The overall goal of this proposal is to determine the role of the stress-neuromodulator corticotropin releasing hormone (CRH) in early-life neuroplasticity that contributes to neurological disease. Studies during previous funding periods have demonstrated that central administration of synthetic CRH to infant rats led to long-term deficits of hippocampus mediated cognitive function, similar to those described after severe early-life stress in human infants. We have also demonstrated the presence of the 'cellular machinery' for endogenous CRH in immature hippocampus, i.e., substantial populations of CRH-expressing interneurons and abundant CRH receptors on hippocampal pyramidal cells innervated by these interneurons. Therefore, the current proposal aims to definitively test the hypothesis that enduring upregulation and excessive release of endogenous hippocampal CRH contribute crucially to the impaired functional integrity of the hippocampus following early-life adverse events such as chronic psychological stress or recurrent seizures. The driving hypothesis of this research is that certain stresses occurring during a period of heightened hippocampal plasticity elevate the 'set-point' of hippocampal CRH expression, increasing the peptide's levels in hippocampus longterm. Therefore, subsequent, acute stress at any point in life will evoke 'excessive' release of CRH from hippocampal interneurons. Pathological levels of CRH provoke acute and long-term hippocampal neuronal dysfunction, associated with synaptic reorganization. This research proposal focuses on understanding this process at the synaptic, cellular and system levels, defining the means for interrupting the deleterious actions of excessive endogenous CRH on hippocampal function and integrity. Therefore, the proposal aims to: (1) Investigate the effects of early-life (P2-P9) chronic 'psychological1 stress on hippocampal CRH expression long-term. (2) Delineate the unique synaptic machinery by which CRH (an excitatory neuropeptide), is stored in inhibitory interneurons, define the site of the postsynaptic elements mediating the peptide's actions, and determine whether stress activates post-synaptic hippocampal pyramidal cells via the release of endogenous CRH. (3) Characterize the functional, electrophysiological and structural hippocampal changes induced by early-life chronic psychological stress in a novel model. (4) Determine whether these effects of early-life stress are abrogated by blocking the actions of endogenous, stress-released CRH; in other words, whether the endogenous peptide is a required, crucial mediator of the enduring, life-long adverse effects of early-life stress on hippocampal functional integrity. These studies address the impact of early-life chronic psychological stress, such as child abuse and neglect (and perhaps recurrent seizures), on critical learning & memory functions. By defining the role of the stress-activated neuropeptide, CRH, in the mechanisms of the established adverse effects of these early-life events, these studies will provide truly innovative and exciting targets for prevention of a tremendous loss of human potential. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS028912-13
Application #
7195041
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Fureman, Brandy E
Project Start
1992-03-01
Project End
2009-02-28
Budget Start
2007-03-01
Budget End
2008-02-29
Support Year
13
Fiscal Year
2007
Total Cost
$267,506
Indirect Cost
Name
University of California Irvine
Department
Pediatrics
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Gunn, Benjamin G; Sanchez, Gissell A; Lynch, Gary et al. (2018) Hyper-diversity of CRH interneurons in mouse hippocampus. Brain Struct Funct :
Singh-Taylor, A; Molet, J; Jiang, S et al. (2018) NRSF-dependent epigenetic mechanisms contribute to programming of stress-sensitive neurons by neonatal experience, promoting resilience. Mol Psychiatry 23:648-657
Sandman, Curt A; Curran, Megan M; Davis, Elysia Poggi et al. (2018) Cortical Thinning and Neuropsychiatric Outcomes in Children Exposed to Prenatal Adversity: A Role for Placental CRH? Am J Psychiatry 175:471-479
Bolton, Jessica L; Molet, Jenny; Regev, Limor et al. (2018) Anhedonia Following Early-Life Adversity Involves Aberrant Interaction of Reward and Anxiety Circuits and Is Reversed by Partial Silencing of Amygdala Corticotropin-Releasing Hormone Gene. Biol Psychiatry 83:137-147
Walker, Claire-Dominique; Bath, Kevin G; Joels, Marian et al. (2017) Chronic early life stress induced by limited bedding and nesting (LBN) material in rodents: critical considerations of methodology, outcomes and translational potential. Stress 20:421-448
Gunn, B G; Baram, T Z (2017) Stress and Seizures: Space, Time and Hippocampal Circuits. Trends Neurosci 40:667-679
Curran, Megan M; Sandman, Curt A; Poggi Davis, Elysia et al. (2017) Abnormal dendritic maturation of developing cortical neurons exposed to corticotropin releasing hormone (CRH): Insights into effects of prenatal adversity? PLoS One 12:e0180311
Molet, J; Heins, K; Zhuo, X et al. (2016) Fragmentation and high entropy of neonatal experience predict adolescent emotional outcome. Transl Psychiatry 6:e702
Chen, Yuncai; Molet, Jenny; Lauterborn, Julie C et al. (2016) Converging, Synergistic Actions of Multiple Stress Hormones Mediate Enduring Memory Impairments after Acute Simultaneous Stresses. J Neurosci 36:11295-11307
Molet, Jenny; Maras, Pamela M; Kinney-Lang, Eli et al. (2016) MRI uncovers disrupted hippocampal microstructure that underlies memory impairments after early-life adversity. Hippocampus 26:1618-1632

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