Targeting three thalamic circuits in Parkinson's disease

Targeting three distinct thalamic circuits could help improve locomotion, motor learning and depression in PD, respectively. In a male mouse model of acute PD, inhibiting a subpopulation of parafascicular thalamus cells that project to the caudate putamen — via a tool compound that inhibits a transgenic mutant M4 muscarinic receptor expressed in those cells — rescued locomotion defects. In the same model, strengthening a subpopulation of parafascicular thalamus cells projecting to the subthalamic nucleus via transgenic expression of opsins rescued motor learning defects, and activating another subset of cells projecting to the nucleus accumbens via optogenetics improved depression.

Also in the model, local infusions of a nicotinic acetylcholine receptor agonist that strengthened synaptic signaling to the subthalamic nucleus improved motor learning compared with vehicle; an antagonist of a different nicotinic acetylcholine receptor that decreased signaling to the caudate putamen rescued motor defects compared with vehicle; and an antagonist of another nicotinic acetylcholine receptor in the nucleus acumens improved depression behavior compared with vehicle. Next steps include determining if modulating the circuits has the same effects in females, and testing compounds in a primate model of PD...