In Stephen King’s 1981 novel Cujo (adapted to film in 1983), a boy and his mother are trapped in their car as a rabid Saint Bernard dog named Cujo, a good boy gone bad, aims to kill them. If you were a character in the book and survived this ordeal, what might be the possible consequences for you following such a brutal attack?

First, if you were bitten, you would need to get a vaccination as well as any additional medical care. Second, this event is likely to leave some emotional marks as well. Some people might start to feel less at ease in the company of dogs or feel intimidated by them. This fear might not only apply to Saint Bernards but also be generalized to other large dogs or dogs in general, large or small. The generalization will apply not only to stimuli (from Cujo to dogs in general) but also to contexts (from a car to parks, streets, and so on).


In extreme cases, intense experiences such as these might lead to the development of anxiety- and stress-related disorders, for instance, phobias or posttraumatic stress disorder (PTSD). The effects of stress hormones and additional modulators on the brain are the main reason why stressful events are so strongly remembered and easily generalized. In a recently published review, we show that stress itself can also aid in providing a solution.

Cortisol can improve exposure therapy

Let’s go back to the Cujo incident. Imagine that even after the scary experience, you still pay regular visits to your friend, who owns a dog. With multiple safe experiences with this dog, and perhaps other dogs in the park, you gradually learn that the equation “dog = danger” is not necessarily correct, and that “dog = safe” might apply as well. As a result, your fear response to dogs decreases. This learning is termed extinction learning and is the main underlying mechanism of exposure therapy, cognitive-behavioral psychotherapy aimed at the treatment of anxiety, PTSD, and additional disorders. But there’s a catch: since extinction learning does not erase the original fear memory, relapse is likely to occur. This, of course, is a major limitation for the long-term success of treatment.

In recent years, several research groups, ours included, have risen to the challenge, aiming to optimize extinction learning in various ways: cognitive/behavioral modifications (Schiller et al., 2010), brain stimulation (Dittert, Hüttner, Polak, & Herrmann, 2018), or pharmacological interventions, such as cannabinoids (de Bitencourt, Pamplona, & Takahashi, 2013). A particularly promising pharmacological candidate is cortisol, a glucocorticoids hormone. Studies have shown its beneficial effects in exposure therapy, e.g., for PTSD or phobias (de Quervain et al., 2011; Yehuda et al., 2015), as it leads to longer-term results and reduction in symptoms. But how does it work?


Cortisol creates stronger and more generalized memories

Cortisol is secreted from the adrenal gland in a circadian (daily) rhythm; its levels are highest shortly after we wake up, in what is termed the cortisol awakening response. In addition, cortisol levels sharply increase after we experience a stressful event. Here, cortisol has an important role in adjusting our physiological and behavioral response at the time of the event and returning the body to daily routine afterward.

One important role of cortisol is the modulation of learning and memory processes. In particular, cortisol leads to a memory consolidation mode, following which the memories of emotional events will become stronger and more persistent. At the same time, the retrieval of previous events is given a lower priority. This memory consolidation mode was suggested to explain the beneficial effects of cortisol in exposure therapy (de Quervain, Schwabe, & Roozendaal, 2017). However, previous studies did not take into account the question of the timing of cortisol administration (before, during, or after sessions?) and the effects of these variations on extinction vs. relapse.

This question has been the focus of our research group in the last several years. To answer it, we examined the effects of stress/cortisol treatment on extinction learning in healthy participants using two paradigms (contextual fear conditioning and predictive learning task) which allow the examination of renewal, that is, relapse after context change. Importantly, the timing of treatment varied between our studies, and so stress/cortisol was introduced either before extinction learning, after extinction learning, or before a retrieval test. Mainly, we aimed to reveal the right timing needed to achieve stronger and more generalized extinction memory.

Timing is (almost) everything

The results of our work are summarized in the STaR (Stress Timing affects Relapse) model (see Figure). In short, timing does make a difference. First, we found that stress/cortisol before extinction learning leads to a stronger, context-independent extinction memory, which is more resistant to renewal. This means that, under these conditions, extinction (i.e., safe) memories created in one context (e.g., in the clinic) will be generalized to other contexts (e.g., home, school, office).

Image republished with permission from Elsevier from

The advantages of this for daily life improvements in anxiety and PTSD are obvious. Second, we found that stress/cortisol after extinction learning also enhances extinction, but in this case, memories are not easily generalized. Finally, exposure to stress/cortisol before a retrieval test led to an impairment in the retrieval of extinction memories, making relapse more likely to occur. Furthermore, we found that these timing-dependent effects of stress/cortisol on extinction memories are modulated by the amygdala, hippocampus complex, and pre-frontal cortex, brain areas that have a critical role in emotional learning and memory.

