Sex-dependent role of hippocampal BDNF and GSK-3β in mediating PTSD-like behaviors in both sexes of adolescent rats exposed to fear conditioning, extinction, and reinstatement.

Evidence has shown the role of brain-derived neurotrophic factor (BDNF) and glycogen synthase kinase-3 beta (GSK-3β) in the pathophysiology of posttraumatic stress disorder (PTSD). The present research explored the role of BDNF and GSK-3β activity in behavioral alterations in adolescent rats exposed to fear conditioning, extinction, and reinstatement. Three footshocks (0.8 mA for 3 s paired with sound 75 dB, 3 s) were delivered to rats. Extinction was done 1 min, or 1 h, or 1 day, or 5 days after conditioning (sound broadcasted for 20 times with no footshocks, 75 dB, 3 s). Reinstatement (one footshock, 0.8 mA, 3 s, with no sound) was done 1 h after extinction. The results showed extinction + reinstatement only in females decreased PTSD-like behaviors (darting was observed only in females). Fear conditioning decreased locomotion and rearing in both sexes, while extinction + reinstatement increased locomotion more effectively in females and rearing only in females. Fear conditioning decreased BDNF and increased GSK-3β more effectively in females, while extinction + reinstatement increased BDNF and decreased GSK-3β more effectively in females. In conclusion, we showed that BDNF and GSK-3β activity in the hippocampus may be involved in behavioral changes induced by fear conditioning and extinction + reinstatement sessions in females. However, it seems that behavioral changes in males may not be directly related to the function of BDNF and GSK-3β, although due to the absence of protein assessment, this conclusion is made with great caution. Additionally, reinstatement may induce a more powerful effect in males, counteracting the potential therapeutic effects of extinction session.