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Early Stress Evokes Age-Dependent Biphasic Changes in Hippocampal Neurogenesis, Bdnf Expression, and Cognition
Open accessAbstract
Background Adult-onset stressors exert opposing effects on hippocampal neurogenesis and cognition, with enhancement observed following mild stress and dysfunction following severe chronic stress. While early life stress evokes persistent changes in anxiety, it is unknown whether early stress differentially regulates hippocampal neurogenesis, trophic factor expression, and cognition across the life span.Methods Hippocampal-dependent cognitive behavior, neurogenesis, and epigenetic regulation of brain-derived neurotrophic factor (Bdnf) expression was examined at distinct time points across the life span in rats subjected to the early stress of maternal separation (ES) and control groups. We also examined the influence of chronic antidepressant treatment on the neurogenic, neurotrophic, and cognitive changes in middle-aged ES animals.Results Animals subjected to early stress of maternal separation examined during postnatal life and young adulthood exhibited enhanced hippocampal neurogenesis, decreased repressive histone methylation at the Bdnf IV promoter along with enhanced BDNF levels, and improved performance on the stress-associated Morris water maze. Strikingly, opposing changes in hippocampal neurogenesis and epigenetic regulation of Bdnf IV expression, concomitant with impairments on hippocampal-dependent cognitive tasks, were observed in middle-aged ES animals. Chronic antidepressant treatment with amitriptyline attenuated the maladaptive neurogenic, epigenetic, transcriptional, and cognitive effects in middle-aged ES animals.Conclusions Our study provides novel insights into the short- and long-term consequences of ES, demonstrating both biphasic and unique, age-dependent changes at the molecular, epigenetic, neurogenic, and behavioral levels. These results indicate that early stress may transiently endow animals with a potential adaptive advantage in stressful environments but across a life span is associated with long-term deleterious effects.
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“middle-aged rats that experienced early maternal separation exhibited impaired cognition, reduced H3K9me2 regulation of the BDNF expression, and opposite changes in the hippocampal neurogenesis, suggesting both biphasic and distinct, age-dependent changes in the histone methylation in response to ES.169”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [169]
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“Rats exposed to the early stress of maternal separation (ES) exhibited decreased H3K9me2 modification at the BDNF IV promoter site, along with increased BDNF levels, enhanced hippocampal neurogenesis, and better cognitive performance in both the postnatal life and young adulthood.”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [169]
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“In response to early life stress, younger rats had increased neurogenesis, decreased BDNF IV promoter histone methylation, with a complementary increase in hippocampal BDNF concentration, and associated improvements in spatial and non-spatial learning (348).”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [348]
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“In contrast, middle-aged rats demonstrated opposing changes, concomitant with impairments in hippocampal-dependent cognitive tasks.”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [348]
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“Furthermore, chronic antidepressant treatment post-exposure was able to rescue the neurological decline observed in the middle-aged rats (348).”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [348]
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Metadata
- Authors
- Suri, D., Veenit, V., Sarkar, A., Thiagarajan, D., Kumar, A., Nestler, E. J., Galande, S., & Vaidya, V. A.
- Affiliations
- Tata Institute of Fundamental Research (IN)
- Centre for Cellular and Molecular Biology (IN)
- Icahn School of Medicine at Mount Sinai (US)
- Indian Institute of Science Education and Research Pune (IN)
- Corresponding author
- Vaidya, Vidita A.
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2013-04
- Volume
- 73
- Issue
- 7
- Pages
- 658-666
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC4051354
- OpenAlex
- W2121984222
- Cited by
- 208
- References
- 58
- Citations by year
- 2026: 8 · 2025: 9 · 2024: 11 · 2023: 15 · 2022: 7 · 2021: 13 · 2020: 16 · 2019: 15 · 2018: 16 · 2017: 19 · 2016: 26 · 2015: 23 · 2014: 24 · 2013: 6
- FWCI
- 5.70
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Wellcome Trust
- National Institute of Mental Health (P50MH096890)
- National Institute on Drug Abuse (R01DA014133)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- early life stress, maternal separation, hippocampal neurogenesis, BDNF expression, histone methylation, epigenetic regulation, BDNF isoforms, amitriptyline, antidepressant treatment, age-dependent effects, chronic stress
- MeSH terms
- Aging, Amitriptyline, Animals, Animals, Newborn, Antidepressive Agents, Tricyclic, Cognition, Hippocampus, Male, Maternal Deprivation, Maze Learning, Brain-Derived Neurotrophic Factor, Epigenesis, Genetic, Rats, Neurogenesis
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