Portretfoto Ingo Willuhn

Willuhn Group

What happens to our dopamine system when we experience aversive events?

A new study at the Netherlands Institute for Neuroscience has examined how the dopamine system processes aversive unpleasant events.

It is well known that the dopamine system plays a crucial role in motivation, learning and movement. One of the main functions of dopamine is to predict the occurrence of rewarding experiences and the availability of rewards in our environment. In this context, the dopamine system informs our brains about so-called ‘reward prediction errors’ – the difference between received and predicted rewards. Dopamine neurons become more active when a reward occurs unexpectedly or if it is bigger than expected, and they show depressed activity when we receive less reward than predicted. These error signals help us to learn from our mistakes and teach us how to achieve rewarding experiences.

Rewarding versus aversive stimuli

While a large number of studies has focused on the relationship between dopamine release and rewarding stimuli, few have looked at the effect of unpleasant and aversive stimuli on dopamine. Although the results of these few experiments have been inconsistent, it has become clear that aversive stimuli have an impact on the dopamine system. But there is an active debate among neuroscientists on what precise role dopamine neurons play in processing aversive stimuli: Does their activity change in response to aversive events? Do they predict aversive events? Do they encode an aversive prediction error?

New findings on the role of dopamine in aversive events

A new study at the Netherlands Institute for Neuroscience has examined how the dopamine system processes aversive events. The team around PhD student Jessica Goedhoop and group leader Ingo Willuhn exposed rats to white noise in combination with stimuli that predicted the white noise, while they measured the release of dopamine in the brain. White noise is a well-known example of an unpleasant auditory stimulus for rats.

The researchers found that the release of dopamine gradually decreased during the exposure to white noise. Furthermore, after consistent presentation, stimuli that occurred a few seconds before white-noise exposure began to have the same depressing effect on dopamine neurons. However, in contrast to how it processes rewards, dopamine did not encode a prediction error for this aversive stimulus. Overall, this new study demonstrates that the dopamine system helps the brain to anticipate the occurrence and duration of unpleasant events, but without taking prediction errors into account.

Group leader Ingo Willuhn: ‘This is a very thorough and systematic study that takes a lot of variables into account. The results give us a better understanding of the role of dopamine release in processing aversive events. There is a growing interest into the role of dopamine in aversion. We used a novel aversive stimulus that enabled to conduct a more thorough analysis of dopamine than previously possible.’

Addictive drugs hijack and amplify dopamine signals and induce exaggerated, uncontrolled dopamine effects on neuronal plasticity. This study brings us closer to understanding the underlying mechanism behind this pathological phenomenon.

Source: eLife

Portretfoto Ingo Willuhn

Willuhn Group

Neuromodulation & Behavior

This pre-clinical research group headed by Ingo Willuhn is embedded in a larger clinical research team at the AMC department of Psychiatry. The group is driven by the question: “How do we control our behavior?”. Specifically, the Neuromodulation and Behavior group is interested in the neurobiology of compulsive behavior and in mechanisms through which actions become automatic with a focus on basal ganglia function and dopamine signaling. Furthermore, the group studies the effects of deep-brain stimulation (DBS) on brain and behavior.

What is compulsivity? Compulsivity is behavior that is out of control, behavior we perform despite not wanting to perform it or despite its negative outcome. Compulsive behavior is performed persistently, repetitively, and inflexibly. But how does compulsivity develop? What is its neurobiological basis? To answer these questions, we investigate different aspects of compulsivity (e.g., automation of behavior, cognitive (in-)flexibility) and measure/modulate neuronal activity in the brain simultaneously.

Compulsivity is a core feature in several neuropsychiatric disorders, such as obsessive-compulsive disorder (OCD) and drug addiction. In otherwise therapy-resistant patients of such disorders, DBS has been effective. However, our understanding of the mechanisms of action of DBS is still limited. Therefore, we aim to investigate how DBS affects compulsivity and what the neurobiological basis of these effects is.

Our group has a strong collaborative relationship to the Department of Psychiatry at the Amsterdam Medical Center (AMC) lead by Damiaan Denys and therefore has close ties with clinicians and clinical researchers, providing optimal conditions for a translational and multidisciplinary approach. Specifically, we translate clinical findings from studies in humans into relevant animal models, and vice versa we aim to apply our conclusions in the clinical setting. At the very core of our research is the study of rodent behavior. On one hand, we test compulsive behavior itself by using behavioral, (e.g., signal attenuation, schedule-induced polydipsia), pharmacological (drug self-administration), and genetic (SAPAP3-KO mice) animal models. On the other hand, we study “normal’ behavioral faculties such as habit formation, response flexibility, emotion, and cognition (e.g., elevated plus maze, operant chambers) that may contribute to compulsivity when dysregulated. We combine behavioral testing with state-of-the-art research tools including diverse methods for brain stimulation (e.g., DBS, chemogenetics, optogenetics), neurochemical measurements (e.g., microdialysis, fast-scan cyclic voltammetry), calcium imaging (implantable miniaturized microscopes), and electrophysiological recordings (e.g., single-unit activity, local field potentials (LFPs)). Furthermore, we use functional magnetic resonance imaging (fMRI) in rodents to detect the effects of drugs and DBS throughout the brain.


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