Classic heat stroke (CHS) occurs due to prolonged exposure to high environmental temperatures without physical exertion. In contrast, exertional heat stroke (EHS) occurs in physically active individuals during rigorous physical activity (Epstein and Yanovich, 2019). Compared to those without heat-related illness, patients with a history of heat stroke had a higher risk of dementia (Kuo et al., 2024). Rodents with EHS also displayed neurobehavioral disorders (Kuo et al., 2024; Xie et al., 2024). However, relatively little evidence exists regarding the effects of CHS on neurobehavioral disorders.

Cholinergic pathways through α7 nicotinic acetylcholine receptors (α7nAChR) participate in cognitive function (Pastor and Medina, 2024). Their dysfunction is associated with cognitive decline in several neurological disorders. Recent work shows that lonafarnib (LNF) can pass through the blood-brain barrier (BBB) and rescue structural and functional impairments of synapses of Alzheimer's disease mice via α7nAChR upregulation (Cai et al., 2022). This raises the possibility that CHS might cause structural and functional impairments of cognitive brain regions through α7nAChR downregulation.

In the present study, immediately after the onset of CHS, mice received an intraperitoneal dose of LNF (Sugiura et al., 2022) or vehicle twice daily for 14 days thereafter. Following the last dose of LNF or vehicle, we performed the novel object recognition, forced swimming, rotarod, and Morris water maze tests in these groups of mice. We performed Golgi staining to assess dendritic morphology in prefrontal cortical neurons and doublecortin (DCX) immunofluorescence staining to evaluate the number of newly formed neurons in the hippocampus. Finally, we performed the enzyme-linked immunosorbent assay to measure the contents of α7nAChR and pro-inflammatory cytokines in both the prefrontal cortex and hippocampus of the three groups of mice.