L-dopa (l-3,4-dihydroxyphenylalanine)-induced dyskinesia (LID) is a debilitating complication of dopamine replacement therapy for Parkinson's disease. The potential contribution of striatal D₂ receptor (D₂R)-positive neurons and downstream circuits in the pathophysiology of LID remains unclear. In this study, we investigated the role of striatal D₂R⁺ neurons and downstream globus pallidus externa (GPe) neurons in a rat model of LID. Intrastriatal administration of raclopride, a D₂R antagonist, significantly inhibited dyskinetic behavior, while intrastriatal administration of pramipexole, a D₂-like receptor agonist, yielded aggravation of dyskinesia in LID rats. Fiber photometry revealed the overinhibition of striatal D₂R⁺ neurons and hyperactivity of downstream GPe neurons during the dyskinetic phase of LID rats. In contrast, the striatal D₂R⁺ neurons showed intermittent synchronized overactivity in the decay phase of dyskinesia. Consistent with the above findings, optogenetic activation of striatal D₂R⁺ neurons or their projections in the GPe was adequate to suppress most of the dyskinetic behaviors of LID rats. Our data demonstrate that the aberrant activity of striatal D₂R⁺ neurons and downstream GPe neurons is a decisive mechanism mediating dyskinetic symptoms in LID rats.
Rats ; Animals ; Levodopa/toxicity* ; Dopamine ; Parkinsonian Disorders/drug therapy* ; Oxidopamine ; Dyskinesia, Drug-Induced ; Corpus Striatum/metabolism* ; Neurons/metabolism* ; Receptors, Dopamine D2/metabolism* ; Antiparkinson Agents/toxicity*

The secondary motor cortex (M2) encodes choice-related information and plays an important role in cue-guided actions. M2 neurons innervate the dorsal striatum (DS), which also contributes to decision-making behavior, yet how M2 modulates signals in the DS to influence perceptual decision-making is unclear. Using mice performing a visual Go/No-Go task, we showed that inactivating M2 projections to the DS impaired performance by increasing the false alarm (FA) rate to the reward-irrelevant No-Go stimulus. The choice signal of M2 neurons correlated with behavioral performance, and the inactivation of M2 neurons projecting to the DS reduced the choice signal in the DS. By measuring and manipulating the responses of direct or indirect pathway striatal neurons defined by M2 inputs, we found that the indirect pathway neurons exhibited a shorter response latency to the No-Go stimulus, and inactivating their early responses increased the FA rate. These results demonstrate that the M2-to-DS pathway is crucial for suppressing inappropriate responses in perceptual decision behavior.
Mice ; Animals ; Motor Cortex ; Corpus Striatum/physiology* ; Neostriatum ; Neurons/physiology* ; Reaction Time

Autapses selectively form in specific cell types in many brain regions. Previous studies have also found putative autapses in principal spiny projection neurons (SPNs) in the striatum. However, it remains unclear whether these neurons indeed form physiologically functional autapses. We applied whole-cell recording in striatal slices and identified autaptic cells by the occurrence of prolonged asynchronous release (AR) of neurotransmitters after bursts of high-frequency action potentials (APs). Surprisingly, we found no autaptic AR in SPNs, even in the presence of Sr²⁺. However, robust autaptic AR was recorded in parvalbumin (PV)-expressing neurons. The autaptic responses were mediated by GABA_A receptors and their strength was dependent on AP frequency and number. Further computer simulations suggest that autapses regulate spiking activity in PV cells by providing self-inhibition and thus shape network oscillations. Together, our results indicate that PV neurons, but not SPNs, form functional autapses, which may play important roles in striatal functions.
Parvalbumins/metabolism* ; Corpus Striatum/metabolism* ; Interneurons/physiology* ; Neurons/metabolism* ; Neostriatum

Corpus Striatum ; Dopaminergic Neurons ; Humans ; Mesencephalon ; Parkinson Disease/drug therapy* ; Pars Compacta ; Substantia Nigra

It has been reported that single-unit activity in the prefrontal cortex (PFC) and striatum represented visual stimulus and reward information. But how to encode these pieces of information is quite complex from the view of single-neuron activity. Different neurons represented stimulus or reward information in different task epochs with increasing or decreasing their activities relative to their baseline firing rates. The present paper was aimed to study whether population neurons in the two brain areas could stably encode task-relevant parameters in a whole trial period. We recorded single-unit activities in the lateral PFC (LPFC) and striatum while the monkey was performing a stimulus- reward prediction task, and analyzed the neuronal activities by the method of a multi-variable regression model and the linear support vector machine. The results showed that, although proportions of task-related neurons in the two areas varied largely in the whole trial period, LPFC population neurons encoded reward and stimulus information stably and reliably. Population neurons in the striatum encoded only reward information, not stimulus information. A group of neurons in the two areas represented combined information of stimulus and reward. Further analysis showed that LPFC neurons encoded reward information for a group of relevant stimuli, while striatal neurons encoded reward information for a specific stimulus. These results suggest that both LPFC and striatal population neurons are able to stably represent task-relevant information, but from different aspects of the task. The different strategies to encode information in the LPFC and striatum suggest their different contributions in reward-based decision making.
Animals ; Corpus Striatum ; Neurons ; Prefrontal Cortex ; Primates ; Reward

