Dynamic Alterations in the Blood Transcriptome Characterize Drug Use Behavior and Co-Morbidities in Cocaine Use...

Area of Science:

• Neuroscience
• Genomics
• Computational Biology

Background:

• Cocaine use disorder (CUD) treatment is challenged by craving and relapse during abstinence.
• Longitudinal studies linking CUD behaviors to blood transcriptome changes are limited and complex.
• Developing novel analytical methods is crucial for understanding CUD recovery.

Purpose of the Study:

• To develop and validate an analytical pipeline for investigating the longitudinal relationship between drug use behaviors and blood transcriptome changes in individuals with CUD.
• To identify dynamic changes in gene expression associated with abstinence duration and behavioral outcomes.
• To provide a scalable approach for blood-based transcriptomic studies in substance use disorders.

Main Methods:

• A longitudinal study involving 12 subjects with CUD, collecting behavioral metrics and blood RNA-sequencing (RNA-seq) data at multiple time points (baseline, 3, 6, 9 months).
• Development of an analytical pipeline including hierarchical k-means clustering, in silico cell deconvolution, differential expression analysis over time, gene set enrichment analysis, and time-dependent gene co-expression analysis.
• Classification of subjects into responder groups based on behavioral scores and abstinence duration.

Main Results:

• The pipeline successfully captured dynamic changes in behavioral scores and abstinence duration within responder groups.
• Differentially expressed genes were enriched in genetic risk loci for substance use and cardiovascular diseases.
• Time-dependent gene co-expression analysis identified dynamic changes in immune processes, cell cycle, RNA-protein synthesis, and signaling pathways related to abstinence duration.

Conclusions:

• The study presents an innovative and scalable analytical pipeline for longitudinal blood-based RNA-seq studies in CUD, applicable to other substance use disorders.
• This data-driven approach enables the analysis of complex longitudinal drug use behaviors alongside blood transcriptomics.
• Significant changes in both drug use behaviors and the blood transcriptome were observed during cocaine abstinence.