Chrysin modulates the BDNF/TrkB/AKT/Creb neuroplasticity signaling pathway: Acting in the improvement of cognitive flexibility and declarative, working and aversive memory deficits caused by hypothyroidism in C57BL/6 female mice

Hypothyroidism is known to affect memory consolidation, and our prior research highlighted the potential of chrysin as a therapeutic agent to restore cognitive function. The present study aimed to investigate the action mechanism of chrysin on memory deficits in hypothyroid in C57BL/6 female mice. We assessed cognitive flexibility, declarative, working, and aversive memories while analyzing the BDNF/TrkB/AKT/Creb neuroplasticity signaling pathway and synaptic function in the hippocampus and prefrontal cortex. To induce hypothyroidism, mice were exposed to 0.1 % methimazole (MTZ) in the drinking water for 31 days. After confirming low thyroid hormones levels, the mice received either vehicle or chrysin (20 mg/kg) intragastrically once a day for 28 consecutive days. Memory tests were conducted in two separate experiments (experiment 1: Y-maze and reverse Morris water maze; experiment 2: object recognition task and step-down latency), ensuring no memories overlap. Following the tests, the brain samples were collected to analyses ex vivo. Hypothyroid mice exhibited deficits in cognitive flexibility and various memory types, along with altered protein expression related to the BDNF/TrkB/Creb signaling pathway and increased AKT levels in hippocampus and prefrontal cortex. Chrysin treatment effectively reversed these memory deficits, restored cognitive flexibility, and improved protein levels. Our findings suggest that hypothyroidism impairs cognitive flexibility and memory through the BDNF/TrkB/AKT/Creb pathway, which chrysin modulates, operating as a neuroprotector in hypothyroidism. This research sheds light on the potential therapeutic benefits of chrysin for memory-related issues in hypothyroidism.