应激激素对恐惧消退作用的神经生理机制

Neurophysiological Mechanism of Stress Hormones on Fear Extinction

恐惧消退是指反复呈现条件刺激而不匹配无条件刺激,从而消除个体已有的恐惧反应。应激激素,如去甲肾上腺素(norepinephrine,NE)和糖皮质激素(glucocorticoids,GCs),可通过影响腹内侧前额叶、杏仁核和海马等与消退学习有关的神经回路的活动,调节恐惧消退学习效果。NE和GCs对恐惧消退学习的调节作用受激素水平与激素用药时间的影响,且其调节效果存在性别差异。未来研究需进一步探索应激激素如何影响恐惧消退学习效果,并思考如何利用其影响效果促进暴露疗法疗效。

Fear extinction, which is the mechanism of exposure therapy, is usually accomplished by repeatedly presenting a conditioned stimulus(CS) without the company of an aversive outcome(i.e., unconditioned stimulus, US). Stress hormones, including glucocorticoids(GCs) and norepinephrine(NE), widely spread in the neural circuits that involve in extinction learning(e.g., vmPFC, amygdale, and hippocampus) and they have significant influence on extinction learning process. The effect of stress hormones on fear extinction is modulated by endogenous hormone levels, manipulation time and gender. An appropriate level of NE is vital to the effect of fear extinction training after trauma. Both an overly high or an overly low level of NE are detrimental to the fear extinction training. After a trauma, the NE level sharply increases and then it decreases over time. Therefore, at different time points, the level of NE should be manipulated for the best function of the training. If the training happens soon after the trauma, its effectiveness can be enhanced by reducing NE to an ideal level;in contrast, a delayed extinction training benefits from raising up the NE level to a proper level. NE affects extinction training through influencing the interaction between amygdale and vmPFC: as the excitatory input from amygdale to vmPFC maintains fear memory, an ideal level of NE could inhibit the activity of amygdala and therefore optimize training outcome. The effect of GCs on fear extinction training depends on its manipulation time. GCs are usually manipulated at three time points: before and after the encoding of extinction memory and before the retrieval of extinction memory. At different manipulation time, GCs cause different alterations in the amygdala-hippocampal-prefrontal cortex network, which leads to the different effects on training. In particular, the pre-encoding GCs manipulation can promote the encoding of extinction memory by inhibiting amygdala activity and enhancing the functional connectivity between vmPFC and hippocampus. The pre-retrieval GCs manipulation can impair the retrieval of extinction memory by imposing an opposite effect on the same neural circuits. The post-encoding GCs manipulation has a complex effect on extinction memory and its underlying mechanisms remain unclear. The effect of stress hormones on fear extinction is influenced by gender. High-estradiol women have better extinction learning performance than low-estradiol women due to the promotive effect of estradiol on vmPFC-amygdala conectivity. It is also suggested that men can benifit from estradiol which is synthesized via the enzyme aromatase from circulating testosterone.The intereaction effect of stress homones and sex homones is still under investigation.There are three potential directions for the future research. First, it is suggested that GCs induced memory enhancement depends on noradrenergic activation, whereas the interative effect of GCs and NE on fear extinction remains unclear. Future research should investigate how GCs interact with NE to influence extinction learning. Second, future research should validate whether stress hormones and sex hormones could be biomarkers of treatment outcomes. Finally, future research should explore the therapeutic efficacy of stress hormones in the treatment of different disorders.