Disrupted basal ganglia output during movement preparation in hemi-parkinsonian mice is consistent with behavioral deficits

2021 ◽  
Author(s):  
Anand Tekriwal ◽  
Mario J. Lintz ◽  
John A Thompson ◽  
Gidon Felsen
Keyword(s):  
Basal Ganglia ◽  
Cell Loss ◽  
Motor Deficits ◽  
Movement Preparation ◽  
Rate Model ◽  
Model Framework ◽  
Behavioral Deficits ◽  
Dopaminergic Cell ◽  
Clinical Observations ◽  
External Stimuli

Parkinsonian motor deficits are associated with elevated inhibitory output from the basal ganglia (BG). However, several features of Parkinson's disease (PD) have not been accounted for by this simple "classical rate model" framework, including the observation in PD patients that movements guided by external stimuli are less impaired than otherwise-identical movements generated based on internal goals. Is this difference due to divergent processing within the BG itself, or to the recruitment of extra-BG pathways by sensory processing? In addition, surprisingly little is known about precisely when, in the sequence from selecting to executing movements, BG output is altered by PD. Here, we address these questions by recording activity in the SNr, a key BG output nucleus, in hemiparkinsonian mice performing a well-controlled behavioral task requiring stimulus-guided and internally-specified directional movements. We found that hemiparkinsonian mice exhibited a bias ipsilateral to the side of dopaminergic cell loss that was stronger when movements were internally specified rather than stimulus guided, consistent with clinical observations in parkinsonian patients. We further found that changes in parkinsonian SNr activity during movement preparation were consistent with the ipsilateral behavioral bias, as well as its greater magnitude for internally-specified movements. While these findings are inconsistent with some aspects of the classical rate model, they are accounted for by a related "directional rate model" positing that SNr output phasically over-inhibits motor output in a direction-specific manner. These results suggest that parkinsonian changes in BG output underlying movement preparation contribute to the greater deficit in internally-specified than stimulus-guided movements.

scholarly journals Disrupted basal ganglia output during movement preparation in hemi-parkinsonian mice accounts for behavioral deficits

2020 ◽  
Author(s):  
Anand Tekriwal ◽  
Mario J. Lintz ◽  
John A. Thompson ◽  
Gidon Felsen
Keyword(s):  
Basal Ganglia ◽  
Cell Loss ◽  
Motor Deficits ◽  
Movement Preparation ◽  
Rate Model ◽  
Model Framework ◽  
Behavioral Deficits ◽  
Dopaminergic Cell ◽  
Clinical Observations ◽  
External Stimuli

AbstractParkinsonian motor deficits are associated with elevated inhibitory output from the basal ganglia (BG). However, several features of Parkinson’s disease (PD) have not been accounted for by this simple “rate model” framework, including the observation in PD patients that movements guided by external stimuli are less impaired than otherwise-identical movements generated based on internal goals. Is this difference in impairment due to divergent processing within the BG itself, or to the recruitment of extra-BG pathways by sensory processing? In addition, surprisingly little is known about precisely when, in the sequence from selecting to executing movements, BG output is altered by PD. Here, we address these questions by recording activity in the SNr, a key BG output nucleus, in hemiparkinsonian (hemi-PD) mice performing a well-controlled behavioral task requiring stimulus-guided and internally-specified directional movements. We found that hemi-PD mice exhibited a bias ipsilateral to the side of dopaminergic cell loss that was stronger when movements were internally specified rather than stimulus guided, consistent with clinical observations in parkinsonian patients. We further found that changes in parkinsonian SNr activity during movement preparation could account for the ipsilateral behavioral bias, as well as its greater magnitude for internally-specified movements, consistent with some aspects of the rate model. These results suggest that parkinsonian changes in BG output underlying movement preparation contribute to the greater deficit in internally-specified than stimulus-guided movements.

scholarly journals Effect of Photobiomodulation in Rescuing Lipopolysaccharide-Induced Dopaminergic Cell Loss in the Male Sprague–Dawley Rat

Biomolecules ◽  
2019 ◽  
Vol 9 (8) ◽  
pp. 381 ◽  
Author(s):  
O’Brien ◽  
Austin
Keyword(s):  
Cell Death ◽  
Cell Loss ◽  
Lesion Size ◽  
Motor Deficits ◽  
Sprague Dawley ◽  
Dopaminergic Cell ◽  
Sprague Dawley Rats ◽  
Neuroprotective Therapy ◽  
Potential Benefits ◽  
Inflammatory Component

