This is a resubmitted renewal proposal for a Conte Center focused on the contribution of early-life experiences, especially unpredictable and fragmented maternal and environmental signals, to adolescent vulnerabilities and adult mental illness via mechanisms involving disruption of the maturation of cognitive and emotional brain circuits. Complex behaviors involve coordinated activities of brain circuits. During development, environment- derived sensory signals influence circuit maturation (e.g., visual, auditory) and may drive aberrant circuit maturation that can promote emotional and cognitive problems. Yet the nature of the signals that contribute to vulnerabilities to mental illness, and how they disrupt brain circuit maturation is unclear. Among environmental influences, early-life adversity is an established risk factor for mental illness, and aspects of adversity (e.g., maternal depression, poverty) explain a significant portion of mental problems later in life. Yet there are serious gaps in our ability to identify early vulnerability to mental illness. Here, we posit that unpredictable, fragmented sensory signals (FRAG) from the mother and environment constitute a previously unrecognized indicator of early-life adversity. This hypothesis originated from mechanistic animal studies where consistent, predictable patterns of maternal-derived signals promote resilience by modulating excitatory synapse number and function of specific cell populations. By contrast, FRAG promotes aberrant maturation of brain circuits involved in emotion and cognition, with commensurate behavioral deficits. During the original award we focused on several cognitive and emotional vulnerabilities and these remain outcomes in this proposal. Additionally, we identified anhedonia as a robust direct consequence of early-life FRAG in experimental systems, associated with evidence of aberrant pleasure / reward circuit maturation. Anhedonia, a dimensional (RDoC) entity linked to multiple mental disorders, is a recently-identified core feature of PTSD. We emphasize anhedonia in the proposed renewal because we find that it follows FRAG in children, adolescents and young adults and predicts risk for post-combat mental illness in a vulnerable population of Marines. Thus, supported by compelling recently-published and preliminary data and guided by the reviews of the original renewal proposal, we test the Center?s overarching hypothesis: It states that, in concert with established types of early-life adversity, fragmented and unpredictable maternal and environmental signals contribute to vulnerabilities to mental illness via mechanisms involving disruption of the maturation of cognitive and emotional brain circuits. The proposed Center will aim to: 1) Test the relative contribution of FRAG, along with other early-life risk factors, to mental health outcomes including anhedonia, considering sex and using tools enabling assessments across diverse cohorts. 2) Test the mechanisms underlying the effects of FRAG on the developing brain, with sensitivity to age- and sex-specific vulnerabilities and age-appropriate assessment tools. We will employ imaging and computational models focusing on brain circuit disruption; we will employ molecular and viral-genetic tools and capitalize on experimental animal systems to identify the underlying neurobiological mechanisms. 3) Create behavioral and neuroimaging sex-specific developmental trajectories from infancy to adulthood using our 3 prospective, well-characterized cohorts and repeated intra-individual measurements; generate predictive models for risk of anhedonia and vulnerability to mental illness; supported by preliminary data, identify intra-individual epigenetic signatures of FRAG in children as potential biomarkers. 4) Serve as a training forum and a magnet for the study and improved understanding of how early life experiences influence emotional and cognitive outcomes. In summary, guided by the reviews of the original, this resubmitted renewal proposal identifies FRAG as a novel source of aberrant brain circuit development that portends vulnerability to mental illness; it integrates FRAG within existing frameworks and offers novel, age-and sex-specific predictive markers of vulnerability to mental illness, and hence experiment-based, transformative paths for preventative interventions.

Public Health Relevance

Mental illness affects 15-20% of the population and its costs are enormous. Mental illness arises from combined genetic and early-life factors. We study the contribution of early-life experiences to aberrant brain maturation that underlies vulnerability to mental illness. Our Center renewal proposal capitalizes on novel, robust discoveries using many different disciplines and approaches in infants, children adolescents and adults. Our studies support the idea that fragmented and unpredictable maternal and environmental sensory signals to the developing brain (FRAG)--in concert with well-established factors such as poverty--contribute to subsequent vulnerabilities to mental illness via mechanisms involving disordered maturation of brain ?wiring?. Benefitting from three well-defined prospective human cohorts, including a high-risk population of Combat Marines, we will generate brain-scan and behavioral trajectories of the effects of FRAG on the brain. This will allow us to identify predictive biomarkers of individuals at risk to mental illness. We will seek additional predictive markers in peripheral cells. We will probe the mechanisms by which FRAG interferes with normal brain wiring by the use of experimental systems where we can establish causality and test mechanisms by interfering with them. If we succeed-- and we have strong data to support our success--then our discoveries will enable early recognition (and eventually mitigation) of novel factors that predispose adolescents and young adults to mental illness around the world.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Specialized Center (P50)
Project #
3P50MH096889-07S1
Application #
10071051
Study Section
Special Emphasis Panel (ZMH1)
Program Officer
Zehr, Julia L
Project Start
2013-06-17
Project End
2024-03-31
Budget Start
2020-08-01
Budget End
2021-03-31
Support Year
7
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 :
Leal, Stephanie L; Yassa, Michael A (2018) Integrating new findings and examining clinical applications of pattern separation. Nat Neurosci 21:163-173
Fox, Molly; Sandman, Curt A; Davis, Elysia Poggi et al. (2018) A longitudinal study of women's depression symptom profiles during and after the postpartum phase. Depress Anxiety 35:292-304
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
Riley, Jeffrey D; Chen, E Elinor; Winsell, Jessica et al. (2018) Network specialization during adolescence: Hippocampal effective connectivity in boys and girls. Neuroimage 175:402-412
Glynn, Laura M; Howland, Mariann A; Fox, Molly (2018) Maternal programming: Application of a developmental psychopathology perspective. Dev Psychopathol 30:905-919
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
Swales, Danielle A; Stout-Oswald, Stephanie A; Glynn, Laura M et al. (2018) Exposure to traumatic events in childhood predicts cortisol production among high risk pregnant women. Biol Psychol 139:186-192
Davis, Elysia Poggi; Hankin, Benjamin L; Swales, Danielle A et al. (2018) An experimental test of the fetal programming hypothesis: Can we reduce child ontogenetic vulnerability to psychopathology by decreasing maternal depression? Dev Psychopathol 30:787-806
Glynn, Laura M; Stern, Hal S; Howland, Mariann A et al. (2018) Measuring novel antecedents of mental illness: the Questionnaire of Unpredictability in Childhood. Neuropsychopharmacology :

Showing the most recent 10 out of 53 publications