The thalamostriatal pathway is implicated in Parkinson's disease (PD); however, PD-related changes in the relationship between oscillatory activity in the centromedian-parafascicular complex (CM/Pf, or the Pf in rodents) and the dorsal striatum (DS) remain unclear. Therefore, we simultaneously recorded local field potentials (LFPs) in both the Pf and DS of hemiparkinsonian and control rats during epochs of rest or treadmill walking. The dopamine-lesioned rats showed increased LFP power in the beta band (12 Hz-35 Hz) in the Pf and DS during both epochs, but decreased LFP power in the delta (0.5 Hz-3 Hz) band in the Pf during rest epochs and in the DS during both epochs, compared to control rats. In addition, exaggerated low gamma (35 Hz-70 Hz) oscillations after dopamine loss were restricted to the Pf regardless of the behavioral state. Furthermore, enhanced synchronization of LFP oscillations was found between the Pf and DS after the dopamine lesion. Significant increases occurred in the mean coherence in both theta (3 Hz-7 Hz) and beta bands, and a significant increase was also noted in the phase coherence in the beta band between the Pf and DS during rest epochs. During the treadmill walking epochs, significant increases were found in both the alpha (7 Hz-12 Hz) and beta bands for two coherence measures. Collectively, dramatic changes in the relative LFP power and coherence in the thalamostriatal pathway may underlie the dysfunction of the basal ganglia-thalamocortical network circuits in PD, contributing to some of the motor and non-motor symptoms of the disease.
Animals ; Brain Waves ; physiology ; Corpus Striatum ; physiopathology ; Cortical Synchronization ; physiology ; Dopaminergic Neurons ; physiology ; Electrocorticography ; Male ; Neural Pathways ; physiopathology ; Oxidopamine ; Parkinsonian Disorders ; physiopathology ; Rats, Wistar ; Thalamic Nuclei ; physiopathology ; Walking ; physiology

The aim of the present study was to reveal the role of cortical-striatum postsynaptic dopamine D2 receptor (D2R) in improving motor behavioral dysfunction in Parkinson's disease (PD) mice by exercise. C57/BL6 male adult mice were randomly divided into control, PD and PD plus exercise groups. The mice were injected with 6-OHDA in striatum to establish a unilateral injury PD model. The exercise intervention program was uniform speed running (16 m/min, 40 min/d, 5 d per week for 4 weeks). Autonomic activity of mice was tested by open field test. Cortical-striatum synaptic transmission efficiency was assessed by peak amplitude of field excitatory postsynaptic potential (fEPSP) recorded from in vitro brain slides. Meanwhile, the effects of D2R agonist on autonomic activity and cortical-striatal synaptic transmission were observed. The results showed that, compared with PD group, PD plus exercise group exhibited significantly increased autonomic motor distance and proportion of fast-moving (P < 0.05), as well as decreased maximum amplitude of fEPSP under increasing stimulation intensity (0.75-3.00 pA) (P < 0.05) and slope of stimulus-response curve. Compared with PD mice without D2R agonist, the movement distance and rapid movement ratio of PD mice treated with D2R agonist were increased significantly (P < 0.05), whereas fEPSP peak amplitude (P < 0.05) and the slope of stimulus-response curve were decreased. These results indicate that either early exercise intervention or D2R agonist treatment can inhibit the abnormal increase of cortical-striatum synaptic transmission and improve the autonomic motor ability in PD mice, suggesting that the cortical-striatum synaptic D2R may be an important molecular target for exercise to improve the autonomic motor ability of PD mice.
Animals ; Corpus Striatum ; physiology ; Male ; Mice ; Mice, Inbred C57BL ; Oxidopamine ; Parkinson Disease ; physiopathology ; therapy ; Physical Conditioning, Animal ; Random Allocation ; Receptors, Dopamine D2 ; agonists ; physiology ; Synaptic Transmission

