Methamphetamine-induced regional-specific transcriptomic and epigenetic changes in the brain of male rats
Drug addiction is a relapsing disorder that results from neural adaptations following repeated drug exposure. Methamphetamine (METH) is a highly addictive central nervous system stimulant. Chronic use of METH is associated with multiple neurological and psychiatric disorders. The misuse of METH can cause neurotoxic brain damage and even death. Mounting evidence indicates that epigenetic changes and functional impairment in the brain occur due to addictive substance exposures. However, the binge METH exposure-induced neurotoxic responses in different brain regions at the molecular levels remains unclear. This study investigated the transcriptomic and epigenetic responses to binge METH exposure in four regions of the male rat brain, including the nucleus accumbens, dentate gyrus, Ammon’s horn, and subventricular zone. We found that 24 hours after acute binge METH exposure, 15.6% of genes showed changes in expression and 27.6% of open chromatin regions exhibited altered chromatin accessibility in all four rat brain regions, and most of these molecular changes were only identified in a single region. Among the four rat brain regions analyzed, 149 transcription factors (TFs) and 31 epigenetic modification factors were significantly affected by binge METH exposure. Moreover, only a few of the genes were affected by METH exposure at both transcription and chromatin accessibility levels simultaneously, suggesting independent regulation between transcriptome and chromatin accessibility in responding to neurotoxic acute METH exposure in the brain. METH exposure also resulted in unexpected opposite-directional regulation of both gene and chromatin accessibility between the dentate gyrus and Ammon’s horn. Approximately 70% of chromatin-accessible regions with METH-induced alterations in the rat brain are conserved at the sequence level in the human genome, and genes around them are highly enriched in neurological processes. Many of these conserved regions are active brain-specific enhancers and harbor SNPs associated with human neurological functions and diseases. Finally, we constructed the brain region-specific gene regulatory networks associated with acute neurotoxicity induced by binge METH exposure. Overall, our study provides detailed regional-specific molecular responses to METH exposure in the rat brain.