The parafascicular nucleus (Pf) of the thalamus provides major projections to the basal ganglia, a set of subcortical nuclei involved in action initiation. Here, we show that Pf projections to the subthalamic nucleus (STN), but not to the striatum, are responsible for movement initiation. Because the STN is a major target of deep brain stimulation treatments for Parkinson’s disease, we tested the effect of selective stimulation of Pf-STN projections in a mouse model of PD. Bilateral dopamine depletion with 6-OHDA created complete akinesia in mice, but Pf-STN stimulation immediately and markedly restored a variety of natural behaviors. Our results therefore revealed a functionally novel neural pathway for the initiation of movements that can be recruited to rescue movement deficits after dopamine depletion. They not only shed light on the clinical efficacy of conventional STN DBS but also suggest more selective and improved stimulation strategies for the treatment of parkinsonian symptoms.

Highlights d Three populations of VTA DA neurons control the impulse vector d DA populations differ in associated force direction, magnitude, and time course d Optogenetic excitation and inhibition produce opposite directions of force exertion d Optogenetic stimulation regulates anticipatory licking

The Ventral Tegmental Area (VTA) is a major source of dopamine, especially to the limbic brain regions. Despite decades of research, the function of VTA dopamine neurons remains controversial. Here, using a novel head-fixed behavioral system with five orthogonal force sensors, we show for the first time that distinct populations of VTA dopamine activity 5 precisely represent the impulse vector (force exerted over time) generated by the animal.Optogenetic excitation of VTA dopamine neurons quantitatively determines impulse in the forward direction, and optogenetic inhibition produces impulse in the backward direction. At the same time, these neurons also regulate the initiation and execution of anticipatory licking. Our results indicate that VTA controls the magnitude, direction, and duration of force used to move 10 towards or away from any motivationally relevant stimuli.One Sentence Summary: VTA dopamine bidirectionally controls impulse vector and anticipatory behavior 15

The ventral tegmental area (VTA) is a midbrain region implicated in a variety of motivated behaviors. However, the function of VTA GABAergic (Vgat+) neurons remains poorly understood. Here, using threedimensional motion capture, in vivo electrophysiology, calcium imaging, and optogenetics, we demonstrate a novel function of VTA Vgat+ neurons. We found three distinct populations of neurons, each representing head angle about a principal axis of rotation: yaw, roll, and pitch. For each axis, opponent cell groups were found that increase firing when the head moves in one direction and decrease firing in the opposite direction. Selective excitation and inhibition of VTA Vgat+ neurons generate opposite rotational movements. Thus, VTA Vgat+ neurons serve a critical role in the control of rotational kinematics while pursuing a moving target. This general-purpose steering function can guide animals toward desired spatial targets in any motivated behavior.

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