Photobiomodulation (PBM) provides neuroprotection against dopaminergic cell death and associated motor deficits in rodent and primate models of Parkinson’s disease (PD). However, it has not yet been tested in the lipopolysaccharide (LPS) model of PD, which leads to dopaminergic cell death through microglia-evoked neuroinflammation. We investigated whether transcranial PBM could protect against dopaminergic cell death within the substantia nigra in male Sprague–Dawley rats following supranigral LPS injection. PBM fully protected rats from 10 µg LPS which would have otherwise caused 15% cell loss, but there was no significant neuroprotection at a 20 µg dose that led to a 50% lesion. Cell loss at this dose varied according to the precise site of injection and correlated with increased local numbers of highly inflammatory amoeboid microglia. Twenty microgram LPS caused motor deficits in the cylinder, adjusted stepping and rotarod tests that correlated with dopaminergic cell loss. While PBM caused no significant improvement at the group level, motor performance on all three tests no longer correlated with the lesion size caused by 20 µg LPS in PBM-treated rats, suggesting extranigral motor improvements in some animals. These results provide support for PBM as a successful neuroprotective therapy against the inflammatory component of early PD, provided inflammation has not reached a devastating level, as well as potential benefits in other motor circuitries.

scholarly journals Subacute administration of both methcathinone and manganese causes basal ganglia damage in mice resembling that in methcathinone abusers

2019 ◽  
Vol 127 (5) ◽  
pp. 707-714 ◽  
Author(s):  
Andres Asser ◽  
Atsuko Hikima ◽  
Mari Raki ◽  
Kim Bergström ◽  
Sarah Rose ◽  
...  
Keyword(s):  
Basal Ganglia ◽  
Motor Behavior ◽  
Neuronal Damage ◽  
Intraperitoneal Administration ◽  
Cell Loss ◽  
Cell Number ◽  
Vesicular Monoamine Transporter ◽  
Dopaminergic Cell ◽  
Extrapyramidal Syndrome ◽  
Neuronal Markers

AbstractAn irreversible extrapyramidal syndrome occurs in man after intravenous abuse of “homemade” methcathinone (ephedrone, Mcat) that is contaminated with manganese (Mn) and is accompanied by altered basal ganglia function. Both Mcat and Mn can cause alterations in nigrostriatal function but it remains unknown whether the effects of the ‘homemade’ drug seen in man are due to Mcat or to Mn or to a combination of both. To determine how toxicity occurs, we have investigated the effects of 4-week intraperitoneal administration of Mn (30 mg/kg t.i.d) and Mcat (100 mg/kg t.i.d.) given alone, on the nigrostriatal function in male C57BL6 mice. The effects were compared to those of the ‘homemade’ mixture which contained about 7 mg/kg of Mn and 100 mg/kg of Mcat. Motor function, nigral dopaminergic cell number and markers of pre- and postsynaptic dopaminergic neuronal integrity including SPECT analysis were assessed. All three treatments had similar effects on motor behavior and neuronal markers. All decreased motor activity and induced tyrosine hydroxylase positive cell loss in the substantia nigra. All reduced 123I-epidepride binding to D2 receptors in the striatum. Vesicular monoamine transporter 2 (VMAT2) binding was not altered by any drug treatment. However, Mcat treatment alone decreased levels of the dopamine transporter (DAT) and Mn alone reduced GAD immunoreactivity in the striatum. These data suggest that both Mcat and Mn alone could contribute to the neuronal damage caused by the ‘homemade’ mixture but that both produce additional changes that contribute to the extrapyramidal syndrome seen in man.

Involvement of Subcortical Structures in the Preparation of Self-Paced Movement

2004 ◽  
Vol 18 (2/3) ◽  
pp. 130-139 ◽  
Author(s):  
Guillermo Paradiso ◽  
Danny Cunic ◽  
Robert Chen
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Basal Ganglia ◽  
Onset Time ◽  
Movement Planning ◽  
Movement Preparation ◽  
Subcortical Structures ◽  
Postoperative Mri ◽  
Deep Brain

Abstract Although it has long been suggested that the basal ganglia and thalamus are involved in movement planning and preparation, there was little direct evidence in humans to support this hypothesis. Deep brain stimulation (DBS) is a well-established treatment for movement disorders such as Parkinson's disease, tremor, and dystonia. In patients undergoing DBS surgery, we recorded simultaneously from scalp contacts and from electrodes surgically implanted in the subthalamic nucleus (STN) of 13 patients with Parkinson's disease and in the “cerebellar” thalamus of 5 patients with tremor. The aim of our studies was to assess the role of the cortico-basal ganglia-thalamocortical loop through the STN and the cerebello-thalamocortical circuit through the “cerebellar” thalamus in movement preparation. The patients were asked to perform self-paced wrist extension movements. All subjects showed a cortical readiness potential (RP) with onset ranging between 1.5 to 2s before the onset of movement. Subcortical RPs were recorded in 11 of 13 with electrodes in the STN and in 4 of 5 patients with electrodes in the thalamus. The onset time of the STN and thalamic RPs were not significantly different from the onset time of the scalp RP. The STN and thalamic RPs were present before both contralateral and ipsilateral hand movements. Postoperative MRI studies showed that contacts with maximum RP amplitude generally were inside the target nucleus. These findings indicate that both the basal ganglia and the cerebellar circuits participate in movement preparation in parallel with the cortex.

