What neurobiological mechanisms are negative expectations based on?

Anxiety, depressed mood, unspecific illness symptoms: Immunotherapies and chemotherapies often have unwanted psychological and physical side effects. Over the course of such therapies, which usually consist of several treatment cycles, these symptoms can intensify and can even be triggered by mere contact with the treatment context (e.g. the hospital environment, smells). This expectation-induced (anticipatory) development of symptoms due to negative experiences of earlier treatments is the consequence of an associative learning process (so-called classical conditioning), and in extreme cases can even lead patients to discontinue their therapy. The molecular and neurobiological bases of negative treatment expectations and their physiological consequences are largely unknown, and are difficult to examine in patients.

The strength of negative treatment expectations depends on the number of previous negative experiences

In Project A10, we want to fill this knowledge gap with the help of animal experiments. In the first funding period, we developed a novel animal model for negative treatment expectations. In experiments with lab rats, we demonstrated that the extent of experimentally induced negative treatment expectations depended on the number of previous negative expectations. In other words, the more frequent the rats’ negative treatment experiences, the stronger were their behavioural symptoms and physical responses. And the rats didn’t forget either – an indication that negative treatment experiences leave a strong memory trace, which presumably has a long-lasting impact in humans too. In our search for the brain regions involved, we were able to identify the insula and the amygdala, among others, as key structures.

Molecular mechanisms and neurobiological foundations

In the second funding period, we want to delve deeper into the molecular and neurobiological mechanisms of negative treatment expectations. What role do the insular cortex and the amygdala play in the development and retrieval of a negative memory trace? To what extent are certain immune messengers involved in this? What happens in the autonomic nervous system during these processes? And does the brain generalize negative experiences to similar situations? In Project A10, we are trying to answer such questions with the help of chemogenetic and pharmacological manipulations and by means of behavioural experiments.

Examining the mechanisms of negative treatment expectations in an animal model can give us a better understanding of these clinically highly relevant processes in humans too. Therefore, we are collaborating with projects examining related questions in healthy people and in patients, with the long-term goal of improving the efficacy and tolerability of therapies.