The Neuropathology of Alcohol Use Disorder: Cellular Insights From Human Post-Mortem Studies.

Alcohol use disorder (AUD) is a complex neurological disorder with limited treatments available. Thus, understanding the neurobiological changes associated with AUD is crucial for the development of effective therapeutic approaches. Analysis of human post-mortem tissue provides insight into the long-term effects of alcohol use and cellular changes that contribute to addiction behavior. Here, we provide a collection of cellular changes found in human AUD post-mortem brain tissue, revealing brain region-specific cellular adaptations that map a complex neurobiological landscape of addiction. Examination across the cortex, striatum, hippocampus, hypothalamus, cerebellum, and midbrain reveals that although degeneration, metabolic disruption, and neuroinflammatory processes are common cellular processes that are impacted, these changes are distinctive by brain region and cell type. For example, white matter loss dominates in the prefrontal cortex, the hippocampus is sensitive to glial cell loss, subtypes of hypothalamic neurons are disproportionately affected, and the striatum shows subregional changes. Although these cellular adaptations are brain region and cell type specific, this review of studies over the last 30 years suggests that neuropathology in AUD undergoes neural network reorganization. Whether these changes are a response to chronic alcohol use or underlying alcohol-seeking behavior is a limitation of post-mortem analysis. However, mechanistic studies of rodent models and convergent evidence from human post-mortem tissue have identified therapeutic candidates such as oxytocin and GLP-1. Insights from animal studies have also highlighted underexplored yet potentially pivotal regions in AUD, such as the anterior insular cortex and the ventral pallidum, in human studies. Other limitations include a lack of sex-specific analyses, the incorporation of advanced neuroscience tools, and multiple regional analyses. Integrating AUD human post-mortem tissue bridges preclinical and clinical research, providing an invaluable understanding of neural mechanisms underpinning AUD and potential avenues for targeted interventions.