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High sodium diet (HSD) is a risk factor for stroke and dementia independent of hypertension, but it remains unclear if dietary salt impairs cognition. To address this question, we fed HSD (8% NaCl) or normal diet (ND; 0.5% NaCl) to males C57BL/6 mice for 12 weeks (n=10/group) and assessed cognitive function. At a novel object recognition task (non-spatial memory) HSD mice failed to identify a new object from a familiar one (ND: 72.4±2%, HSD: 56.4±2%, p<0.05). At the Barnes maze test, HSD mice took longer to locate the escape hole (ND: 26±5sec, HSD: 64±12sec, p<0.05), suggesting impaired spatial memory. Nesting behavior, akin to activities of daily living in humans, was also impaired (ND: 4.6±0.1, HSD: 4.1±0.1, Deacon scale, p<0.05). Since HSD alters endothelial function (Compr Physiol, 6:215, 2015) and endothelial nitric oxide (NO) plays a role in cognition (J Neurosc, 26:11513, 2006), we assessed NO production in isolated brain microvessels using DAF-FM as a marker. In HSD mice, NO levels were markedly reduced (ND: 0.33±0.04, HSD: 0.19±0.02 RFU/μm2, p<0.05) and the NO increase produced by the endothelium-dependent agonist acetylcholine (ACh) was suppressed (ND, Veh: 0.33±0.04, ACh: 0.54±0.05 RFU, p<0.05; HSD, Veh: 0.19±0.02, ACh: 0.25±0.05 RFU/μm2, p>0.05). Endothelial NO participates in synaptic plasticity by contributing to maintain normal levels of the neurotrophic factor BDNF (Eur J Neurosc, 44:2226, 2016). Hippocampal BDNF levels were reduced in HSD mice (-52±3%, p<0.05). Consistent with attenuated BDNF signaling, we also observed reductions in the phosphorylation of the BDNF receptor TrkB (-31±0.1%), and of related signaling molecules (ERK1/2: -36±1%; CREB: -45±1%; p<0.05). Arc, a protein involved in memory formation and dependent on BDNF, was also reduced (-41±1%; p<0.05). The data suggest that HSD-induced endothelial dysfunction leads to reduced NO, which, in turn, suppresses hippocampal BDNF and attendant signaling pathways, resulting in impaired synaptic plasticity and cognitive deficits. The finding that dietary salt has a profound impact of on cognition highlights the harmful effects of endothelial dysfunction on brain health and supports public health efforts to curb salt intake especially in individuals at high vascular risk.