This proposal focuses on understanding the neurobiological mechanisms of resilience to stress-related disorders. Because stress-related disorders--including depression, post-traumatic stress disorder and childhood cognitive and emotional defects that follow neglect and abuse--affect a significant proportion of children and adults and exact a huge human potential and financial toll, understanding the processes that engender resilience to these disorders carries profound impact. Vulnerability and resilience to disease are governed by the interaction of genes and environment / experience. Importantly, experience during early postnatal life influences the expression of stress-related genes, which may promote resilience or vulnerability to stress-related disorders. However, little is known about how these important effects take place. Augmenting early life experience by enhancing maternal care in the rat results in persistent alterations of stress-related genes: reduced expression of hypothalamic corticotropin releasing hormone (CRH) was found by the applicant already by the end of the enriched-experience period on postnatal day 9, preceding attenuation of stress responses and increased expression of hippocampal glucocorticoid receptor (GR). In addition, reducing CRH-CRH-receptor signaling in immature non-enriched rats was sufficient to up-regulate hippocampal GR persistently and to confer enduring resilience to stress. These findings indicate that repression of hypothalamic Crh gene expression is an early and crucial step in the molecular cascade bridging enriched maternal-derived early-life experience and the enduring neuroplasticity of the stress system that promotes resilience to stress-related disorders. The current proposal addresses important gaps in our understanding of the process by which augmented sensory input from maternal care promotes resilience to stress-related disorders: how are maternal-derived signals converted to information that 'commands'hypothalamic neurons to repress Crh gene expression? What molecular mechanisms initiate this repression? Maintain it throughout life? The aims of the proposed research are to (1) Test the hypothesis that augmented early-life maternal-care initiates epigenetic programming of the Crh gene via increased expression of the transcriptional repressor Neural Restrictive Silencing Factor (NRSF) and increased NRSF binding to a cognate binding site (NRSE) in the regulatory region of Crh. (2) Test the hypothesis that NRSF binding to NRSE is required for repression of Crh gene expression in hypothalamic neurons from experience-enriched rats. (3) Employ controlled, in vitro systems to test the hypothesis that NRSF upregulation and Crh repression in hypothalamic neurons are a result of reduced excitatory synaptic input to these neurons. (4) Examine the mechanisms that may be responsible for the maintenance of the suppressed expression of CRH and consequent attenuated stress responses and resilience to stress-related disorders. In summary, resilience to stress-related disorders is of major clinical significance. The paramount contribution of early-life experience to this resilience can be studied in suitable animal models, and information is now available regarding the molecular and functional changes of the 'stress system'that contribute to resilience. The proposed research will define how these molecular changes are initiated and maintained, and identify potential targets for translational clinical use, with profound impact on human health.

Public Health Relevance

Some people are more resilient to stressful situations that can provoke depression or learning and memory problems in other individuals. There is some evidence that having a good experience early in life might promote this resilience. Here we hope to use animal models to discover exactly how this resilience happens. The resulting information would enable us to use the same mechanisms as a basis for therapy in people who have not had the same type of optimal childhood experience.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH073136-12
Application #
8423416
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Panchision, David M
Project Start
1999-12-01
Project End
2015-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
12
Fiscal Year
2013
Total Cost
$354,338
Indirect Cost
$116,738
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
Gunn, B G; Baram, T Z (2017) Stress and Seizures: Space, Time and Hippocampal Circuits. Trends Neurosci 40:667-679
Davis, Elysia Poggi; Stout, Stephanie A; Molet, Jenny et al. (2017) Exposure to unpredictable maternal sensory signals influences cognitive development across species. Proc Natl Acad Sci U S A 114:10390-10395
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
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
Bolton, Jessica L; Molet, Jenny; Ivy, Autumn et al. (2017) New insights into early-life stress and behavioral outcomes. Curr Opin Behav Sci 14:133-139
Molet, J; Heins, K; Zhuo, X et al. (2016) Fragmentation and high entropy of neonatal experience predict adolescent emotional outcome. Transl Psychiatry 6:e702

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