scholarly journals Delta oscillations are a robust biomarker of dopamine depletion severity and motor dysfunction in awake mice

2020 ◽  
Vol 124 (2) ◽  
pp. 312-329
Author(s):  
Timothy C. Whalen ◽  
Amanda M. Willard ◽  
Jonathan E. Rubin ◽  
Aryn H. Gittis
Keyword(s):  
Basal Ganglia ◽  
D2 Receptor ◽  
Receptor Activation ◽  
Motor Dysfunction ◽  
Motor Symptoms ◽  
Strongly Correlated ◽  
Dopamine Depletion ◽  
Neural Noise ◽  
Novel Method ◽  
Delta Oscillations

This work introduces a novel method to detect spike oscillations amidst neural noise. Using this method, we demonstrate that delta oscillations in the basal ganglia are a defining feature of awake, dopamine-depleted mice and are strongly correlated with dopamine loss and parkinsonian motor symptoms. These oscillations arise from a loss of D2-receptor activation and do not require motor cortex. Similar oscillations in human patients may be an underappreciated marker and target for Parkinson’s disease (PD) treatment.

scholarly journals Delta Oscillations Are a Robust Biomarker of Dopamine Depletion Severity and Motor Dysfunction in Awake Mice

2020 ◽  
Author(s):  
Timothy C. Whalen ◽  
Amanda M. Willard ◽  
Jonathan E. Rubin ◽  
Aryn H. Gittis
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
D2 Receptor ◽  
Receptor Activation ◽  
Motor Dysfunction ◽  
Dopamine Depletion ◽  
Novel Approach ◽  
Strong Indicator ◽  
Insight Into ◽  
Delta Oscillations

AbstractDelta oscillations (0.5–4 Hz) are a robust but often overlooked feature of basal ganglia pathophysiology in Parkinson’s disease and their relationship to parkinsonian akinesia has not been investigated. Here, we establish a novel approach to detect spike oscillations embedded in noise to provide the first study of delta oscillations in awake, dopamine depleted mice. We find that approximately half of neurons in the substantia nigra reticulata exhibit delta oscillations in dopamine depletion and that these oscillations are a strong indicator of dopamine loss and akinesia, outperforming measures such as changes in firing rate, irregularity, bursting and synchrony. We further establish that these oscillations are caused by the loss of D2 receptor activation and do not require motor cortex, contrary to previous findings in anesthetized animals. These results give insight into how dopamine loss leads to dysfunction and suggest a reappraisal of delta oscillations as a biomarker in Parkinson’s disease.

scholarly journals Dopamine receptors mediate strategy abandoning via modulation of a specific prelimbic cortex–nucleus accumbens pathway in mice

2018 ◽  
Vol 115 (21) ◽  
pp. E4890-E4899 ◽  
Author(s):  
Qiaoling Cui ◽  
Qian Li ◽  
Hongyan Geng ◽  
Lei Chen ◽  
Nancy Y. Ip ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Dopamine Receptors ◽  
Cortical Neurons ◽  
Critical Role ◽  
D2 Receptor ◽  
Receptor Activation ◽  
Prelimbic Cortex ◽  
Dopamine Depletion ◽  
Dopaminergic Tone ◽  
Type Receptor

The ability to abandon old strategies and adopt new ones is essential for survival in a constantly changing environment. While previous studies suggest the importance of the prefrontal cortex and some subcortical areas in the generation of strategy-switching flexibility, the fine neural circuitry and receptor mechanisms involved are not fully understood. In this study, we showed that optogenetic excitation and inhibition of the prelimbic cortex–nucleus accumbens (NAc) pathway in the mouse respectively enhances and suppresses strategy-switching ability in a cross-modal spatial-egocentric task. This ability is dependent on an intact dopaminergic tone in the NAc, as local dopamine denervation impaired the performance of the animal in the switching of tasks. In addition, based on a brain-slice preparation obtained from Drd2-EGFP BAC transgenic mice, we demonstrated direct innervation of D2 receptor-expressing medium spiny neurons (D2-MSNs) in the NAc by prelimbic cortical neurons, which is under the regulation by presynaptic dopamine receptors. While presynaptic D1-type receptor activation enhances the glutamatergic transmission from the prelimbic cortex to D2-MSNs, D2-type receptor activation suppresses this synaptic connection. Furthermore, manipulation of this pathway by optogenetic activation or administration of a D1-type agonist or a D2-type antagonist could restore impaired task-switching flexibility in mice with local NAc dopamine depletion; this restoration is consistent with the effects of knocking down the expression of specific dopamine receptors in the pathway. Our results point to a critical role of a specific prelimbic cortex–NAc subpathway in mediating strategy abandoning, allowing the switching from one strategy to another in problem solving.

