Portretfoto Ingo Willuhn

Willuhn Group

A yet unknown neural mechanism of habit formation identified

There is little doubt that dopamine transmission in the brain plays a role in habit formation. However, two central questions that remain are which of the different dopamine projection pathways in the brain are critical, and how pathway-specific dopamine signaling changes over the course of habit development. Researchers from the Netherlands institute of Neuroscience (NIN) now show findings that challenge the status quo in the field of behavioral neuroscience.

“It is widely assumed that dopamine signaling ceases once a habit is fully developed”, says Ingo Willuhn, researcher at the Netherlands Institute for Neuroscience and Amsterdam UMC. Other theoretical models assume that during the process of habit development dopamine signaling shifts between different regions of the striatum – a brain area crucial for motor function and reward learning. For example, dopamine release in the limbic and associative regions of the striatum is important when a new behavior is learned, whereas dopamine in the sensorimotor striatum is coming ‘online’ later with increasing practice of a behavior and is thought to be critical for habit information. “With this study, we reform the widely accepted theoretical models on dopamine signaling with the finding that striatal dopamine signals neither cease nor shift between regions during habit formation,” says Willuhn.

Tracking striatal dopamine during the development of habitual behavior

In this study, Willuhn and his colleagues tracked striatal dopamine signaling during the development of habitual behavior. In the associative striatum – a brain region previously associated with non-habitual behavior – dopamine release increased during action initiation in habitual rats and decreased during action completion, whereas non-habitual rats showed the opposite pattern. Optogenetic stimulation of dopamine release in this region was sufficient to accelerate habit information. Answering these questions has been hindered both by lacking appropriate neuro-measurement tools to record brain activity from all the relevant pathways, as well lacking behavioral testing paradigms with sufficient sensitivity. However, by utilizing an optimized voltammetric technique, members of the Willuhn lab measured second-by-second dopamine release simultaneously in limbic, associative, and sensorimotor domains of the striatum across ten weeks of behavioral training in a novel custom-designed task.

Identification of brain mechanisms that drive the development of habitual behavior has been of great interest for decades. This is because this type of action automation is a fundamental building block of behavior and, at the same time, is thought to be dysregulated in many psychiatric disorders. Willuhn: “This research represents a step forward in our understanding of the behavioral function of dopamine signaling in the striatum”.

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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