# Fragmented early-life experiences, aberrant circuit maturation, emotional vulnerabilities

> **NIH NIH P50** · UNIVERSITY OF CALIFORNIA-IRVINE · 2022 · $2,931,489

## Abstract

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 mechanis...

## Key facts

- **NIH application ID:** 10379266
- **Project number:** 5P50MH096889-09
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Tallie Z. Baram
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $2,931,489
- **Award type:** 5
- **Project period:** 2013-06-17 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10379266

## Citation

> US National Institutes of Health, RePORTER application 10379266, Fragmented early-life experiences, aberrant circuit maturation, emotional vulnerabilities (5P50MH096889-09). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10379266. Licensed CC0.

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