# Dysregulation of the opioid system in early life adversity

> **NIH NIH R01** · YALE UNIVERSITY · 2022 · $836,047

## Abstract

PROJECT SUMMARY
Childhood maltreatment is associated with insecure attachment, emotional dysregulation, and abnormal threat
detection. Here we propose that abnormal dysregulation of the brain beta-endorphin signaling pathway plays a
central role linking childhood maltreatment with insecure attachment and with long-term behavioral
abnormalities. This idea is supported by work showing that dysregulation of the main beta-endorphin receptor
(mu-opioid receptor, or MOR) is associated with insecure attachment, emotional dysregulation, and abnormal
threat detection. To test this premise, we developed a mouse model of complex trauma, abbreviated UPS. UPS
recapitulates several key features of childhood maltreatment including the presence of multiple adversities,
fragmented abusive maternal care, insecure attachment, impaired maternal buffering, increased threat detection,
and abnormal social exploration. We also discovered that neurons in the hypothalamus expressing the agouti-
related peptide (Agrp) are rapidly activated in response to unpredictable maternal separation in infant mice.
Activation of Agrp neurons triggers the emission of ultrasonic vocalizations—the equivalent of the infant cry—
and solicited dam’s attention and care. Thus, Agrp neurons function as an alarm system for the infant during
distress. Intertwined with Agrp neurons are proopiomelanocortin (POMC) neurons, which are the main source of
beta-endorphin in the brain. We found that POMC neurons of infant mice are rapidly activated by reunion with
the dam. Activation of POMC neurons suppressed, while their ablation increased, the emission of ultrasonic
vocalizations in infant mice. Thus, POMC neurons function as a buffering/safety system for the infant that is
triggered during interactions with the mother. Based on these and other observations detailed in the proposal,
we hypothesize that complex trauma in childhood—modeled by UPS in mice—impairs the ability of the mother
to activate POMC neurons leading to reduced MOR signaling in Agrp neurons. This in turn causes prolonged
activation of Agrp neurons and sustained distress that further erodes maternal buffering, secure attachment, and
the ability of UPS mice to socialize and assess threat later in life. Work in Aim 1 will use fiber photometry in live
moving pups and slice electrophysiology to characterize the effects of UPS on POMC and Agrp neuronal
activation and its impact on MOR signaling in Agrp neurons. Work in Aim 2 will determine the contribution that
POMC neurons and MOR signaling make to maternal affiliation/buffering and threat detection/social behavior in
adolescence. Work in Aim 3 will test the extent to which sustained activation of Agrp neurons in infants is
responsible for the behavioral abnormalities seen in mice exposed to UPS. Successful completion of this work
will provide new insights into the mechanisms by which complex trauma in childhood programs abnormal
attachment, enhances threat detection, and impairs social b...

## Key facts

- **NIH application ID:** 10587155
- **Project number:** 1R01MH130825-01A1
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Marcelo Dietrich
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $836,047
- **Award type:** 1
- **Project period:** 2022-09-06 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10587155

## Citation

> US National Institutes of Health, RePORTER application 10587155, Dysregulation of the opioid system in early life adversity (1R01MH130825-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10587155. Licensed CC0.

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