Our STaR model provides further support for the use of cortisol in exposure therapy and suggests that cortisol administration before extinction is the key for maximal benefits. Our findings may also suggest additional modifications of treatment, for instance, time-of-day variations that will harness the natural daily variations of cortisol (Lass-Hennemann & Michael, 2014). In addition, our work demonstrates the importance of further research on factors that might affect cortisol levels (either in general or in response to stress), such as circadian disruption (e.g., a result of shift work), chronic stress, sex hormones (e.g., during the female menstrual cycle), health status, and the use of additional medications. Taken together, our model shows that it is possible to fight fire with fire: Stress hormones, which initially led to the problem, can be used as part of the solution.

These findings are described in the article entitled How stress and glucocorticoids timing-dependently affect extinction and relapse, recently published in the journal Neuroscience & Biobehavioral Reviews.

Funding sources: Our work on memory extinction and reconsolidation is supported by Project A09 of the Collaborative Research Center 1280 “Extinction Learning” (PIs Christian J. Merz & Oliver T. Wolf).

Full citation:

  • Meir Drexler, S., Merz, C. J., Jentsch, V. L., & Wolf, O. T. (2019). How stress and glucocorticoids timing-dependently affect extinction and relapse. Neuroscience & Biobehavioral Reviews, 98, 145–153;


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  2. de Quervain, D. J.-F., Bentz, D., Michael, T., Bolt, O. C., Wiederhold, B. K., Margraf, J., & Wilhelm, F. H. (2011). Glucocorticoids enhance extinction-based psychotherapy. Proceedings of the National Academy of Sciences, 108(16), 6621–6625.
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About The Author

Shira Meir Drexler is a postdoctoral researcher in the Department of Cognitive Psychology at Ruhr University Bochum, Germany.

My research focuses on the effects of stress and cortisol on emotional learning and memory, in particular, extinction and reconsolidation of fear memories. I am interested in the relevance of these mechanisms to the understanding and treatment of fear- and anxiety- related disorders. As part of my research work I have gained experience in stress induction and conditioning paradigms in both humans and (earlier in my career) in rats.

I am now working on an eye-opening (pun intended) new project on learning and stress. Details will follow.

Christian J. Merz is a research scientist and professor of Cognitive Psychology at Ruhr University Bochum.

In particular, my research interests concern the investigation of experimental questions regarding learning and memory processes, cognitive neuroscience, Psychoneuroendocrinology, their clinical applications, and neuronal correlates. One focus of my research is the exploration of the influence of stress and sex hormones on emotional learning. In humans, the sex-dependent effect of the stress hormone cortisol on the fear acquisition and fear extinction was demonstrated for the first time. In several fMRI studies (Merz et al., 2010a, 2012a, 2013, 2014a; Tabbert et al., 2010), exogenous cortisol administration as well as acute stress reduced conditioned responding in the fear circuit in men but enhanced it in women. However, this pattern only occurred in women taking oral contraceptives. Besides, the neuronal correlates of fear extinction are also affected by the intake of oral contraceptives (Merz et al., 2012b). Furthermore, a direct effect of the cortisol administration on the fear extinction network could be observed (Merz et al., 2014a; 2018a).

Valerie L. Jentsch is a postdoctoral researcher in the Department of Cognitive Psychology at Ruhr University Bochum, Germany.

My research focuses on the effects of stress and stress hormones on emotional learning and memory processes, in particular on the neural mechanisms of extinction learning and its retrieval. In my work, I, therefore, combine functional neuroimaging with acute stress induction methods or pharmacological manipulations in order to unravel the underlying mechanisms mediating such learning processes and their alterations by stress in healthy humans.

Another main research question I address in my work is how acute stress affects emotion regulatory processes and vice versa. In particular, I am interested in how stress may alter the ability to successfully regulate our emotions in adverse situations but also how emotion regulation skills alter an individual’s psychological and neuroendocrine response to acute stressors.

Oliver T. Wolf is a research scientist and professor of neuroscience at Ruhr-Universität Bochum.

Our laboratory investigates how stress influences learning and memory processes in humans. The focus is on stress hormones, most notably cortisol the end product of the hypothalamus, pituitary adrenal axis. Stress is induced in the laboratory in an experimental fashion using well-established paradigms. Moreover, pharmacological approaches are taken. We could show that stress and its associated increase in the stress hormone cortisol enhances memory consolidation but impairs memory retrieval. Both effects are more pronounced for emotional arousing material. Functional imaging studies indicate that these effects reflect specific actions of the stress hormone on the human amygdala and hippocampus (Wolf, 2009).