Role of Stereotaxis in the Treatment of Cerebral Palsy

1996 ◽  
Vol 11 (1_suppl) ◽  
pp. S43-S50 ◽  
Author(s):  
Antonio A. F. De Salles
Keyword(s):  
Magnetic Resonance Imaging ◽  
Cerebral Palsy ◽  
Basal Ganglia ◽  
Magnetic Resonance ◽  
Treatment Plan ◽  
Motor Dysfunction ◽  
Comprehensive Treatment ◽  
Motor Symptoms ◽  
Resonance Imaging ◽  
Stereotactic Technique

There is a renewed interest in basal ganglia surgery for improvement of motor symptoms in cerebral palsy Rigidity, choreoathetosis, and tremor can be improved or abolished by a well-placed radiofrequency lesion, either in the ventrolateral nucleus of the thalamus or ventroposterior pallidum. The target is chosen based on the predominance of the symptoms in a given patient. A review of the main reports on surgery of the basal ganglia for cerebral palsy, as well as the author's data, shows that the surgery can have a remarkable impact on patients' quality of life when motor dysfunction is improved. An update of the physiopathology of cerebral palsy motor symptoms related to anatomic findings on experimental work, magnetic resonance imaging, and autopsy is used to rationalize surgery of the basal ganglia. Modem stereotactic technique based on exquisite demonstration of the basal ganglia anatomy by magnetic resonance imaging is described and supported by intraoperative electricophysiologic studies. The author stresses the importance of a multidisciplinary approach to provide the cerebral palsy patient with a comprehensive treatment plan before stereotactic surgery. (J Child Neurol 1996;11(Suppl 1):S43-S50).

scholarly journals State transitions in the substantia nigra reticulata predict the onset of motor deficits in models of progressive dopamine depletion in mice

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Amanda M Willard ◽  
Brian R Isett ◽  
Timothy C Whalen ◽  
Kevin J Mastro ◽  
Chris S Ki ◽  
...  
Keyword(s):  
Basal Ganglia ◽  
Substantia Nigra ◽  
Neurodegenerative Disorder ◽  
State Transitions ◽  
Motor Deficits ◽  
Motor Symptoms ◽  
Dopamine Depletion ◽  
Discrete State ◽  
Substantia Nigra Reticulata ◽  
Diseased State

Parkinson’s disease (PD) is a progressive neurodegenerative disorder whose cardinal motor symptoms are attributed to dysfunction of basal ganglia circuits under conditions of low dopamine. Despite well-established physiological criteria to define basal ganglia dysfunction, correlations between individual parameters and motor symptoms are often weak, challenging their predictive validity and causal contributions to behavior. One limitation is that basal ganglia pathophysiology is studied only at end-stages of depletion, leaving an impoverished understanding of when deficits emerge and how they evolve over the course of depletion. In this study, we use toxin- and neurodegeneration-induced mouse models of dopamine depletion to establish the physiological trajectory by which the substantia nigra reticulata (SNr) transitions from the healthy to the diseased state. We find that physiological progression in the SNr proceeds in discrete state transitions that are highly stereotyped across models and correlate well with the prodromal and symptomatic stages of behavior.

Constipation is Associated with Development of Cognitive Impairment in de novo Parkinson’s Disease: A Longitudinal Analysis of Two International Cohorts

2021 ◽  
pp. 1-11
Author(s):  
Valentina Leta ◽  
Daniele Urso ◽  
Lucia Batzu ◽  
Daniel Weintraub ◽  
Nataliya Titova ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cognitive Impairment ◽  
De Novo ◽  
Motor Dysfunction ◽  
Group Differences ◽  
Motor Symptoms ◽  
Kaplan Meier ◽  
Patients At Risk ◽  
Non Motor Symptoms