BACKGROUND AND OBJECTIVES: Parkinson’s disease (PD) is a fatal and progressive degenerative disease of the nervous system. Until recently, its promising treatment and underlying mechanisms for neuronal death are poorly understood. This study was investigated to identify the molecular mechanism of neuronal death in the substantia nigra and corpus striatum of PD. METHODS: The soluble RAGE (sRAGE) secreting Umbilical Cord Blood—derived Mesenchymal Stem Cell (UCB-MSC) was generated by gene editing method using clustered regularly interspaced short palindromic repeats/CRISPR associated protein 9 (CRISPR/Cas9). These cells were transplanted into Corpus Striatum of rotenone-induced PD animal models then behavioral test, morphological analysis, and immunohistochemical experiments were performed to determine the neuronal cell death and recovery of movement. RESULTS: The neuronal cell death in Corpus Striatum and Substantia Nigra was dramatically reduced and the movement was improved after sRAGE secreting UCB-MSC treatment in PD mice by inhibition of RAGE in neuronal cells. CONCLUSIONS: We suggest that sRAGE secreting UCB-MSC based therapeutic approach could be a potential treatment strategy for neurodegenerative disease including PD.
Animals ; Behavior Rating Scale ; Cell Death ; Corpus Striatum ; Mesenchymal Stromal Cells ; Methods ; Mice ; Microglia ; Models, Animal ; Nervous System ; Neurodegenerative Diseases ; Neurons ; Parkinson Disease ; Rage ; Substantia Nigra ; Umbilical Cord

As an environmental risk factor, psychological stress may trigger the onset or accelerate the progression of Parkinson's disease (PD). Here, we evaluated the effects of acute restraint stress on striatal dopaminergic terminals and the brain metabolism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which has been widely used for creating a mouse model of PD. Exposure to 2 h of restraint stress immediately after injection of a low dose of MPTP caused a severe loss of striatal dopaminergic terminals as indicated by decreases in the dopamine transporter protein and dopamine levels compared with MPTP administration alone. Both striatal 1-methyl-4-phenylpyridinium ion (MPP) and MPTP concentrations were significantly increased by the application of restraint stress. Striatal monoamine oxidase-B, which catalyzes the oxidation of MPTP to MPP, was not changed by the restraint stress. Our results indicate that the enhanced striatal dopaminergic terminal loss in the stressed mice is associated with an increase in the transport of neurotoxin into the brain.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine ; metabolism ; 1-Methyl-4-phenylpyridinium ; metabolism ; Animals ; Corpus Striatum ; drug effects ; metabolism ; Disease Models, Animal ; Dopaminergic Neurons ; drug effects ; MPTP Poisoning ; chemically induced ; metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Neurotoxins ; metabolism ; Restraint, Physical ; Stress, Psychological ; metabolism

Attention deficit hyperactivity disorder (ADHD) is a common childhood neuropsychiatric disorder that has been linked to the dopaminergic system. This study aimed to investigate the effects of regulation of the dopamine D4 receptor (DRD4) on functional brain activity during the resting state in ADHD children using the methods of regional homogeneity (ReHo) and functional connectivity (FC). Resting-state functional magnetic resonance imaging data were analyzed in 49 children with ADHD. All participants were classified as either carriers of the DRD4 4-repeat/4-repeat (4R/4R) allele (n = 30) or the DRD4 2-repeat (2R) allele (n = 19). The results showed that participants with the DRD4 2R allele had decreased ReHo bilaterally in the posterior lobes of the cerebellum, while ReHo was increased in the left angular gyrus. Compared with participants carrying the DRD4 4R/4R allele, those with the DRD4 2R allele showed decreased FC to the left angular gyrus in the left striatum, right inferior frontal gyrus, and bilateral lobes of the cerebellum. The increased FC regions included the left superior frontal gyrus, medial frontal gyrus, and rectus gyrus. These data suggest that the DRD4 polymorphisms are associated with localized brain activity and specific functional connections, including abnormality in the frontal-striatal-cerebellar loop. Our study not only enhances the understanding of the correlation between the cerebellar lobes and ADHD, but also provides an imaging basis for explaining the neural mechanisms underlying ADHD in children.
Attention Deficit Disorder with Hyperactivity ; diagnostic imaging ; genetics ; pathology ; Brain ; diagnostic imaging ; Cerebellum ; diagnostic imaging ; Child ; Corpus Striatum ; diagnostic imaging ; Female ; Frontal Lobe ; diagnostic imaging ; Genotype ; Humans ; Image Processing, Computer-Assisted ; Magnetic Resonance Imaging ; Male ; Minisatellite Repeats ; genetics ; Neural Pathways ; diagnostic imaging ; Oxygen ; blood ; Receptors, Dopamine D4 ; genetics ; metabolism ; Rest