Carbon tetrachloride (CCl4), a potent hepatotoxin, is known to induce liver injury, but its effects on neuropsychiatric behavior through the liver-brain axis remain poorly understood. This study investigates how subacute versus chronic CCl4 exposure drives distinct behavioral phenotypes via monoamine oxidase A (MAOA)-mediated serotonin dysregulation. Male C57BL/6 mice were subjected to subacute (23 days) or chronic (49 days) CCl4 exposure (n = 10/group). Liver injury was assessed through serum ALT/AST, histopathology, and fibrotic markers. Neurobehavioral changes were evaluated using open field, tail suspension, and sucrose preference tests. MAOA, serotonin (5HT), and its metabolite 5-hydroxyindoleacetic acid (5HIAA) were quantified in liver and brain tissues. In vitro, conditioned medium from CCl 4 -exposed hepatocytes (AML12/MIHA) was applied to C17.2 neural cells to assess neuroinflammatory responses. Subacute CCl4 exposure induced hepatotoxicity alongside depressive-like behaviors, correlating with elevated hepatic MAOA protein expression, 5HT depletion, and elevated 5HIAA. In contrast, chronic exposure resulted in sustained liver damage but a behavioral shift toward hyperactivity and aggression, linked to brain reduced MAOA protein levels and partial 5HT recovery. Conditioned medium from CCl4-treated hepatocytes triggered neuroinflammation and synaptic dysfunction in neural cells. Hippocampal reduced MAOA protein levels, particularly in the dentate gyrus, was associated with hyperlocomotion. CCl4 drives distinct neuropsychiatric changes at subacute and chronic timepoints through time-dependent altered MAOA protein expression: early elevated hepatic MAOA protein levels deplete serotonin (depressive phase), while late brain reduced MAOA protein levels and COMT upregulation suggest potential dysregulation of catecholamine metabolism (hyperactive/aggressive phase). These findings uncover a novel liver-brain axis mechanism in which hepatocyte-derived factors alter monoaminergic homeostasis, providing new insights into hepatic encephalopathy-related behavioral disorders. Proposed model of time-dependent liver-brain axis dysregulation following CCl4 exposure. The schematic summarizes the key findings and hypotheses for the subacute (23-day) and chronic (49-day) phases. Solid arrows represent direct measurements from this study; dashed arrows indicate inferred or hypothesized pathways requiring future validation
Liu et al. (2026) studied this question.