Background: Constipation is regarded as one of the prodromal features of Parkinson’s disease (PD) and there is emerging evidence linking gastrointestinal dysfunction and cognitive impairment (CI) in PD. Objective: We explored whether constipation is associated with development of CI in two independent cohorts of de novo PD patients (n = 196 from the Non-motor International Longitudinal Study [NILS] and n = 423 from the Parkinson’s Progression Markers Initiative [PPMI] study). Methods: Constipation was clinically defined using the Non-Motor Symptoms Scale (NMSS) item-21 [NILS] and Scales for Outcomes in PD-Autonomic (SCOPA-AUT) item-5 [PPMI]. We assessed baseline group differences (PD with or without constipation) in CI, global non-motor symptoms burden, motor dysfunction, and striatal dopaminergic denervation. Kaplan-Meier method estimated group differences in cumulative proportion of patients with incident CI over three years. In PPMI, we subsequently performed univariate and multivariate Cox survival analyses to evaluate whether constipation predicts incident mild cognitive impairment or dementia over a 6-year period, including constipation and other known predictors of CI as covariates. Results: Patients with constipation had greater motor and global non-motor burden in both cohorts at baseline (p <  0.05). Kaplan-Meier plots showed faster conversion to CI in patients with constipation in both cohorts (p <  0.05). In PPMI, 37 subjects developed dementia during a mean follow-up of 4.9 years, and constipation was an independent predictor of dementia onset (hazard ratio = 2.311; p = 0.02). Conclusion: Constipation in de novo PD patients is associated with development of cognitive decline and may serve as a clinical biomarker for identification of patients at risk for cognitive impairment.

scholarly journals The Adenosine A2A Receptor Activation in Nucleus Accumbens Suppress Cue-Induced Reinstatement of Propofol Self-administration in Rats

2021 ◽  
Author(s):  
Zhanglei Dong ◽  
Bingwu Huang ◽  
Chenchen Jiang ◽  
Jiangfan Chen ◽  
Han Lin ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
D2 Receptor ◽  
Fixed Ratio ◽  
Receptor Activation ◽  
Addictive Behaviors ◽  
Self Administration ◽  
A2a Receptors ◽  
Mediated Effects ◽  
Seeking Behavior ◽  
Adenosine A2a

AbstractPropofol has shown strong addictive properties in rats and humans. Adenosine A2A receptors (A2AR) in the nucleus accumbens (NAc) modulate dopamine signal and addictive behaviors such as cocaine- and amphetamine-induced self-administration. However, whether A2AR can modulate propofol addiction remains unknown. AAV-shA2AR was intra-NAc injected 3 weeks before the propofol self-administration training to test the impacts of NAc A2AR on establishing the self-administration model with fixed ratio 1 (FR1) schedule. Thereafter, the rats were withdrawal from propofol for 14 days and tested cue-induced reinstatement of propofol seeking behavior on day 15. The propofol withdrawal rats received one of the doses of CGS21680 (A2AR agonist, 2.5–10.0 ng/site), MSX-3 (A2AR antagonist, 5.0–20.0 μg/site) or eticlopride (D2 receptor (D2R) antagonist, 0.75–3.0 μg/site) or vehicle via intra-NAc injection before relapse behavior test. The numbers of active and inactive nose-poke response were recorded. Focal knockdown A2AR by shA2AR did not affect the acquisition of propofol self-administration behavior, but enhance cue-induced reinstatement of propofol self-administration compared with the AAV-shCTRLgroup. Pharmacological activation of the A2AR by CGS21680 (≥ 5.0 ng/site) attenuated cue-induced reinstatement of propofol self-administration behavior. Similarly, pharmacological blockade of D2R by eticlopride (0.75–3.0 μg/site) attenuated propofol seeking behavior. These effects were reversed by the administration of MSX-3 (5.0–20.0 μg/site). The A2AR- and D2R-mediated effects on propofol relapse were not confounded by the learning process, and motor activity as the sucrose self-administration and locomotor activity were not affected by all the treatments. This study provides genetic and pharmacological evidence that NAc A2AR activation suppresses cue-induced propofol relapse in rats, possibly by interacting with D2R.

scholarly journals In vivo electrophysiology of nigral and thalamic neurons in alpha-synuclein-overexpressing mice highlights differences from toxin-based models of parkinsonism

