Research projects

The Willuhn lab is interested in the neurobiology of compulsive behavior and in mechanisms through which actions become habitual and outcome-independent. At the very core of the research is the study of rodent behavior, whereby the lab’s interests are both physiological, normal functions such as behavioral flexibility and models for pathological, compulsive behavior such as drug addiction and obsessive-compulsive disorder. Basal ganglia interactions with the cortex and the modulatory role of dopamine in these structures are the primary focus.

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 such behavioral testing of freely moving transgenic rats and mice with state-of-the-art research tools including 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. Below a summary of our research projects:

1. Coordination of regional dopamine release in the striatum during habit formation and compulsive behavior (Wouter van Elzelingen and Rudolf Faust).

Rudi and Wouter investigate the neurocircuitry underlying differential recruitment of dopamine release in limbic and sensorimotor regions of the striatum (Rudi) and its involvement in the transition from goal-directed to habitual execution of actions (Wouter). Furthermore, we aim to test whether “dysregulated” habits contribute to compulsive behavior (e.g., drug abuse) and whether this is driven by altered coordination of dopamine signaling in limbic and sensorimotor striatum. These aims will be addressed using electrode arrays for fast-scan cyclic voltammetry (FSCV) in both anesthetized and behaving animals combined with virus-based gene delivery for in vivo optogenetics in transgenic rats.

2. The role of striatal cholinergic interneurons in compulsivity and its behavioral components (Jessica Goedhoop).

Jessica studies the role of cholinergic interneurons (CIN) in the striatum in habit formation and compulsive behaviors, and how CIN affect striatal dopamine signaling. She pursues these aims by applying voltammetric (FSCV) measurements and optogenetic/chemocogenetic interventions targeting CIN in awake behaving, transgenic rats.

3. Perturbation of functional brain connectivity in compulsivity (Tara Arbab).

To study neural correlates of compulsive behavior, Tara measures neuronal firing and LFPs in CTSC circuits in behaving rats. In her experiments, she investigates the neural mechanisms responsible for the transition from flexible to inflexible actions. One of the aspects Tara focuses on are the brain circuits that enable disengagement from one behavior in order to perform another.

4. Effects of DBS and developmental drug exposure on functional connectivity in rat brain circuits (Maik Derksen).

DBS in cortico-striatal-thalamo-cortical (CSTC) circuits has proven to be an effective treatment in OCD and other psychiatric disorders. By conducting fMRI studies in awake rats, Maik assesses changes in functional connectivity within CSTC circuits resulting from DBS and optogenetic stimulation in various target areas. In a second project, in collaboration with Dr. Liesbeth Reneman (Radiology, AMC), Maik measures changes in functional brain connectivity after MDMA exposure using phMRI.

5. behavioral & genetic models of compulsive behavior: Interaction of different types of compulsivity and involvement of habits (Isabell Ehmer).

Isabell aims to increase our understanding of compulsivity a) by testing and comparing different automatic behaviors (compulsive grooming, habit formation, signal attenuation) in a mutant mouse model of OCD, b) by collecting FSCV recordings in the striatum of these mice to clarify the role dopamine and elucidate the putative relative switch in neural activity from dorsomedial to dorsolateral striatum that is associated with the development of habit-like responding, and c) by optogenetic manipulation of CTSC circuits in these models.

6. The neural code of Striatal projection neurons and MIDBRAIN dopamine neurons during the automation of behavior (Bastijn van den Boom).

Bastijn focuses on the role of both dopamine neurons in the midbrain and their target, medium spiny projection neurons, in the striatum during automation of motivated behavior and stereotypies. Specifically, he combines behavioral testing with simultaneous deep-brain, one-photon calcium imaging using implantable miniaturized fluorescent microscopes to visualize real-time neuronal activity over extended periods of task performance.

7. Computational modeling of neurotransmitter release and neuronal activity involved in the automation of motivated behavior (Pascal Warnaar).

Pascal applies his abilities in computational modeling and his analytical skills to data obtained in different projects of the lab. This includes both neurotransmitter release (FSCV) and neuronal activity (calcium imaging) in the striatum and the prefrontal cortex. In the future, he will monitor changes in these variables in novel reinforcement learning tasks.

8. DBS-evoked modulation of global neural activity and reward-driven behavior (Chris Klink).

The effects of DBS are not limited to the local area where stimulation is applied. By combining DBS with fMRI and cognitive tasks that involve reward-based decisions and cognitive flexibility, Chris aims to identify functional neural networks involved in the DBS treatment of depression and OCD (in collaboration with Roelfsema group).

9. Neural correlates of compulsivity in a genetic model of OCD and the effects of DBS in  corticostriatal circuits (Mariana Duque Quintero)

Mariana studies corticostriatal function during the expression of compulsive behavior and how deep brain stimulation; a therapeutic alternative for OCD patients, affects altered corticostriatal activity, and can ultimately reduce compulsive symptoms. Her goal is to identify network and single neuron correlates of compulsivity in corticostriatal circuits using electrophysiology and calcium imaging in Sapap3 mice, a genetic model of OCD.

10. Dissecting the behavioral function of region-specific pre- and postsynaptic dopamine transmission (Lizz Fellinger)

In an effort to understand how the regional involvement of dopamine signaling promotes healthy and pathological behavioral functions, Lizz employs behavioral paradigms that disentangle two of dopamine’s main functions: reward prediction and movement. Lizz applies in vivo fast-scan cyclic voltammetry (FSCV) and calcium imaging (fiber photometry or miniaturized fluorescent microscope) in several transgenic rat lines to measure pre- and image postsynaptic dopamine signaling respectively in a specific striatal region and/or related to a specific basal ganglia output pathway (“D1” or “D2”).