关键词: 恐惧消退, 糖皮质激素, 去甲肾上腺素, 神经机制

Abstract: 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 point, 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 by reason of 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,but the interative effect of GCs and NE on fear extinction is remain 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.

Key words: Fear extinction, glucocorticoids, norepinephrine, neural mechanisms