High dietary phosphate intake induces anxiety in normal male mice.

Background: Diet is increasingly recognized as an important risk factor for mental health. Inorganic phosphate (Pi) is currently used as a flavor enhancer or preservative at an unregulated amount in the western diet despite evidence that excessive dietary Pi intake associates with metabolic and cardiovascular disorders. The impact of high Pi on brain function remains poorly understood. This study aimed to evaluate the effects of chronic consumption of high dietary phosphate on behavior, neurovascular health, and neuroimmune populations, and cortical gene expression in key brain regions associated with emotional regulation. Methods: Adult C57BL/6 male mice were fed either a normal phosphate (NP) or high phosphate (HP) diet for 12 weeks. Behavioral assessments included the open field test (OFT) and fear conditioning. Histological analyses assessed neuronal densities and vascularization. Flow cytometry quantified brain-resident immune cell populations and microglia. Unbiased analysis of hippocampal gene expression was performed using RNA sequencing (RNA-Seq). Results: HP-fed mice exhibited increased anxiety-like behaviors compared to NP-fed controls, as indicated by increased thigmotaxis (i.e., more time close to the walls and, consequently, less time spent in the central area, HP: 164 ± 61 vs. NP: 215 ± 54 s, Conclusions: Collectively, this study highlights that habitual consumption of high dietary phosphate in mice may induce chronic anxiety