Short-term exposure to a high-fat diet leads to neuroinflammation and impairs memory and cholinergic signaling in the hippocampal CA3 region of male mice

• HFD impairs cholinergic signaling and promotes inflammation in the hippocampal CA3 region. • HFD-intake is linked to reduced performance in the novel object recognition test. • α7nAChR in hippocampal CA3 region regulates neuroinflammation and memory in HFD mice. • HFD-fed Chrna7-/- mice displayed impaired performance in the novel object recognition test. • α7nAChR activation mitigates memory deficits and neuroinflammation in HFD mice. Consumption of a high-fat diet (HFD) can lead to cognitive dysfunction and neuroinflammation in the hippocampus, particularly the CA3 region, which is vital for associative memory. Cholinergic input from the basal forebrain to the hippocampus is critical for regulating excitability, plasticity, and overall cognitive function in this area. Neuroinflammation may disrupt the expression of the α7 nicotinic acetylcholine receptor (α7nAChR), essential for the anti-inflammatory cholinergic pathway. We sought to assess the effects of brief HFD exposure on hippocampal cholinergic function and neurobehavior. Adult Swiss male mice were fed either a standard chow diet (Control; CTR) or a 60% HFD for three days. The Open Field (OF) and Novel Object Recognition (NOR) tests were used to evaluate anxiety-like behavior and memory performance, respectively. Following testing, the CA3 region of the hippocampus was analyzed using Western Blotting, PCR, and immunofluorescence techniques. Additionally, HFD-fed mice treated intracerebroventricularly with the α7nAChR-selective agonist PNU-282987 and α7nAChR knockout ( Chrna7 -/-) mice were evaluated to elucidate the role of cholinergic signaling in cognition. Results showed that HFD-fed mice performed worse on the NOR test compared to CTR mice and exhibited reduced α7nAChR expression and increased acetylcholinesterase (AChE) levels, along with signs of neuroinflammation in the CA3 area. Treatment with PNU-282987 for three days mitigated memory impairments and neuroinflammation. In contrast, Chrna7 -/- mice fed a HFD displayed poorer performance on the NOR test. Our findings suggest that short-term HFD intake is linked to cholinergic impairment and inflammation in the CA3 region, indicating that targeted agonist therapy may help alleviate HFD-induced memory deficits. These results highlight the critical role of α7nAChR activation in memory regulation during neuroinflammatory episodes.