Nucleus accumbens D1-receptors regulate and focus transitions to reward-seeking action.

It is well established that dopamine transmission is integral in mediating the influence of reward expectations on reward-seeking actions. However, the precise causal role of dopamine transmission in moment-to-moment reward-motivated behavioral control remains contentious, particularly in contexts where it is necessary to refrain from responding to achieve a beneficial outcome. To examine this, we manipulated dopamine transmission pharmacologically as rats performed a Go/No-Go task that required them to either make or withhold action to gain either a small or large reward. D1R Stimulation potentiated cue-driven action initiation, including fast impulsive actions on No-Go trials. By contrast, D1R blockade primarily disrupted the successful completion of Go trial sequences. Surprisingly, while after global D1R blockade this was characterized by a general retardation of reward-seeking actions, nucleus accumbens core (NAcC) D1R blockade had no effect on the speed of action initiation or impulsive actions. Instead, fine-grained analyses showed that this manipulation decreased the precision of animals' goal-directed actions, even though they usually still followed the appropriate response sequence. Strikingly, such "unfocused" responding could also be observed off-drug, particularly when only a small reward was on offer. These findings suggest that the balance of activity at NAcC D1Rs plays a key role in enabling the rapid activation of a focused, reward-seeking state to enable animals to efficiently and accurately achieve their goal.

Subthalamic beta-targeted neurofeedback speeds up movement initiation but increases tremor in Parkinsonian patients.

Previous studies have explored neurofeedback training for Parkinsonian patients to suppress beta oscillations in the subthalamic nucleus (STN). However, its impacts on movements and Parkinsonian tremor are unclear. We developed a neurofeedback paradigm targeting STN beta bursts and investigated whether neurofeedback training could improve motor initiation in Parkinson's disease compared to passive observation. Our task additionally allowed us to test which endogenous changes in oscillatory STN activities are associated with trial-to-trial motor performance. Neurofeedback training reduced beta synchrony and increased gamma activity within the STN, and reduced beta band coupling between the STN and motor cortex. These changes were accompanied by reduced reaction times in subsequently cued movements. However, in Parkinsonian patients with pre-existing symptoms of tremor, successful volitional beta suppression was associated with an amplification of tremor which correlated with theta band activity in STN local field potentials, suggesting an additional cross-frequency interaction between STN beta and theta activities.

Beta Oscillation-Targeted Neurofeedback Training Based on Subthalamic LFPs in Parkinsonian Patients.

Increased oscillatory activities in the beta frequency band (13-30 Hz) in the subthalamic nucleus (STN), and in particular prolonged episodes of increased synchrony in this frequency band, have been associated with motor symptoms such as bradykinesia and rigidity in Parkinson's disease (PD). Numerous studies have investigated sensorimotor cortical beta oscillations either as a control signal for Brain Computer Interfaces (BCI) or as target signal for neurofeedback training (NFB). However, it still remains unknown whether patients with PD can gain control of the pathological oscillations recorded from a subcortical site - the STN - with neurofeedback training. We tried to address this question in the current study. Specifically, we designed a simple basketball game, in which the position of a basketball changes based on the occurrence of events of temporally increased beta power quantified in real-time. Participants practised in the game to control the position of the basketball, which requires modulation of the beta oscillations recorded from STN local field potentials (LFPs). Our results suggest that it is possible to use neurofeedback training for PD patients to downregulate pathological beta oscillations in STN LFPs, and that this can lead to a reduction of beta oscillations in the cortical-STN motor network.

Representation of spontaneous movement by dopaminergic neurons is cell-type selective and disrupted in parkinsonism.

