Effect of acute alarm odor exposure and biological sex on generalized avoidance and glutamatergic signaling in the hippocampus of Wistar rats

Post-traumatic stress disorder (PTSD) is characterized by the development of paradoxical memory disturbances including intrusive memories and amnesia for specific details of the traumatic experience. Despite evidence that women are at higher risk to develop PTSD, most animal research has focused on the processes by which male rodents develop adaptive fear memory. As such, the mechanisms contributing to sex differences in the development of PTSD-like memory disturbances are poorly understood. In this investigation, we exposed adult male and female Wistar rats to the synthetic alarm odor 2,4,5-trimethylthiazole (TMT) to assess development of generalized fear behavior and rapid modulation of glutamate uptake and signaling cascades associated with hippocampus-dependent long-term memory. We report that female Wistar rats exposed to alarm odor exhibit context discrimination impairments relative to TMT-exposed male rats, suggesting the intriguing possibility that females are at greater risk in developing generalized fear memories. Mechanistically, alarm odor exposure rapidly modulated signaling cascades consistent with activation of the CREB shut-off cascade in the male, but not the female hippocampus. Moreover, TMT exposure dampened glutamate uptake and affected expression of the glutamate transporter, GLT-1 in the hippocampus. Taken together, these results provide evidence for rapid sex-dependent modulation of CREB signaling in the hippocampus by alarm odor exposure which may contribute to the development of generalized fear.

创伤后应激障碍（Post-traumatic stress disorder, PTSD）以矛盾性记忆障碍为主要特征，具体表现为闯入性记忆与创伤经历特定细节的遗忘。尽管已有证据表明女性罹患PTSD的风险更高，但绝大多数动物研究均聚焦于雄性啮齿类形成适应性恐惧记忆的相关过程。因此，导致PTSD样记忆障碍发生存在性别差异的具体机制，目前仍未得到充分阐明。本研究将成年雄性与雌性Wistar大鼠暴露于合成警戒气味2,4,5-三甲基噻唑（2,4,5-trimethylthiazole, TMT），以此评估其广泛性恐惧行为的发展情况，并检测与海马依赖性长时记忆相关的谷氨酸摄取与信号级联反应的快速调控变化。研究结果显示，与暴露于TMT的雄性大鼠相比，暴露于警戒气味的雌性Wistar大鼠表现出情境辨别能力受损，这提示雌性个体更易形成广泛性恐惧记忆，这一发现具有重要的研究价值。从机制层面分析，警戒气味暴露可快速调控雄性大鼠海马中的信号级联反应，该反应与CREB关闭级联的激活相符，但在雌性大鼠海马中未观察到此现象。此外，TMT暴露可抑制谷氨酸摄取，并影响海马中谷氨酸转运体GLT-1的表达。综上，本研究结果表明，警戒气味暴露可通过性别依赖性方式快速调控海马中的CREB信号通路，这或可参与广泛性恐惧记忆的形成过程。