# Dissecting neural circuits underlying early life stress-induced PFC dysfunction

> **NIH NIH R21** · UNIVERSITY OF COLORADO DENVER · 2021 · $233,250

## Abstract

Project Summary
Autism Spectrum Disorders (ASDs) comprise a group of severe neurodevelopmental disorders that are typified
by communication deficits and social impairment. Given that the onset of symptoms occurs by the age of 3, it is
largely agreed that neuronal dysfunction arises during early brain development. A developing brain shows a
remarkable capacity for plastic changes in response to experiences; thus, its development is most vulnerable to
the environmental factors that can derail normal brain function. Exposure to early life stress in the form of
abuse/neglect during a critical period of brain development has demonstrated behavioral and psychological
deficits that closely resemble autistic symptoms in both animal models and human studies. Thus, it is essential
to identify the neural mechanisms underlying early life stress-induced social dysfunction for the development of
treatment strategies for complex behavioral deficits in children with ASD. Recent studies have shown that early
life stress in rodents induces long-lasting brain alterations similar to the deficits seen in patients with ASDs,
including dysfunctions in the prefrontal cortex (PFC) and the stress/reward-related circuitry originating in the
ventral tegmental area (VTA). Formation of excitatory synapses in the PFC is known to be essential for the initial
establishment of functional neural circuits. Conversely, disrupted synapse development impairs PFC function
and is thought to underlie the pathology of multiple neurodevelopmental disorders. The PFC is densely
innervated by dopaminergic axon terminals and associated with higher cognitive processes that may be
disrupted in illnesses such as ASDs. In this R21 proposal, we utilize a novel combination of methods including
early social deprivation stress paradigm and two-photon imaging and uncaging to test our hypothesis that early
life stress-induced dysregulation of PFC-projecting dopamine neurons constitutes a neural mechanism by which
adverse events early in life alter PFC function and may cause behavioral dysfunction in adulthood. Guided by
strong preliminary data, we will examine this hypothesis in two specific aims: 1) Define functional changes in
PFC-projecting VTA dopamine neurons following early life stress. 2) Determine mechanisms of dopamine-
induced synapse development in the PFC following early life stress. Results from these studies will further our
understanding of the unique and detailed mechanisms by which dopamine regulates brain development, with
critical relevance to cellular underpinnings of neurodevelopmental disorders. Approximately 1 per 100 children
in the U.S. is a victim of abuse and neglect. We expect that our results will highlight new avenues into the
investigation of the pathophysiology underlying neurodevelopmental disorders resulting from early perturbation
of dopamine signaling.

## Key facts

- **NIH application ID:** 10189334
- **Project number:** 1R21MH126073-01
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Won Chan Oh
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $233,250
- **Award type:** 1
- **Project period:** 2021-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10189334

## Citation

> US National Institutes of Health, RePORTER application 10189334, Dissecting neural circuits underlying early life stress-induced PFC dysfunction (1R21MH126073-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10189334. Licensed CC0.

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