scholarly journals Parallel Movement-suppressing Striatal Output Pathways

2020 ◽  
Author(s):  
Qiaoling Cui ◽  
Xixun Du ◽  
Isaac Y. M. Chang ◽  
Arin Pamukcu ◽  
Varoth Lilascharoen ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Basal Ganglia ◽  
Body Movement ◽  
Disease Model ◽  
Projection Neurons ◽  
Indirect Pathway ◽  
Direct Pathway ◽  
Striatal Projection Neurons ◽  
6 Hydroxydopamine

AbstractThe classic basal ganglia circuit model asserts a complete segregation of the two striatal output pathways. Empirical data argue that, in addition to indirect-pathway striatal projection neurons (iSPNs), direct-pathway striatal projection neurons (dSPNs) innervate the external globus pallidus (GPe). However, the functions of the latter were not known. In this study, we interrogated the organization principles of striatopallidal projections and how they are involved in full-body movement in mice (both males and females). In contrast to the canonical motor-promoting role of dSPNs in the dorsomedial striatum (DMSdSPNs), optogenetic stimulation of dSPNs in the dorsolateral striatum (DLSdSPNs) suppressed locomotion. Circuit analyses revealed that dSPNs selectively target Npas1+ neurons in the GPe. In a chronic 6-hydroxydopamine lesion model of Parkinson’s disease, the dSPN-Npas1+ projection was dramatically strengthened. As DLSdSPN-Npas1+ projection suppresses movement, the enhancement of this projection represents a circuit mechanism for the hypokinetic symptoms of Parkinson’s disease that has not been previously considered.Significance statementIn the classic basal ganglia model, the striatum is described as a divergent structure—it controls motor and adaptive functions through two segregated, opponent output streams. However, the experimental results that show the projection from direct-pathway neurons to the external pallidum have been largely ignored. Here, we showed that this striatopallidal sub-pathway targets a select subset of neurons in the external pallidum and is motor-suppressing. We found that this sub-pathway undergoes plastic changes in a Parkinson’s disease model. In particular, our results suggest that the increase in strength of this sub-pathway contributes to the slowness or reduced movements observed in Parkinson’s disease.

scholarly journals Dopamine modulates the size of striatal projection neuron ensembles

2019 ◽  
Author(s):  
Marta Maltese ◽  
Jeffrey R. March ◽  
Alexander G. Bashaw ◽  
Nicolas X. Tritsch
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Projection Neuron ◽  
Projection Neurons ◽  
Voluntary Movements ◽  
Indirect Pathway ◽  
Two Photon ◽  
Direct Pathway ◽  
Brain Circuits

SUMMARYDopamine (DA) is a critical modulator of brain circuits that control voluntary movements, but our understanding of its influence on the activity of target neurons in vivo remains limited. Here, we use two-photon Ca2+ imaging to simultaneously monitor the activity of direct and indirect-pathway spiny projection neurons (SPNs) in the striatum of behaving mice during acute and prolonged manipulations of DA signaling. We find that, contrary to prevailing models, DA does not modulate activity rates in either pathway strongly or differentially. Instead, DA exerts a prominent influence on the overall number of direct and indirect pathway SPNs recruited during behavior. Chronic loss of midbrain DA neurons in a model of Parkinson’s disease selectively impacts direct pathway ensembles and profoundly alters how they respond to DA elevation. Our results indicate that DA regulates striatal output by dynamically reconfiguring its sparse ensemble code and provide novel insights into the pathophysiology of Parkinson’s disease.

scholarly journals Do human recordings reveal drastic modulations in the discharge of striatal projection neurons in Parkinson’s disease?

2020 ◽  
Author(s):  
Dan Valsky ◽  
Zvi Israel ◽  
Thomas Boraud ◽  
Hagai Bergman ◽  
Marc Deffains
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Deep Brain Stimulation ◽  
Basal Ganglia ◽  
Neuronal Activity ◽  
Discharge Rate ◽  
Projection Neurons ◽  
Dopamine Depletion ◽  
Striatal Projection Neurons ◽  
Deep Brain

AbstractDopamine depletion of the striatum plays a key role in the pathophysiology of Parkinson’s disease (PD), but our understanding of the changes in the discharge rate and pattern of the striatal projection neurons (SPNs) remains limited. Here, we recorded multi-unit signals from the striatum of PD (N = 934) and dystonic (N = 718) patients undergoing deep brain stimulation surgeries. Using an innovative automated data-driven approach to classify striatal units, we showed that the SPN discharge rate is inversely proportional to the isolation quality and stationarity of the SPNs. In contrast to earlier studies in both PD patients and the non-human primate model of PD, we found no drastic changes in the spiking activity (discharge rate and pattern) of the well-isolated and stationary SPNs of PD patients compared to either dystonic patients or the normal levels of striatal activity reported in healthy animals. Moreover, cluster analysis using SPN discharge properties did not characterize two well-separated SPN subpopulations. There was therefore no specific SPN subpopulation (D1 or D2 SPNs) strongly affected by the pathological state. Instead, our results suggest that moderate changes in SPN discharge are most likely amplified by basal ganglia downstream structures, thus leading to the clinical (motor and non-motor) symptoms of PD.Significance statementIn Parkinson’s disease (PD), the loss of the midbrain dopaminergic neurons leads to massive striatal dopamine depletion that provokes abnormal activity throughout the basal ganglia. However, the impact of dopamine depletion on neuronal activity in the striatum is still highly debated. We recorded and examined the neuronal activity in striatum of PD and dystonic patients undergoing deep brain stimulation surgeries. We found that striatal activity was not drastically higher in PD patients compared to either dystonic patients or the normal levels of striatal activity reported in animal studies. In PD, moderate changes in striatal basal activity are therefore most likely amplified by basal ganglia downstream structures.

