Association of Subclinical Thyroid Dysfunction with Cognitive Impairment in Rats: The Role of Autophagy

Background: We investigated the effect of subclinical hyperthyroidism and subclinical hypothyroidism on cognitive function in rats and the role of autophagy in this process.Methods: Forty Wistar rats were randomized into normal control (NC), hyperthyroidism (Hyper), hypothyroidism (Hypo), subclinical hyperthyroidism (sHyper), and subclinical hypothyroidism (sHypo) groups. Cognitive function (spatial learning and memory) was tested by the Morris water maze test. Hippocampal histopathology was analyzed by H&E staining, and expression levels of caspase-3 in hippocampal CA1 neurons were measured. In addition, immunoblot analysis was performed to detect hippocampal autophagy-related proteins.Results: Escape latency from day 1 to day 4 was significantly longer in the Hypo, Hyper, and sHyper groups than in the NC group (P < 0.01). In addition, the number of rats crossing the virtual platform was significantly lower in the Hypo, Hyper, and sHyper groups than in the NC group (P < 0.01). Compared with the NC group, all four groups had significantly lower residence time in the target quadrant (P < 0.05). Beclin-1 and LC3-II protein expression in hippocampal tissues was significantly higher in the Hyper and sHyper groups than in the NC group (P < 0.01). Beclin-1 and LC3-II protein expression in hippocampal tissues did not significantly differ between the sHypo group and NC group (P > 0.05).Conclusions: Subclinical thyroid dysfunction in rats might lead to cognitive impairment. Subclinical hyperthyroidism might be associated with excessive activation of autophagy and hippocampal neuron damage and necrosis. (J Nippon Med Sch 2023; 90: 372 & horbar;380)