Midbrain dopaminergic neurons are essential for appropriate voluntary movement, as epitomized by the cardinal motor impairments arising in Parkinson's disease. Understanding the basis of such motor control requires understanding how the firing of different types of dopaminergic neuron relates to movement and how this activity is deciphered in target structures such as the striatum. By recording and labeling individual neurons in behaving mice, we show that the representation of brief spontaneous movements in the firing of identified midbrain dopaminergic neurons is cell-type selective. Most dopaminergic neurons in the substantia nigra pars compacta (SNc), but not in ventral tegmental area or substantia nigra pars lateralis, consistently represented the onset of spontaneous movements with a pause in their firing. Computational modeling revealed that the movement-related firing of these dopaminergic neurons can manifest as rapid and robust fluctuations in striatal dopamine concentration and receptor activity. The exact nature of the movement-related signaling in the striatum depended on the type of dopaminergic neuron providing inputs, the striatal region innervated, and the type of dopamine receptor expressed by striatal neurons. Importantly, in aged mice harboring a genetic burden relevant for human Parkinson's disease, the precise movement-related firing of SNc dopaminergic neurons and the resultant striatal dopamine signaling were lost. These data show that distinct dopaminergic cell types differentially encode spontaneous movement and elucidate how dysregulation of their firing in early Parkinsonism can impair their effector circuits.

Action initiation shapes mesolimbic dopamine encoding of future rewards.

It is widely held that dopamine signaling encodes predictions of future rewards and such predictions are regularly used to drive behavior, but the relationship between these two is poorly defined. We found in rats that nucleus accumbens dopamine following a reward-predicting cue was attenuated unless movement was correctly initiated. Our results indicate that dopamine release in this region is contingent on correct action initiation and not just reward prediction.

Effect of sensory stimulation in rat barrel cortex, dorsolateral striatum and on corticostriatal functional connectivity.

The striatum integrates sensory information to enable action selection and behavioural reinforcement. In the rat, a large topographical projection from the rat barrel cortex to widely distributed areas of the striatum is assumed to be an important structural component supporting these processes. The striatal sensory response is, however, not comprehensively understood at a network level. We used a 10-Hz, 100-ms air puff, allowing undamped movement of multiple whiskers, to look at functional connectivity in contralateral cortex and striatum in response to sensory stimulation. Simultaneous recordings of cortical and striatal local field potentials (LFPs) were made under isoflurane anaesthesia in 15 male Brown Norway rats. Four electrodes were placed in the barrel cortex while the dorsolateral striatum was mapped with a 500-µm resolution, resulting in a maximum of 315 recording positions per animal. Significant event-related responses were unevenly distributed throughout the striatum in 34.8% of positions recorded within this area. Only 10.3% of recorded positions displayed significant total power increases in the LFPs during the stimulation period at the stimulus frequency. This suggests that the responses seen in the LFPs are due to phase rearrangement rather than an amplitude increase in the signal. Analysis of corticostriatal imaginary coherence revealed stimulus-induced changes in the functional connectivity of 12% of corticostriatal pairs, the sensory response of sparsely distributed neuronal ensembles within the dorsolateral striatum is reflected in the phase relationship between the cortical and striatal local fields.

A modified MPTP treatment regime produces reproducible partial nigrostriatal lesions in common marmosets.

Standard MPTP treatment regimens in primates result in > 85% destruction of nigral dopaminergic neurons and the onset of marked motor deficits that respond to known symptomatic treatments for Parkinson's disease (PD). The extent of nigral degeneration reflects the late stages of PD rather than events occurring at its onset. We report on a modified MPTP treatment regimen that causes nigral dopaminergic degeneration in common marmosets equivalent to that occurring at the time of initiation of motor symptoms in man. Subcutaneous administration of MPTP 1 mg/kg for 3 consecutive days caused a reproducible 60% loss of nigral tyrosine hydroxylase (TH)-positive cells, which occurred mainly in the calbindin-D(28k)-poor nigrosomes with a similar loss of TH-immunoreactivity (TH-ir) in the caudate nucleus and the putamen. The animals showed obvious motor abnormalities with reduced bursts of activity and the onset of motor disability. However, the loss of striatal terminals did not reflect early PD because a greater loss of TH-ir occurred in the caudate nucleus than in the putamen and a marked reduction in TH-ir occurred in striatal patches compared to the matrix. Examination of striatal fibres following a partial MPTP lesion showed a conspicuous increase in the number and the diameter of large branching fibres in the putaminal and to some extent caudatal matrix, pointing to a possible compensatory sprouting of dopaminergic terminals. In addition, these partially lesioned animals did not respond to acute treatment with L-DOPA. This primate partial lesions model may be useful for examining potential neuroprotective or neurorestorative agents for PD.