Hippocampal Glutamatergic Neuron Inhibition Mediates Berberine's Cognitive Benefits in High-Fat Diet-Induced Obesity

Dysregulated lipid metabolism, particularly due to a high-fat diet (HFD), disrupts the balance between excitatory and inhibitory neurons, contributing to cognitive impairment. Abnormal activation of hippocampal glutamatergic neurons is implicated in obesity-related cognitive dysfunction. Berberine (BBR), a potential therapeutic agent, may restore lipid metabolism balance and mitigate neuronal imbalance in HFD-induced cognitive impairment. This study aimed to investigate the effects of BBR on cognitive dysfunction in obese mice and its underlying mechanisms. We fed the mice with HFD for four months, during which hippocampal glutamatergic neurons were chemically inhibited. We administered BBR (10 mg/kg) intraperitoneally thrice weekly. Behavioral, electrophysiological, and pathological changes were assessed using novel object recognition, fear conditioning, local field potential, recordings, and immunofluorescence. HFD mice exhibited shorter exploration time, increased context freezing, and disrupted hippocampal gamma and theta rhythms. Immunofluorescence revealed an increase in VGLUT1-positive glutamatergic neurons in the CA1 region. Chemical inhibition of glutamatergic neurons reversed these changes, and similarly, BBR administration reduced gamma rhythm power and alleviated cognitive impairment. BBR improved cognitive function in HFD-fed mice by inhibiting overactive glutamatergic neurons, probably through the modulation of inflammation, which supports its neuroprotective properties.