This pre-clinical research group headed by Ingo Willuhn is embedded in a larger clinical research team (led by Damiaan Denys, AMC Psychiatry) that is driven by the central question: “How do we control our behavior?”. The Neuromodulation and Behavior group is specifically interested in “compulsivity” and the effects of “deep-brain stimulation” on compulsive behavior. Our group 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 the conclusions from our basic science findings in the clinical setting. Our research tools include behavioral (e.g., signal attenuation, Vogel conflict) and genetic (SAPAP3 mice) animal models and methods for intracerebral stimulation (e.g., DBS, optogenetics, pharmacogenetics) in freely moving rodents, in combination with tests for emotional and cognitive behavior (in set-ups such as elevated plus maze and operant chambers), neurochemical measurements (e.g., microdialysis, fast-scan cyclic voltammetry), and electrophysiological recordings (single-unit activity and local field potentials (LFPs) combined with simultaneous reverse dialysis). Furthermore, we established pharmacologic and functional magnetic resonance imaging (phMRI and fMRI) in rodents to detect the effects of drugs, DBS, and optical stimulation throughout the brain. Below a summary of the lab projects:
1. Coordination of regional dopamine release in the striatum during habit formation and compulsive behavior (future PhD student and postdoc positions). The aims of these PhD/postdoc projects will be to investigate the involvement of the sequential recruitment of dopamine release in limbic and sensorimotor striatum in the transition from goal-directed actions to habitual execution of actions. Furthermore, we aim to test whether “dysregulated” habits contribute to compulsive behavior (drug abuse and other behaviors) and whether this is driven by altered coordination of dopamine signaling in limbic and sensorimotor striatum. These aims will be addressed using chronically implanted electrode arrays for fast-scan cyclic voltammetry (FSCV) in behaving animals and virus-based gene delivery for in vivo optogenetics in transgenic rats.
2. The role of striatal dopamine in flexibility and in the effects of neuromodulation in cortico-striatal-thalamo-cortical (CSTC) circuits on motivated behavior (Marianne Klanker). Marianne focuses on the role of dopamine in reversal learning and the effects of DBS in CSTC circuits on motivated behavior and dopamine release. Specifically, she combines DBS in several subcortical target areas with measurements of phasic dopamine release in the striatum using FSCV in behaving animals.
3. Perturbation of functional brain connectivity in a rat model of OCD and identification of crucial DBS targets (Soon-Lim Shin).
To study neural correlates of compulsive behavior, Soon-Lim measures LFPs in CTSC circuits in an OCD model, where repeated quinpirole injections produce compulsive choice in a rat maze. In another project, she Lim optogenetically stimulates the internal capsule while measuring single-cell responses and LFPs in the prefrontal cortex and other relay stations of CSTC circuits to identify projections that are crucial for successful DBS treatment.
4. Effects of DBS and developmental drug exposure on functional connectivity in rat brain circuits (Maik Derksen). DBS in CSTC circuits has proven to be an effective treatment in OCD. By conducting fMRI studies (resting state) in awake animals, 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. The role of stress in behavioral and genetic models of compulsive behavior (Isabell Ehmer). Isabell aims to increase our understanding of compulsivity a) by testing the impact of stress on compulsive grooming and habit formation in a mutant mouse model of OCD, b) by collecting electrophysiological recordings in the dorsal striatum to find out how stress affects the 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. 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.