Chronic stress early in life (ES), including neglect, abuse, loss of parent and severe poverty, affects the majority of the world's children (UNESCO report, 2004). This is of major clinical importance because chronic childhood stress is associated with cognitive (and psychiatric) disorders later in life. Because elimination of global ES is not feasible, effective therapies that can be given post hoc to prevent the effects of ES on mid- life cognitive decline are necessary. Having defined a rodent model of ES which results in enduring deficits of hippocampus-dependent cognitive function and LTP, together with dendritic atrophy, we found that post hoc blocking of the receptor (CRFR1) of the stress-activated neuropeptide, corticotropin releasing hormone (CRH) immediately after the ES period, abrogated these deficits. Whereas these data are encouraging, major gaps in our knowledge require study in order to translate these experimental findings into therapies for children. In this revised continuation proposal, we propose (1) to test if pathological activation of central or of peripheral CRFR1 is responsible for ES-provoked learning and memory defects and dendritic atrophy;(2) to distinguish between the hypothesis that ES leads to enduring changes in hippocampal structure and function that are irreversible after a "critical period" of development, and the possibility that ES initiates hippocampal derangements that progress throughout life. In the latter case, therapeutic interventions in young adult ES graduates will still prevent the cognitive and structural deficits;(3) Because the structural changes provoked by ES-dendritic atrophy and synapse / spine loss--underlie the cognitive deficits, the mechanisms of dendritic atrophy will be studied, focusing ontheroleof hippocampal CRH-CRFR1 signaling; (4)Becausedendriticatrophyderivesfromchroniclossofdendriticspines,themechanismsbywhichstress, via CRFR1 activation, provokes dendritic spine collapse will be examined. The proposed studies, spanning in vivo and in vitro systems, will provide insight into the mechanisms by whichESimpactsneuronalintegrity,synapticplasticityandcognitivefunctionlong-term.BecauseESaffects the majority of the world's children, these studies address a problem of paramount importance, which is strikingly understudied. The proposed studies will identify a novel mechanism, CRH-CRFR1 signaling, as pivotal in the disturbances provoked by ES. Because the proposed studies will demonstrate the potential for post hoc intervention, and because compounds targeting CRFR1 are under clinical development, the results of these studies have tremendous translational potential.

Public Health Relevance

This project studies how chronic stress early in life impacts our brain. The United Nations has found that more than half of the world's young children grow up under chronic stress (e.g., hunger, war, loss of parent). It is also known that early-life stress is associated with impairments of memory and other cognitive functions subserved by the brain's hippocampus region, and that these deficits persist during adulthood and worsen with age. We plan to test the possibility that a brain-specific stress hormone (CRH) contributes in a major way to the adverse, long-lasting effects of early stress on memory during adulthood and middle-age, and find out how this happens. Our studies will identify new therapies (blocking the actions of CRH) for prevention and/or reversal of the severe impact of early stress on cognitive function- a major advancement in world health.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Neuroendocrinology, Neuroimmunology, and Behavior Study Section (NNB)
Program Officer
Fureman, Brandy E
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Irvine
Schools of Medicine
United States
Zip Code
Cope, Jessica L; Regev, Limor; Chen, Yuncai et al. (2014) Differential contribution of CBP:CREB binding to corticotropin-releasing hormone expression in the infant and adult hypothalamus. Stress 17:39-50
Regev, Limor; Baram, Tallie Z (2014) Corticotropin releasing factor in neuroplasticity. Front Neuroendocrinol 35:171-9
Maras, P M; Molet, J; Chen, Y et al. (2014) Preferential loss of dorsal-hippocampus synapses underlies memory impairments provoked by short, multimodal stress. Mol Psychiatry 19:811-22
Andres, Adrienne L; Regev, Limor; Phi, Lucas et al. (2013) NMDA receptor activation and calpain contribute to disruption of dendritic spines by the stress neuropeptide CRH. J Neurosci 33:16945-60
Vogel-Ciernia, Annie; Matheos, Dina P; Barrett, Ruth M et al. (2013) The neuron-specific chromatin regulatory subunit BAF53b is necessary for synaptic plasticity and memory. Nat Neurosci 16:552-61
Karsten, Carley A; Baram, Tallie Z (2013) How Does a Neuron "know" to Modulate Its Epigenetic Machinery in Response to Early-Life Environment/Experience? Front Psychiatry 4:89
McClelland, Shawn; Korosi, Aniko; Cope, Jessica et al. (2011) Emerging roles of epigenetic mechanisms in the enduring effects of early-life stress and experience on learning and memory. Neurobiol Learn Mem 96:79-88
Ivy, Autumn S; Rex, Christopher S; Chen, Yuncai et al. (2010) Hippocampal dysfunction and cognitive impairments provoked by chronic early-life stress involve excessive activation of CRH receptors. J Neurosci 30:13005-15
Korosi, Aniko; Baram, Tallie Z (2010) Plasticity of the stress response early in life: mechanisms and significance. Dev Psychobiol 52:661-70
Chen, Yuncai; Rex, Christopher S; Rice, Courtney J et al. (2010) Correlated memory defects and hippocampal dendritic spine loss after acute stress involve corticotropin-releasing hormone signaling. Proc Natl Acad Sci U S A 107:13123-8

Showing the most recent 10 out of 84 publications