Molecular rhythm alterations in prefrontal cortex and nucleus accumbens associated with opioid use disorder

Abstract

Severe and persistent disruptions to sleep and circadian rhythms are common in people with opioid use disorder (OUD). Preclinical evidence suggests altered molecular rhythms in the brain modulate opioid reward and relapse. However, whether molecular rhythms are disrupted in the brains of people with OUD remained an open question, critical to understanding the role of circadian rhythms in opioid addiction. Using subjects’ times of death as a marker of time of day, we investigated transcriptional rhythms in the brains of subjects with OUD compared to unaffected comparison subjects. We discovered rhythmic transcripts in both the dorsolateral prefrontal cortex (DLPFC) and nucleus accumbens (NAc), key brain areas involved in OUD, that were largely distinct between OUD and unaffected subjects. Fewer rhythmic transcripts were identified in DLPFC of subjects with OUD compared to unaffected subjects, whereas in the NAc, nearly double the number of rhythmic transcripts was identified in subjects with OUD. In NAc of subjects with OUD, rhythmic transcripts peaked either in the evening or near sunrise, and were associated with an opioid, dopamine, and GABAergic neurotransmission. Associations with altered neurotransmission in NAc were further supported by co-expression network analysis which identified OUD-specific modules enriched for transcripts involved in dopamine, GABA, and glutamatergic synaptic functions. Additionally, rhythmic transcripts in DLPFC and NAc of subjects with OUD were enriched for genomic loci associated with sleep-related GWAS traits, including sleep duration and insomnia. Collectively, our findings connect transcriptional rhythm changes in opioidergic, dopaminergic, GABAergic signaling in the human brain to sleep-related traits in opioid addiction.

A Glitch in the Matrix: The Role of Extracellular Matrix Remodeling in Opioid Use Disorder

“…Opioids lead to long-lasting changes in gene transcription, protein signaling, receptor activity, synaptic morphology and plasticity, as well as neural circuit function that contribute to the development of addiction ( Hearing, 2019 ; Li et al, 2019 ; Madayag et al, 2019 ; Song et al, 2019 ; Valentinova et al, 2019 ; Koob, 2020 ; Jiang et al, 2021 ; Seney et al, 2021 ; Tavares et al, 2021 ; Trieu et al, 2022 ; Xue et al, 2022 ). A major class of signaling proteins involved in opioid-induced neural plasticity, include cell adhesion molecules (CAMs), matrix metalloproteinases (MMPs), and proteoglycans, and these proteins provide structural support to neurons, astrocytes, microglia in the formation of the extracellular matrix (ECM) and perineuronal nets (PNNs).…”

Circadian rhythms as modulators of brain health during development and throughout aging

“…Furthermore, analysis of the NAc revealed that transcripts heavily involved in dopamine (DA), GABAergic, and glutamatergic synaptic functions were altered between control and opioid use disorder individuals. Lastly, the rhythmic transcripts found in the NAc and the dorsolateral prefrontal 10.3389/fncir.2022.1059229 cortex of patients with opioid use disorder were enriched for genomic loci associated with sleep-related issues (Xue et al, 2022). In summary, studies in humans are beginning to more fully reveal potential mechanisms involved in the relationships between sleep, circadian rhythms, and neural plasticity.…”

The Ventral Tegmental Area and Nucleus Accumbens as Circadian Oscillators: Implications for Drug Abuse and Substance Use Disorders

“…This is also seen in human post-mortem NAc tissue RNA-sequencing analyses where transcript levels are organized by time-of-death and tested for rhythmicity. In the NAc of healthy neurotypical control donors, robust rhythms in the canonical clock genes have been seen (e.g., Bmal1 , Npas2 , Period , Cryptochrome , and Rev-erbα ), as well as pathway analyses revealing Circadian Rhythm Signaling as a pathway enriched among the top rhythmic genes ( Li et al, 2013 ; Ketchesin et al, 2021 ; Xue et al, 2022 ). Finally, though these findings point to a functional molecular clock at the whole NAc level, functional investigation of these rhythms has largely been in MSNs or MSN subtypes.…”

“…Finally, although preclinical findings suggest disrupted NAc molecular rhythms are associated with altered reward and drug abuse, whether molecular rhythms are disrupted in brains of people with SUD is largely understudied. In a preliminary report using human post-mortem NAc tissue from healthy donors and individuals previously diagnosed with opioid use disorder, total RNA sequencing analysis of the transcriptome was organized by time-of-death and uncovered robust molecular rhythms in the NAc that were significantly altered in those with opioid use disorder ( Xue et al, 2022 ). Though it is unclear what functional role these rhythm alterations contributed to the development of the donor’s opioid use disorder, this is some of the first evidence in humans to suggest altered NAc molecular rhythms are associated with SUDs.…”