Ketogenic Diet Promotes Reward Learning by Upregulating Hippocampal CAMK2A Expression and Activating Dopamine Synaptic Signaling

Various neuromodulatory benefits of the ketogenic diet (KD) have been demonstrated, yet its influence on reward learning and underlying mechanisms remain poorly defined. This study combined proteomics and metabolomics to identify key molecular changes in the hippocampus of KD-fed mice. Our analysis revealed significant upregulation of the “dopaminergic synapse” pathway, with CAMK2A emerging as a central regulator. In vitro, treatment of the hippocampal neuronal cell line HT22 with β-hydroxybutyrate (BHB), a primary KD metabolite, increased the protein expression of CAMK2A and increased the phosphorylation of its downstream target, GluA1. Crucially, Camk2a knockdown completely blocked BHB-induced p-GluA1 enhancement. To determine the behavioral relevance, we stereotaxically delivered AAV-shCamk2a into the hippocampus of KD-fed mice. Knockdown of Camk2a reversed the pro-reward effects of KD, as measured by the sucrose preference test and conditioned place preference test, without impairing general locomotor activity in the open field test. Together, these results suggest a novel BHB–CAMK2A–dopaminergic signaling axis through which KD enhances reward learning, thus bridging systemic metabolism with cognitive function and expanding our understanding of KD-mediated neuromodulation.