Spontaneous Partial Recovery of Striatal Dopaminergic Uptake Despite Nigral Cell Loss in Asymptomatic MPTP-Lesioned Minipigs

2021 ◽  
Author(s):  
Anne M. Landau ◽  
Thea P. Lillethorup ◽  
Ove Noer ◽  
Aage Kristian Olsen Alstrup ◽  
Kathrine Stokholm ◽  
...  
Keyword(s):  
Animal Model ◽  
Spontaneous Recovery ◽  
Ethical Issues ◽  
Cell Loss ◽  
Large Animal Model ◽  
Large Animal ◽  
Partial Recovery ◽  
Behavioral Deficits ◽  
Large Animal Models ◽  
Human Primate

Abstract The gold standard animal model of Parkinson’s disease is the non-human primate rendered parkinsonian with the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxin. Low availability, ethical issues, and primate-specific biohazards make alternative large animal models necessary. Here, we investigate the temporal evolution of presynaptic dopaminergic function after MPTP in another large animal model, the Göttingen minipig. We subcutaneously injected seven sedated minipigs with 1–2 mg/kg of MPTP, and two minipigs with saline, three times a week over 4 weeks. We monitored behavioral deficits using a validated motor scale and a Gait4Dog® walking mat. Minipig brains were imaged with (+)-⍺-[11C]-dihydrotetrabenazine ([11C]-DTBZ) and [18F]-fluorodopa ([18F]-FDOPA) PET at baseline and 1, 3, 9 and 12 months after the final MPTP injection. Immunohistochemical tyrosine hydroxylase (TH) staining was used to assay nigral TH + area loss post-mortem. The minipigs showed only mild bradykinesia and impaired coordination at early timepoints after MPTP. PET revealed decreases of striatal [11C]-DTBZ and [18F]-FDOPA uptake post-MPTP with a partial spontaneous recovery of [18F]-FDOPA after 9 months. Postmortem histological analysis showed a loss of 71% TH-immunopositive area in the substantia nigra. When testing the efficacy of putative neuroprotective agents, partial spontaneous recovery of dopamine terminal function must be taken into account in the MPTP minipig model of parkinsonism.

PAX6 expression may be protective against dopaminergic cell loss in Parkinson's disease

2016 ◽  
Vol 15 (1) ◽  
pp. 73-79 ◽  
Author(s):  
Meghan G. Thomas ◽  
Caitlyn Welch ◽  
Leah Stone ◽  
Peter Allan ◽  
Roger A. Barker ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Loss ◽  
Pax6 Expression ◽  
Dopaminergic Cell

scholarly journals Neuroprotection in Parkinson’s disease: facts and hopes

2019 ◽  
Vol 127 (5) ◽  
pp. 821-829 ◽  
Author(s):  
András Salamon ◽  
Dénes Zádori ◽  
László Szpisjak ◽  
Péter Klivényi ◽  
László Vécsei
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Loss ◽  
Substantia Nigra Pars Compacta ◽  
Neuroprotective Agents ◽  
Dopaminergic Cell ◽  
Pathological Mechanism ◽  
Positive Results

AbstractParkinson’s disease (PD) is the second most common neurodegenerative disease worldwide. Behind the symptoms there is a complex pathological mechanism which leads to a dopaminergic cell loss in the substantia nigra pars compacta. Despite the strong efforts, curative treatment has not been found yet. To prevent a further cell death, numerous molecules were tested in terms of neuroprotection in preclinical (in vitro, in vivo) and in clinical studies as well. The aim of this review article is to summarize our knowledge about the extensively tested neuroprotective agents (Search period: 1991–2019). We detail the underlying pathological mechanism and summarize the most important results of the completed animal and clinical trials. Although many positive results have been reported in the literature, there is still no evidence that any of them should be used in clinical practice (Cochrane analysis was performed). Therefore, further studies are needed to better understand the pathomechanism of PD and to find the optimal neuroprotective agent(s).

scholarly journals miR-9 regulates basal ganglia-dependent developmental vocal learning and adult vocal performance in songbirds

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Zhimin Shi ◽  
Zoe Piccus ◽  
Xiaofang Zhang ◽  
Huidi Yang ◽  
Hannah Jarrell ◽  
...  
Keyword(s):  
Basal Ganglia ◽  
Vocal Communication ◽  
Vocal Learning ◽  
Vital Role ◽  
Language Impairments ◽  
Vocal Performance ◽  
Behavioral Deficits ◽  
Expression Of Genes ◽  
Dopamine Signaling ◽  
Area X

miR-9 is an evolutionarily conserved miRNA that is abundantly expressed in Area X, a basal ganglia nucleus required for vocal learning in songbirds. Here, we report that overexpression of miR-9 in Area X of juvenile zebra finches impairs developmental vocal learning, resulting in a song with syllable omission, reduced similarity to the tutor song, and altered acoustic features. miR-9 overexpression in juveniles also leads to more variable song performance in adulthood, and abolishes social context-dependent modulation of song variability. We further show that these behavioral deficits are accompanied by downregulation of FoxP1 and FoxP2, genes that are known to be associated with language impairments, as well as by disruption of dopamine signaling and widespread changes in the expression of genes that are important in circuit development and functions. These findings demonstrate a vital role for miR-9 in basal ganglia function and vocal communication, suggesting that dysregulation of miR-9 in humans may contribute to language impairments and related neurodevelopmental disorders.

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