This competing renewal proposal probes how early-life experiences induce synaptic `rewiring' of stress-sensitive neurons, and the nature of the resulting molecular and epigenetic mechanisms that promote life-long emotional resilience. Experiences during sensitive periods early in life exert indelible influence on an individual's resilience or vulnerability to stress-related disorders. This occurs, at least in part, by modulation of neuronal function via changes in gene expression programs through epigenetic processes. However, it is not known how neonatal experiences `signal' to specific neuronal populations and how these signals influence the orchestrated programs of gene expression that mediate phenotypic resilience or vulnerability. We have discovered that a resilience-promoting neonatal experience, augmented maternal care (AUG), reduces glutamatergic synapses onto individual stress-sensitive hypothalamic neurons and represses expression of the stress-sensitive gene, Crh. In hypothalamic explants, reduced glutamatergic synapse function sufficed to recapitulate the repressive effects of AUG on Crh in a mechanism requiring the transcriptional repressor REST/NRSF. Here we capitalize on these findings to probe pivotal knowledge gaps that prevent translational application of our discoveries. First, we shall identify the mechanisms by which AUG reduces the number of excitatory synapses onto stress- sensitive hypothalamic CRH-expressing neurons. Because reduced excitatory synapse function suffices to repress Crh, understanding how this reduction takes place is important. We will test the hypothesis that microglia activation by AUG prunes glutamatergic synapses. Second, we shall probe the molecular mechanisms by which reduced excitatory input upregulates NRSF. Enhanced levels and function of NRSF, involved in numerous fundamental developmental processes, are required for the resilience-promoting effects of AUG, but the repressor is a poor molecular target. Therefore, we will identify how NRSF is upregulated, aiming for translatable targets. Capitalizing on pilot data we will test the hypothesis that miR124 repression promotes NRSF upregulation, generating the resilient phenotype. Third, we shall investigate the epigenetic mechanisms involved in the persistent alteration of cellular and behavioral phenotype generated by augmented maternal care. We will employ innovative single-neuron RNA- seq methods in identified neurons together with NRSF-ChIP-seq and multiple levels of analysis to discover both NRSF-dependent and independent gene expression changes that contribute to the resilient phenotype. Fourth, we shall capitalize on tantalizing preliminary data to examine the sex-specificity of the processes and outcomes described above. These studies will have major impact, as they are the first to causally connect neonatal experience with synaptic `rewiring' that promotes epigenetic processes within select neuronal populations. The proposed studies provide a novel mechanistic and `translatable' pathway from early-life experience to phenotypes that govern human vulnerability and resilience to neuropsychiatric diseases.

Public Health Relevance

Experiences during sensitive periods early in life exert indelible influence on an individual's resilience or vulnerability to depression and to some cognitive disorders. There is evidence that neonatal experiences modulate the function of neurons involved in these crucial behaviors by modifying the genes expressed in these neurons in a long-lasting manner. However, it is not known how neonatal experiences `signal' to specific brain cells and how these signals influence the orchestrated programs of gene expression that mediate phenotypic resilience or vulnerability. The studies proposed here will build on robust rodent models and will employ cutting-edge scientific tools to solve these important mysteries. The information that we will gain from these studies can then be used to enhance resilience to depression in individuals who have suffered difficult experiences early life and who are prone to mental disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH073136-18
Application #
9922987
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Panchision, David M
Project Start
1999-12-01
Project End
2021-05-31
Budget Start
2020-06-01
Budget End
2021-05-31
Support Year
18
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of California Irvine
Department
Pediatrics
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92617
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
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
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
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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