Sex differences in the effect of chronic REM sleep deprivation and extinction learning on freezing behavior and BDNF and GSK-3β expression levels in a rat model of fear conditioning

Abstract

Fear conditioning is among the most useful methods to induce posttraumatic stress disorder (PTSD)-like model in rodents, while extinction learning is a useful method to ameliorate PTSD-like behaviors. On the other hand, rapid-eye movement (REM) sleep deprivation (SD) has deleterious effects on behavioral functions, and fear learning and memory. The present study aimed to assess PTSD-like behavior and other behavioral functions along with changes in brain-derived neurotrophic factor (BDNF) and glycogen synthase kinase-3beta (GSK-3β) in the prefrontal cortex of both sexes of rats exposed to extinction learning, REM SD, or both. REM SD was performed for 14 days (6h/d). Fear conditioning was done using three footshocks (0.8 mA, 3 s) paired with sound (75 dB, 3 s), with 30 s intervals. Extinction was done with broadcasting three sounds (75 dB, 3 s, 30 s intervals) without footshocks. The results showed REM SD decreased freezing in both sexes with greater effect in males. REM SD in combination with extinction showed stronger effect in the reduction of freezing in males. Locomotor activity and rearing in all males were decreased. Pain threshold was increased only in males exposed to fear conditioning. BDNF was decreased following fear conditioning in both sexes, while extinction increased it. GSK-3β was not changed in males, while in females, fear conditioning increased GSK-3β and extinction restored it. In conclusion, the present study revealed significant sex differences in all parameters except BDNF. Interestingly, the results showed that REM SD can restore PTSD-like behavior as much as extinction training in males.