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Hippocampal Dysfunction and Cognitive Impairments Provoked by Chronic Early-Life Stress Involve Excessive Activation of CRH Receptors
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Chronic stress impairs learning and memory in humans and rodents and disrupts long-term potentiation (LTP) in animal models. These effects are associated with structural changes in hippocampal neurons, including reduced dendritic arborization. Unlike the generally reversible effects of chronic stress on adult rat hippocampus, we have previously found that the effects of early-life stress endure and worsen during adulthood, yet the mechanisms for these clinically important sequelae are poorly understood. Stress promotes secretion of the neuropeptide corticotropin-releasing hormone (CRH) from hippocampal interneurons, activating receptors (CRF 1 ) located on pyramidal cell dendrites. Additionally, chronic CRF 1 occupancy negatively affects dendritic arborization in mouse organotypic slice cultures, similar to the pattern observed in middle-aged, early-stressed (CES) rats. Here we found that CRH expression is augmented in hippocampus of middle-aged CES rats, and then tested whether the morphological defects and poor memory performance in these animals involve excessive activation of CRF 1 receptors. Central or peripheral administration of a CRF 1 blocker following the stress period improved memory performance of CES rats in novel-object recognition tests and in the Morris water maze. Consonant with these effects, the antagonist also prevented dendritic atrophy and LTP attenuation in CA1 Schaffer collateral synapses. Together, these data suggest that persistently elevated hippocampal CRH–CRF 1 interaction contributes importantly to the structural and cognitive impairments associated with early-life stress. Reducing CRF 1 occupancy post hoc normalized hippocampal function during middle age, thus offering potential mechanism-based therapeutic interventions for children affected by chronic stress.
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“potential threats activate the hypothalamic-pituitary-adrenal (HPA) axis, leading to enhanced expression of corticotropin releasing hormone (CRH) in the hippocampus and damage to hippocampal neurons (Brunson et al., 2001; Ivy et al., 2010).”
From Childhood adversity and neural development: Deprivation and threat as distinct dimensions of early experience (2014) · cites this paper as Ivy et al., 2010
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Metadata
- Authors
- Ivy, A. S., Rex, C. S., Chen, Y., Dubé, C., Maras, P. M., Grigoriadis, D. E., Gall, C. M., Lynch, G., & Baram, T. Z.
- Affiliations
- University of California, Irvine (US)
- Neurocrine Biosciences (United States) (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2010-09-29
- Volume
- 30
- Issue
- 39
- Pages
- 13005-13015
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC2991143
- OpenAlex
- W2080496806
- Cited by
- 402
- References
- 70
- Citations by year
- 2026: 11 · 2025: 21 · 2024: 27 · 2023: 25 · 2022: 34 · 2021: 21 · 2020: 26 · 2019: 31 · 2018: 20 · 2017: 29 · 2016: 24 · 2015: 26 · 2014: 39 · 2013: 18 · 2012: 28
- FWCI
- 9.37
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (NS045260)
- National Institute on Aging (AG00358)
- National Institute of Mental Health (MH087467, F31MH087467, MH73136, R01MH073136)
- National Institute of Neurological Disorders and Stroke (P01NS045260, NS 28912, NS045260, R01NS028912, NS051823, R01NS051823, T32NS045540)
- 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
- hippocampal dysfunction, corticotropin-releasing factor, CRF1 receptor, dendritic atrophy, long-term potentiation, learning and memory impairment, novel object recognition, Morris water maze, CRF1 receptor antagonist, hippocampal interneurons, middle-aged rats, organotypic slice cultures
- MeSH terms
- CRF Receptor, Type 1, Animals, Animals, Newborn, Chronic Disease, Cognition Disorders, Corticotropin-Releasing Hormone, Disease Models, Animal, Female, Hippocampus, Humans, Male, Mice, Transgenic, Neurons, Organ Culture Techniques, Stress, Psychological, Rats, Sprague-Dawley, Receptors, Corticotropin-Releasing Hormone, Mice, Rats
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