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. Characterizing dysfunctional neuronal network activity underlying compulsivity (Tara Arbab).
Compulsivity is a hallmark of many psychiatric disorders. In obsessive-compulsive disorder, electrical stimulation throughout basal ganglia is used to treat compulsivity. However, the mechanism by which this stimulation works is poorly understood, as the physiological manifestation of compulsivity itself is yet to be discovered. Across different projects, Tara aims to identify electrophysiological correlates of compulsive behavior in human OCD patients and rodent models of compulsivity, at the level of single neurons, neural networks, and neuronal communication between brain areas. Identifying these signatures of compulsivity paves the way toward improving treatment thereof, by specifically targeting the aberrant neural activity that causes it.
2. General principles of deep-brain stimulation and functional activity in cortico-striatal circuits (Bastijn van den Boom)
Deep-brain stimulation (DBS) of the internal capsule is used to treat therapy-resistant obsessive-compulsive disorder (OCD) patients. However, the underlying mechanisms remain unclear. Bastijn combines behavioral testing of a compulsive-like mouse model with DBS, simultaneous one-photon calcium imaging using implantable miniaturized fluorescent microscopes (so-called miniscopes) to visualize real-time neuronal activity, and optogenetic manipulations. In addition, he uses miniscopes and fiber photometry to image genetically defined cortico-striatal neuronal cell-types in rats during a novel Go/No-go task to disentangle function contribution to action selection and decision making.
3. Neurobiology of compulsive behavior and its components: Tracking prefrontal neuronal activity during habit development (Felice Veen).
Felice her work centers around the study of inflexible behavior and it’s neuronal mechanisms. She uses one-photon calcium imaging employing implantable miniaturized fluorescent microscopes to visualize real-time neuronal activity over the course of habit formation. She aims to identify inter-individual differences in the prefrontal neural correlate of inflexible behavior.
4. Parsing dopamine’s role in learning and motor function (Eugenia Poh).
Appropriate selection of situation-appropriate behaviour in our everyday life requires both learning and motor control, and a key neuromodulator involved in these processes is dopamine. Eugenia’s research focuses on understanding how dopamine signalling varies within functionally distinct regions of the striatum, a large input structure of the basal ganglia. In particular, she records real-time dopamine release using fast-scan cyclic voltammetry while subjects perform a behavioural task that considers reward prediction error and movement.
5. 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.
6. 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 fiber photometry and optogenetics in freely behaving animals to measure and manipulate pre- and postsynaptic dopamine signaling in several striatal regions and/or related to a specific basal ganglia output pathway (“D1” or “D2”).