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.

No abstract

Most adaptive behaviors require precise tracking of targets in space. In pursuit behavior with a moving target, mice use distance to target to guide their own movement continuously. Here, we show that in the sensorimotor striatum, parvalbumin-positive fast-spiking interneurons (FSIs) can represent the distance between self and target during pursuit behavior, while striatal projection neurons (SPNs), which receive FSI projections, can represent self-velocity. FSIs are shown to regulate velocity-related SPN activity during pursuit, so that movement velocity is continuously modulated by distance to target. Moreover, bidirectional manipulation of FSI activity can selectively disrupt performance by increasing or decreasing the self-target distance. Our results reveal a key role of the FSI-SPN interneuron circuit in pursuit behavior and elucidate how this circuit implements distance to velocity transformation required for the critical underlying computation.

Many studies in neuroscience use head-fixed behavioral preparations, which confer a number of advantages, including the ability to limit the behavioral repertoire and use techniques for large-scale monitoring of neural activity. But traditional studies using this approach use extremely limited behavioral measures, in part because it is difficult to detect the subtle movements and postural adjustments that animals naturally exhibit during head fixation. Here we report a new head-fixed setup with analog load cells capable of precisely monitoring the continuous forces exerted by mice. The load cells reveal the dynamic nature of movements generated not only around the time of taskrelevant events, such as presentation of stimuli and rewards, but also during periods in between these events, when there is no apparent overt behavior. It generates a new and rich set of behavioral measures that have been neglected in previous experiments. We detail the construction of the system, which can be 3D-printed and assembled at low cost, show behavioral results collected from head-fixed mice, and demonstrate that neural activity can be highly correlated with the subtle, whole-body movements continuously produced during head restraint.

25Most adaptive behaviors require precise tracking of targets in space. In pursuit 26 behavior with a moving target, mice use distance to target to guide their own movement 27 continuously. Here we show that in the sensorimotor striatum, parvalbumin-positive fast-28 spiking interneurons (FSIs) can represent the distance between self and target during 29 pursuit behavior, while striatal projection neurons (SPNs), which receive FSI projections, 30 can represent self-velocity. FSIs are shown to regulate velocity-related SPN activity during 31 pursuit, so that movement velocity is continuously modulated by distance to target. 32 Moreover, bidirectional manipulation of FSI activity can selectively disrupt performance 33 by increasing or decreasing the self-target distance. Our results reveal a key role of the 34 FSI-SPN interneuron circuit in pursuit behavior, and elucidate how this circuit implements 35 distance to velocity transformation required for the critical underlying computation. 36 37 38 39 40 41 42 43 44 45 46 47 48 50Whether pursuing a prey or approaching a mate, natural behaviors often involve 51 continuous tracking of targets in space. Yet the neural substrates of such pursuit behavior remain 52 poorly understood. Technical limitations have prevented the study of natural pursuit behavior in 53 freely moving animals [1][2][3][4] . In this study we designed a new behavioral task for freely moving 54 mice. In this task, mice follow a continuously moving target that delivers sucrose reward. Using 55 3D motion capture, we were able to track not only the position of the animal but also the distance 56 to target, a crucial variable for accurate pursuit. This task allows us to compare, for the first 57 time, continuous behavioral variables and neural activity recorded at the same time in freely 58 moving animals. 59 We studied the contribution of the inhibitory interneuron circuit in the sensorimotor 60 striatum to pursuit behavior. The striatum is a major basal ganglia (BG) nucleus that has been 61 implicated in motor control, compulsive behavior, and habit formation [5][6][7][8][9] . A critical circuit in 62 the striatum is formed by the parvalbumin positive GABAergic fast-spiking interneurons (FSIs) 63 and striatal projection neurons (SPNs) 10, 11 . FSIs, which constitute less than 1% of the striatal 64 neuronal population, receive glutamatergic inputs from the cerebral cortex and project to many 65 SPNs, which make up over 90% of the population 12, 13 . The sensorimotor striatum is 66 characterized by the highest expression of FSIs. Reduced numbers of FSIs is associated with 67 neuropsychiatric disorders such as Tourette's syndrome and obsessive-compulsive disorder 14, 15 . 68 Behavioral studies have also implicated the FSIs in choice behavior and habitual lever pressing 69 13, 16 . 70 Recent work has shown that sensorimotor SPN activity is often highly correlated with 71 movement velocity 17, 18 , and stimulation of striatal output alters movement velocity frequency-72 dependently 19 ....