scholarly journals The Multimodal Serotonergic Agent Vilazodone Inhibits L-DOPA-Induced Gene Regulation in Striatal Projection Neurons and Associated Dyskinesia in an Animal Model of Parkinson’s Disease

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2265
Author(s):  
Feras Altwal ◽  
Connor Moon ◽  
Anthony R. West ◽  
Heinz Steiner
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Animal Model ◽  
Gene Regulation ◽  
Selective Serotonin Reuptake Inhibitors ◽  
Partial Agonist ◽  
Projection Neurons ◽  
Dopamine Depletion ◽  
Indirect Pathway ◽  
Direct Pathway

Levodopa (L-DOPA) treatment in Parkinson’s disease is limited by the emergence of L-DOPA-induced dyskinesia. Such dyskinesia is associated with aberrant gene regulation in neurons of the striatum, which is caused by abnormal dopamine release from serotonin terminals. Previous work showed that modulating the striatal serotonin innervation with selective serotonin reuptake inhibitors (SSRIs) or 5-HT1A receptor agonists could attenuate L-DOPA-induced dyskinesia. We investigated the effects of a novel serotonergic agent, vilazodone, which combines SSRI and 5-HT1A partial agonist properties, on L-DOPA-induced behavior and gene regulation in the striatum in an animal model of Parkinson’s disease. After unilateral dopamine depletion by 6-hydroxydopamine (6-OHDA), rats received repeated L-DOPA treatment (5 mg/kg) alone or in combination with vilazodone (10 mg/kg) for 3 weeks. Gene regulation was then mapped throughout the striatum using in situ hybridization histochemistry. Vilazodone suppressed the development of L-DOPA-induced dyskinesia and turning behavior but did not interfere with the prokinetic effects of L-DOPA (forelimb stepping). L-DOPA treatment drastically increased the expression of dynorphin (direct pathway), 5-HT1B, and zif268 mRNA in the striatum ipsilateral to the lesion. These effects were inhibited by vilazodone. In contrast, vilazodone had no effect on enkephalin expression (indirect pathway) or on gene expression in the intact striatum. Thus, vilazodone inhibited L-DOPA-induced gene regulation selectively in the direct pathway of the dopamine-depleted striatum, molecular changes that are considered critical for L-DOPA-induced dyskinesia. These findings position vilazodone, an approved antidepressant, as a potential adjunct medication for the treatment of L-DOPA-induced motor side effects.

scholarly journals Intranasal delivery of mitochondria for treatment of Parkinson’s Disease model rats lesioned with 6-hydroxydopamine

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jui-Chih Chang ◽  
Yi-Chun Chao ◽  
Huei-Shin Chang ◽  
Yu-Ling Wu ◽  
Hui-Ju Chang ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Olfactory Bulb ◽  
Disease Model ◽  
Intranasal Delivery ◽  
The Difference ◽  
And Migration ◽  
6 Hydroxydopamine ◽  
Locomotor Behaviors ◽  
Migratory Stream

AbstractThe feasibility of delivering mitochondria intranasally so as to bypass the blood–brain barrier in treating Parkinson's disease (PD), was evaluated in unilaterally 6-OHDA-lesioned rats. Intranasal infusion of allogeneic mitochondria conjugated with Pep-1 (P-Mito) or unconjugated (Mito) was performed once a week on the ipsilateral sides of lesioned brains for three months. A significant improvement of rotational and locomotor behaviors in PD rats was observed in both mitochondrial groups, compared to sham or Pep-1-only groups. Dopaminergic (DA) neuron survival and recovery > 60% occurred in lesions of the substantia nigra (SN) and striatum in Mito and P-Mito rats. The treatment effect was stronger in the P-Mito group than the Mito group, but the difference was insignificant. This recovery was associated with restoration of mitochondrial function and attenuation of oxidative damage in lesioned SN. Notably, P-Mito suppressed plasma levels of inflammatory cytokines. Mitochondria penetrated the accessory olfactory bulb and doublecortin-positive neurons of the rostral migratory stream (RMS) on the ipsilateral sides of lesions and were expressed in striatal, but not SN DA neurons, of both cerebral hemispheres, evidently via commissural fibers. This study shows promise for intranasal delivery of mitochondria, confirming mitochondrial internalization and migration via RMS neurons in the olfactory bulb for PD therapy.

scholarly journals What is the true discharge rate and pattern of the striatal projection neurons in Parkinson’s disease and Dystonia?

