# Molecular rhythm alterations in human post-mortem brain associated with opioid use disorder

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $496,340

## Abstract

PROJECT SUMMARY
Opioid use and dependence prevalence have skyrocketed in the United States. A majority of patients with opioid
use disorder (OUD) relapse within months despite treatment. Recent human neuroimaging and postmortem
brain studies in OUD reveal the degree of dysfunction within cortical and striatal brain circuits, particularly within
dorsolateral prefrontal cortical (DLPFC) and nucleus accumbens (NAc) regions, strongly relates to the opioid
use and dependence risk. The PFC provides top-down inhibitory cognitive and emotional control to the NAc,
which mediates goal-directed and reward behaviors. Relapse vulnerability in OUD is strongly associated with
the severity and persistency of disruptions to sleep and circadian rhythms, raising the possibility that therapeutic
interventions which mitigate these disruptions during abstinence may be effective for reducing opioid craving
and relapse. However, our understanding of the biological mechanisms underlying the relationships between
circadian rhythms and OUD is limited, especially at the molecular level in the brains of people with OUD. We
and others have developed novel, innovative approaches using time of death (TOD) to measure molecular
rhythms in the human postmortem brain to investigate the mechanistic links between substance use and
molecular brain rhythms. Using TOD approaches, we recently found a marked loss of molecular rhythms in the
prefrontal cortex associated with normal aging and psychiatric disorders. Notably, we also discovered a gain of
rhythmicity in genes within disease-specific molecular pathways, providing novel insights into the biology of brain
aging and psychiatric pathology. Preliminary TOD analyses on large-scale gene expression in human subjects
with OUD revealed enrichment for pathways related to circadian rhythms in the PFC and NAc. In our proposal,
we will directly investigate the relationship between molecular rhythm disruption and opioid use and relapse
using both human postmortem brains from subjects with OUD and mouse models of circuit-specific targeting
and opioid self-administration. Specifically, we will investigate molecular rhythms in postmortem DLPFC and
NAc using RNA-sequencing from a large cohort of subjects with OUD (Aim 1A). We will also examine the impact
of specific clinical features (e.g., toxicology reports and overdoses, comorbid psychiatric disorders, history of
use, polysubstance use, illness duration) on molecular rhythms in OUD (Aim 1B). We will then directly test the
functional relevance of molecular rhythm disruptions in specific brain regions (PFC and NAc; Aim 2A) and circuits
(PFC projections to NAc; Aim 2B) during opioid self-administration behavior in mice. Our studies will identify
molecular rhythm abnormalities in the brains of subjects with OUD and begin to determine the mechanisms
linking circadian rhythms and addiction, which will provide important insight into disease-related pathways and
also potential treatment strategies.

## Key facts

- **NIH application ID:** 10026764
- **Project number:** 1R01DA051390-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Ryan W Logan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $496,340
- **Award type:** 1
- **Project period:** 2020-06-15 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10026764

## Citation

> US National Institutes of Health, RePORTER application 10026764, Molecular rhythm alterations in human post-mortem brain associated with opioid use disorder (1R01DA051390-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10026764. Licensed CC0.

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