Portretfoto Ingo Willuhn

Willuhn Group

A map of dopamine signals across the brain

Dopamine signals in the brain are critical for motivated behavior. However, their regional specificity and the precise information conveyed by dopamine signals is under debate. For a long time, the idea dominated that dopamine encodes a reward-prediction error and that this signal is broadcasted uniformly throughout the brain. Researchers from the Netherlands Institute for Neuroscience now demonstrate that this prediction error is restricted to a specific portion of the striatum and that dopamine signals are also otherwise regionally heterogeneous.

Dopamine neurotransmission is pivotal for neuronal processing of, and behavioral responding to, appetitive and aversive stimuli. The dopamine system is thought to be dysregulated in many psychiatric disorders. The largest releasable pool of dopamine is found in the striatum, a large brain nucleus that is the main input structure of the basal ganglia and the primary projection target of midbrain dopamine neurons. The striatum crucially mediates dopamine’s role in motivated behavior. Although it is undisputed that striatal dopamine plays a prominent role in motivated behavior and learning, the precise information content of dopamine signals as such is under active debate.

The researchers found that dopamine release is, regionally, extremely heterogeneous in many aspects and that a prediction error-like signal is predominantly found in the relatively small limbic domain of the striatum. “Despite all heterogeneity, another striking organizing principle is that stimulus valence directs dopamine concentration homogeneously across all regions which means that appetitive stimuli increase dopamine and aversive stimuli decrease dopamine” says Ingo Willuhn, group leader at the Netherlands Institute for Neuroscience.

Willuhn: “Until now both the lack of neuro-measurement tools that can cover all of the relevant pathways, as much as the lack of simultaneous investigation across different regions of the striatum hindered research into the precise information conveyed by dopamine signals”. For the first time, the scientists looked at six regions simultaneously. Using an electro-analytic method, they tracked second-by-second dopamine release in all functionally relevant domains of the striatum of rats across behavioral conditioning.

These findings contribute to unraveling the long-standing question of how regional dopamine in the striatum realizes its many functions.

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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