Hippocampal single-cell RNA Atlas of chronic methamphetamine abuse-induced cognitive decline in mice

Abstract Background Chronic methamphetamine abuse leads to cognitive decline, posing a significant threat to human health and contributing to loss of productivity. However, the intricate and multifaceted mechanisms underlying methamphetamine-induced neurotoxicity have impeded the development of effective therapeutic interventions. Methods To establish a mouse model of cognitive decline induced by chronic methamphetamine exposure, we employed a large sample size and conducted two behavioral tests (Y-maze and novel object recognition test) at 2 and 4 weeks post-exposure. Subsequently, single-cell RNA sequencing was utilized to delineate the mRNA expression profiles of individual cells within the hippocampus. Comprehensive bioinformatics analyses, including cell clustering and identification, differential gene expression analysis, cellular communication analysis, pseudotemporal trajectory analysis, and transcription factor regulation analysis, were performed to elucidate the cellular-level changes in mRNA profiles caused by chronic methamphetamine exposure. Results Our findings demonstrated impairments in working memory, spatial cognition, learning, and cognitive memory. After 4 weeks of behavioral testing, we identified diverse cell types in the hippocampi of METH- and saline-treated mice through scRNA-seq, including glial cells, stromal cells, vascular cells, and immune cells. We observed that methamphetamine exerts cell-specific effects on gene expression changes associated with neuroinflammation, blood-brain barrier disruption, neuronal support dysfunction, and immune dysregulation. Furthermore, cross-talk analysis revealed extensive alterations in cellular communication patterns and signal changes within the hippocampal microenvironment induced by methamphetamine exposure. Pseudotime analysis predicted hippocampal neurogenesis disorders and identified key regulatory genes implicated in chronic methamphetamine abuse. Transcription factor analysis uncovered regulators and pathways linked to astrocyte-mediated neuroinflammation, endothelial junction integrity, microglial synaptic remodeling, and oligodendrocyte-supported neuronal cell bodies and axons. Additionally, it highlighted the role of neural precursor cells in various forms of neurodegeneration. Conclusions This study establishes a robust mouse model of cognitive impairment induced by chronic methamphetamine exposure. It provides valuable biological insights, characterizes the single-cell atlas of the hippocampus, and offers novel directions for investigating neurological damage associated with chronic methamphetamine-induced cognitive decline.