Research
Survival depends on the ability to adapt rapidly, a process critically shaped by dopamine (DA). By encoding reward prediction and energizing selected motor programs, DA enables animals and humans to balance effort, risk, and benefit. When this system is disrupted, consequences range from loss of motor control in Parkinson’s disease to compulsive behaviours in addiction. Yet, despite decades of research, how DA drives behaviour through striatal circuits remains incompletely understood.
The striatum has long been described as a dual system: DA excites D1 receptor neurons to promote movement, while it inhibits D2 neurons to suppress it. Our recent discovery of a third population, D1/D2 co-expressing neurons (D1/D2-MSNs), overturns this model. Strikingly, these neurons project to inhibitory basal ganglia nuclei where D1 receptor activation can paradoxically enhance inhibition, revealing that DA can suppress as well as facilitate action. Understanding how this hybrid pathway interacts with classical ones is key to revising DA theories and functions.
This project will deliver the first systematic comparison of all three striatal pathways, asking how distinct DA firing patterns (phasic bursts, tonic baseline, pauses) recruit them, shape synaptic plasticity, and regulate motor learning. Its originality lies in a uniquely multilevel approach: bridging synaptic and microcircuit mechanisms ex vivo with pathway dynamics during behaviour in vivo. Exclusive genetic access to D1/D2 neurons, combined with convergent methods such as electrophysiology, single-cell sequencing, in vivo imaging of calcium and dopamine, optogenetics, molecular mapping, and machine-learning-based motion tracking; ensures robust and cross-validated insights.
By integrating the overlooked D1/D2 pathway into the DA framework, the project will provide a transformative model of basal ganglia computation, clarifying how DA both drives and restrains action, and opening new avenues for treating disorders of DA imbalance.