Single-nucleus transcriptome profiling of prefrontal cortex induced by chronic methamphetamine treatment

Area of Science:

• Neuroscience
• Molecular Biology
• Addiction Research

Background:

• Methamphetamine (METH) addiction poses a significant societal burden.
• The prefrontal cortex (PFC) plays a crucial role in emotion, cognition, and addiction neurocircuitry.
• Previous bulk RNA sequencing studies indicated METH-induced gene alterations in the mouse PFC, but cell-type-specific effects remained unclear.

Purpose of the Study:

• To elucidate the specific effects of chronic METH treatment on distinct cell types within the mouse PFC.
• To identify potential molecular pathways implicated in METH-related disorders at a single-cell level.

Main Methods:

• Single-nucleus RNA sequencing (snRNA-seq) was employed to analyze transcriptomes from 20,465 nuclei from the PFC of METH-treated and control mice.
• Identification of major cell types and differentially expressed genes (DEGs).
• Validation of key findings using RNA fluorescence in situ hybridization (FISH) and immunofluorescence.

Main Results:

• Six principal cell types were identified in the mouse PFC.
• Mature oligodendrocytes exhibited significant DEGs enriched in pathways related to myelin sheath, ATP metabolism, and mitochondrial function.
• Decreased mRNA levels of *Aldoc* and *Atp5l*, reduced TOM40 protein levels, and evidence of myelin damage (reduced thickness) were observed in METH-treated mice.

Conclusions:

• Single-nucleus RNA sequencing effectively revealed cell-type-specific transcriptomic alterations in the mouse PFC following chronic METH exposure.
• The findings highlight the impact of METH on mature oligodendrocytes, myelin integrity, and mitochondrial function.
• These molecular changes in the PFC may contribute to the development or exacerbation of psychiatric disorders associated with METH addiction.