Unilateral mastication‐induced memory deficits linked to disrupted hippocampal cholesterol metabolism in rats

Abstract Masticatory dysfunction induces astrocyte hyperplasia and disrupts brain cholesterol homeostasis, but the specific mechanism by which unilateral mastication drives cognitive decline remains unclear. A rat model of experimental unilateral mastication (EUM) was established via unilateral maxillary anterior and posterior tooth extraction, characterized by asymmetric masseter electromyography (EMG), muscle fiber type distribution, and acetylcholinesterase activity. Behavioral tests assessed learning and memory. Hippocampal changes were analyzed for astrocyte reactivity and synaptic integrity. Targeted cholesterol metabolomics profiled cholesterol species, with correlation analyses exploring links between metabolic perturbations and synaptic dysfunction. EUM rats showed accelerated learning deficits and memory decline. Hippocampal analyses revealed reactive astrocytosis and synaptic degeneration. Metabolomics identified hippocampal cholesterol ester accumulation, with dysregulated biosynthesis and efflux/metabolism pathways. Correlation analyses linked cholesterol dysregulation to synaptic impairment, with reduced 24‐hydroxycholesterol as a key mediator. Unilateral mastication impacts brain health via hippocampal cholesterol dysregulation, suggesting targeting cholesterol metabolism may mitigate associated cognitive decline. These findings highlight a potential connection between masticatory dysfunction and cognitive decline mediated by cholesterol metabolic pathways, providing mechanistic insights into oral‐brain axis interactions with implications for preventing cognitive impairment.