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 features of people with opioid use disorder (OUD). Preclinical findings suggest altered molecular rhythms in the brain are involved in opioid reward and dependence. However, whether molecular rhythms are disrupted in brains of people with OUD remained an open question, critical to understanding the role of circadian rhythms in opioid addiction. We previously used subjects' times of death (TOD) as a marker of time of day to investigate transcriptional rhythm alterations in psychiatric disorders. Using TOD and RNA sequencing, we discovered rhythmic transcripts in both the dorsolateral prefrontal cortex (DLPFC) and nucleus accumbens (NAc), key brain areas involved in opioid addiction, were largely distinct between OUD and unaffected comparison subjects. Further, fewer rhythmic transcripts were identified in DLPFC of OUD subjects compared to unaffected subjects, but nearly double the number of rhythmic transcripts were found in the NAc of OUD subjects. In OUD, rhythmic transcripts in the NAc peaked either in the evening or near sunrise, and were associated with dopamine, opioid, and GABAergic neurotransmission. Co-expression network analysis identified several OUD-specific modules in the NAc, enriched for transcripts involved in the modulation of dopamine and GABA synapses, including glutamatergic signaling and extracellular matrices. Integrative analyses with human GWAS revealed that rhythmic transcripts in DLPFC and NAc were enriched for genomic loci associated with sleep duration and insomnia. Overall, our results connect transcriptional rhythm changes in dopamine, opioid, and GABAergic synaptic signaling in human brain to sleep-related phenotypes and OUD.

Altered expression of somatostatin signaling molecules and clock genes in the hippocampus of subjects with substance use disorder

“…In addition, mice carrying deletions of Npas2, a homolog of Clock with preferential expression in the striatum and nucleus accumbens (NAc), display increased cocaine-seeking and self-administration behavior ( DePoy et al, 2021 ). Recent evidence from the same group has identified altered diurnal rhythms of dopamine, opioid, and GABAergic synaptic signaling in the NAc and dorsolateral prefrontal cortex in human subjects with opioid use disorder ( Xue et al, 2021 ).…”

“…Furthermore, recent preclinical evidence indicates that reduced slow wave sleep enhances cue induced reinstatement of alcohol seeking ( Reeves-Darby et al, 2021 ), indicating that sleep disturbances may be a causal factor in relapse. In addition to the evidence for involvement of sleep disturbances in SUD, a growing number of studies highlight the involvement of the circadian system in this disorder ( McClung et al, 2005 ; Falcon and McClung, 2009 ; Ozburn et al, 2013 ; DePoy et al, 2017 ; Edwards et al, 2018 ; Logan et al, 2018 ; Xue et al, 2021 ). Substances of abuse can disrupt circadian rhythms, and conversely, circadian rhythm disruption contributes to substance use ( Parekh and McClung, 2015 ; DePoy et al, 2017 ; Logan et al, 2018 ).…”

Chronic jet lag-like conditions dysregulate molecular profiles of neurological disorders in nucleus accumbens and prefrontal cortex

“…In neurological disorders such as Huntington's disease, Down syndrome and epilepsy, cell-type specific alterations or genetic alterations lead to functional imbalance in brain regions especially striatum, prefrontal cortex and hippocampus (Ghiglieri et al, 2011). Prefrontal cortex and nucleus accumbens are also involved in emotional, cognitive control, and regulation of reward-seeking behaviors (Xue et al, 2022). CJL may increase the risk of neurological diseases and alter the expression levels of genes associated with these diseases in aforementioned brain regions.…”