 · Cited by 170 · see citing works
O'Hara, R., Schröder, C. M., Mahadevan, R., Schatzberg, A. F., Lindley, S., Fox, S., Weiner, M., Kraemer, H. C., Noda, A., Lin, X., et al. (2007) · Molecular Psychiatry · doi:10.1038/sj.mp.4001978 · Cited by 171 · see citing works
2006 Curt P. Richter award winner
DeVries, A. C., Craft, T. K. S., Glasper, E. R., Neigh, G. N., & Alexander, J. K. (2007) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2007.04.007 · Cited by 153 · see citing works
Critical age windows for neurodevelopmental psychiatric disorders: evidence from animal models
Marco, E. M., Macrì, S., & Laviola, G. (2011) · Neurotoxicity Research · doi:10.1007/s12640-010-9205-z · Cited by 144 · see citing works
Juárez, I., Gratton, A., & Flores, G. (2008) · Journal of Comparative Neurology · doi:10.1002/cne.21651 · Cited by 89 · see citing works
Kofink, D., Boks, M. P. M., Timmers, H. T. M., & Kas, M. J. (2013) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2013.03.020 · Cited by 83 · see citing works
Environmental regulation of the neural epigenome
Caldji, C., Hellstrom, I. C., Zhang, T.-Y., Diorio, J., & Meaney, M. J. (2011) · FEBS Letters · doi:10.1016/j.febslet.2011.03.032 · Cited by 82 · see citing works
Self-citationLovic, V., Keen, D., Fletcher, P. J., & Fleming, A. S. (2011) · Behavioral Neuroscience · doi:10.1037/a0024367 · Cited by 72 · see citing works
Weaver, I. C. G., Hellstrom, I. C., Brown, S. E., Andrews, S. D., Dymov, S., Diorio, J., Zhang, T.-Y., Szyf, M., & Meaney, M. J. (2014) · Philosophical Transactions of the Royal Society B: Biological Sciences · doi:10.1098/rstb.2013.0513 · Cited by 67 · see citing works
Self-citation<i>EGR3</i> as a potential susceptibility gene for schizophrenia in Korea
Kim, S. H., Song, J. Y., Joo, E., Lee, K. Y., Ahn, Y. M., & Kim, Y. S. (2010) · American Journal of Medical Genetics Part B: Neuropsychiatric Genetics · doi:10.1002/ajmg.b.31115 · Cited by 41 · see citing works
Machado, T. D., Salum, G. A., Bosa, V. L., Goldani, M. Z., Meaney, M. J., Agranonik, M., Manfro, G. G., & Silveira, P. P. (2015) · International Journal of Developmental Neuroscience · doi:10.1016/j.ijdevneu.2015.10.005 · Cited by 34 · see citing works
Self-citationPrenatal Glucocorticoids: Short-Term Benefits and Long-Term Risks
Manojlovic-Stojanoski, M., Nestorovic, N., & Milosevic, V. (2012) · Glucocorticoids - New Recognition of Our Familiar Friend · doi:10.5772/51106 · Cited by 19 · see citing works
- Authors
- Meaney, M. J., Diorio, J., Francis, D., Weaver, S., Yau, J., Chapman, K., & Seckl, J. R.
- Affiliations
- Douglas Mental Health University Institute (CA)
- University of Edinburgh (GB)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2000-05-15
- Volume
- 20
- Issue
- 10
- Pages
- 3926-3935
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6772700
- OpenAlex
- W1886309510
- Cited by
- 266
- References
- 4
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 2 · 2023: 3 · 2022: 2 · 2021: 2 · 2019: 3 · 2018: 8 · 2017: 3 · 2016: 7 · 2015: 11 · 2014: 8 · 2013: 15 · 2012: 12
- FWCI
- 4.58
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Funders
- Wellcome Trust
- Medical Research Council Canada
- Medical Research Council
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- postnatal handling, hippocampus, cAMP signaling, protein kinase A, glucocorticoid receptor, NGFI-A, Zif268, AP-2, thyroid hormones, serotonin, adenylate cyclase, early life environment, neural development, propylthiouracil, ketanserin, neonatal rats
- MeSH terms
- Cyclic AMP, Adenylyl Cyclases, Animals, DNA-Binding Proteins, Colforsin, Handling, Psychological, Hippocampus, Ketanserin, Male, Neuronal Plasticity, Neurons, Phosphorylation, Propylthiouracil, RNA, Messenger, Serotonin, Serotonin Antagonists, Antithyroid Agents, Thyroid Hormones, Transcription Factors, Tritium, Blotting, Western, Gene Expression Regulation, Enzymologic, Cyclic AMP Response Element-Binding Protein, Cyclic AMP-Dependent Protein Kinases, Immediate-Early Proteins, Rats, Long-Evans, Transcription Factor AP-2, Rats, Early Growth Response Protein 1
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