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Dan Valsky ◽  
Shai Heiman Grosberg ◽  
Zvi Israel ◽  
Thomas Boraud ◽  
Hagai Bergman ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Cluster Analysis ◽  
Parkinson's Disease ◽  
Deep Brain Stimulation ◽  
Discharge Rate ◽  
Spontaneous Discharge ◽  
Projection Neurons ◽  
Pathological State ◽  
Striatal Projection Neurons ◽  
Deep Brain

Dopamine and striatal dysfunctions play a key role in the pathophysiology of Parkinson’s disease (PD) and Dystonia, but our understanding of the changes in the discharge rate and pattern of striatal projection neurons (SPNs) remains limited. Here, we recorded and examined multi-unit signals from the striatum of PD and dystonic patients undergoing deep brain stimulation surgeries. Contrary to earlier human findings, we found no drastic changes in the spontaneous discharge of the well-isolated and stationary SPNs of the PD patients compared to the dystonic patients or to the normal levels of striatal activity reported in healthy animals. Moreover, cluster analysis using SPN discharge properties did not characterize two well-separated SPN subpopulations, indicating no SPN subpopulation-specific (D1 or D2 SPNs) discharge alterations in the pathological state. Our results imply that small to moderate changes in spontaneous SPN discharge related to PD and Dystonia are likely amplified by basal ganglia downstream structures.

Locomotor Assessment of 6-Hydroxydopamine-induced Adult Zebrafish-based Parkinson's Disease Model

10.3791/63355 ◽  
2021 ◽  
Author(s):  
Naemah Md Hamzah ◽  
Siong Meng Lim ◽  
Yuganthini Vijayanathan ◽  
Fei Tieng Lim ◽  
Abu Bakar Abdul Majeed ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Disease Model ◽  
Adult Zebrafish ◽  
6 Hydroxydopamine

scholarly journals Dopamine differentially modulates the size of projection neuron ensembles in the intact and dopamine-depleted striatum

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Marta Maltese ◽  
Jeffrey R March ◽  
Alexander G Bashaw ◽  
Nicolas X Tritsch
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Population Level ◽  
Projection Neuron ◽  
Projection Neurons ◽  
Voluntary Movements ◽  
Indirect Pathway ◽  
Two Photon ◽  
Brain Circuits

Dopamine (DA) is a critical modulator of brain circuits that control voluntary movements, but our understanding of its influence on the activity of target neurons in vivo remains limited. Here, we use two-photon Ca2+ imaging to monitor the activity of direct and indirect-pathway spiny projection neurons (SPNs) simultaneously in the striatum of behaving mice during acute and prolonged manipulations of DA signaling. We find that increasing and decreasing DA biases striatal activity towards the direct and indirect pathways, respectively, by changing the overall number of SPNs recruited during behavior in a manner not predicted by existing models of DA function. This modulation is drastically altered in a model of Parkinson's disease. Our results reveal a previously unappreciated population-level influence of DA on striatal output and provide novel insights into the pathophysiology of Parkinson's disease.

scholarly journals Moxibustion Exerts a Neuroprotective Effect through Antiferroptosis in Parkinson’s Disease

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Juan Lu ◽  
Xuelei Liu ◽  
Ye Tian ◽  
Hang Li ◽  
Zhenxing Ren ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neuroprotective Effect ◽  
Disease Model ◽  
Protective Mechanism ◽  
Neural Cells ◽  
Ferritin Heavy Chain ◽  
Functional Pathway ◽  
6 Hydroxydopamine ◽  
The Right

The objective of this study was to explore the neuroprotective effect of moxibustion on rats with Parkinson’s disease (PD) and its mechanism. A Parkinson’s disease model was established in rats using a two-point stereotactic 6-hydroxydopamine injection in the right substantia nigra (SN) and ventral tegmental area. The rats received moxibustion at the Baihui (GV20) and Sishencong (EX-HN1) acupoints for 20 minutes, six times a week, for 6 weeks. The right SN tissue was histologically and immunohistochemically examined. Differentially expressed genes (DEGs) were identified through RNA sequencing. In addition, the levels of tyrosine hydroxylase (TH), glutathione peroxidase 4 (GPX4), and ferritin heavy chain 1 (FTH1) in SN were measured. In comparison to the model group, the moxibustion group showed a significantly greater TH immunoreactivity and a higher behavioural score. In particular, moxibustion led to an increase in the number and morphological stability of SN neural cells. The functional pathway analysis showed that DEGs are closely related to the ferroptosis pathway. GPX4 and FTH1 in the SN were significantly overexpressed in the moxibustion-treated rats with PD. Moxibustion can effectively reduce the death of SN neurons, decrease the occurrence of ferroptosis, and increase the TH activity to protect the neurons in rats with PD. The protective mechanism may be associated with suppression of the ferroptosis.

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