2013 ◽  
Vol 110 (12) ◽  
pp. 2792-2805 ◽  
Author(s):  
C. J. Lobb ◽  
A. K. Zaheer ◽  
Y. Smith ◽  
D. Jaeger
Keyword(s):  
Primary Motor Cortex ◽  
Alpha Synuclein ◽  
Motor Dysfunction ◽  
Motor Deficits ◽  
Dopamine Depletion ◽  
Wild Type ◽  
Beta Oscillations ◽  
Nigrostriatal Dopamine ◽  
6 Hydroxydopamine

Numerous studies have suggested that alpha-synuclein plays a prominent role in both familial and idiopathic Parkinson's disease (PD). Mice in which human alpha-synuclein is overexpressed (ASO) display progressive motor deficits and many nonmotor features of PD. However, it is unclear what in vivo pathophysiological mechanisms drive these motor deficits. It is also unknown whether previously proposed pathophysiological features (i.e., increased beta oscillations, bursting, and synchronization) described in toxin-based, nigrostriatal dopamine-depletion models are also present in ASO mice. To address these issues, we first confirmed that 5- to 6-mo-old ASO mice have robust motor dysfunction, despite the absence of significant nigrostriatal dopamine degeneration. In the same animals, we then recorded simultaneous single units and local field potentials (LFPs) in the substantia nigra pars reticulata (SNpr), the main basal ganglia output nucleus, and one of its main thalamic targets, the ventromedial nucleus, as well as LFPs in the primary motor cortex in anesthetized ASO mice and their age-matched, wild-type littermates. Neural activity was examined during slow wave activity and desynchronized cortical states, as previously described in 6-hydroxydopamine-lesioned rats. In contrast to toxin-based models, we found a small decrease, rather than an increase, in beta oscillations in the desynchronized state. Similarly, synchronized burst firing of nigral neurons observed in toxin-based models was not observed in ASO mice. Instead, we found more subtle changes in pauses of SNpr firing compared with wild-type control mice. Our results suggest that the pathophysiology underlying motor dysfunction in ASO mice is distinctly different from striatal dopamine-depletion models of parkinsonism.

Dose-Dependent Effects of Dopamine (D2) Receptor Activation on Non-Focal Plasticity in Humans

2008 ◽  
Vol 1 (3) ◽  
pp. 282
Author(s):  
K. Monte-Silva ◽  
M. Kuo ◽  
W. Paulus ◽  
M. Nitsche
Keyword(s):  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
Receptor Activation ◽  
Dopamine D2 ◽  
Dose Dependent

Dynamic Changes in the Cortex-Basal Ganglia Network After Dopamine Depletion in the Rat

2008 ◽  
Vol 100 (1) ◽  
pp. 385-396 ◽  
Author(s):  
Cyril Dejean ◽  
Christian E. Gross ◽  
Bernard Bioulac ◽  
Thomas Boraud
Keyword(s):  
Basal Ganglia ◽  
Local Field ◽  
Signal Transmission ◽  
Local Field Potentials ◽  
Cellular Level ◽  
Cortical Activation ◽  
Field Potentials ◽  
Dopamine Depletion ◽  
Indirect Pathway ◽  
Before And After

It is well established that parkinsonian syndrome is associated with alterations in the temporal pattern of neuronal activity and local field potentials in the basal ganglia (BG). An increase in synchronized oscillations has been observed in different BG nuclei in parkinsonian patients and animal models of this disease. However, the mechanisms underlying this phenomenon remain unclear. This study investigates the functional connectivity in the cortex-BG network of a rodent model of Parkinson's disease. Single neurons and local field potentials were simultaneously recorded in the motor cortex, the striatum, and the substantia nigra pars reticulata (SNr) of freely moving rats, and high-voltage spindles (HVSs) were used to compare signal transmission before and after dopaminergic depletion. It is shown that dopaminergic lesion results in a significant enhancement of oscillatory synchronization in the BG: the coherence between pairs of structures increased significantly and the percentage of oscillatory auto- and cross-correlograms. HVS episodes were also more numerous and longer. These changes were associated with a shortening of the latency of SNr response to cortical activation, from 40.5 ± 4.8 to 10.2 ± 1.07 ms. This result suggests that, in normal conditions, SNr neurons are likely to be driven by late inputs from the indirect pathway; however, after the lesion, their shorter latency also indicates an overactivation of the hyperdirect pathway. This study confirms that neuronal signal transmission is altered in the BG after dopamine depletion but also provides qualitative evidence for these changes at the cellular level.

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