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

Willard, Amanda M; Isett, Brian R.; Whalen, Timothy C; Mastro, Kevin J; Ki, Chris S; Mao, Xiaobo; Gittis, Aryn H.

doi:10.7554/elife.42746

Cited by 55 publications

(75 citation statements)

References 98 publications

(152 reference statements)

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“…To confirm this in another manner, we rebuilt the models using the same cross-validated 179 training and testing sets as above using only a single parameter at a time, or using all of the 180 parameters except oscillations. The first four parameters fall outside (FR) or on the edge (CV 181 performs better than any individual parameter ( Figure 4d), confirming results seen previously 183 (Willard et al, 2019). However, the model built using only oscillations as a predictor is, on 184 average, better than any other model including the combined parameter model, providing further 185 evidence that other physiological parameters are not additionally informative when oscillations 186 are considered.…”

Section: Of Dysfunction 139supporting

confidence: 71%

“…Hammond et al, 2007; Jenkinson & Brown, 2011). Here, we demonstrate dopamine loss and 321 PD-like symptoms in mice without the presence of beta oscillations, and we have previously 322 demonstrated their absence in LFP signals in awake mice as well(Willard et al, 2019). Indeed, 323to our knowledge, no study has demonstrated the presence of beta oscillations in mouse 324 models of PD.…”

mentioning

confidence: 67%

“…To understand how delta oscillations relate to the severity of dopamine depletion, we 140 used an existing dataset of SNr recordings from mice gradually depleted to varying levels of 141 dopamine loss through successive small injections of 6-OHDA (Willard et al, 2019). In this data, 142…”

Section: Of Dysfunction 139mentioning

confidence: 99%

“…To determine if two units were synchronous, we used the method and parameters 576 outlined in Willard et al 2019, which determines the fraction of synchronous spikes above 577 chance after correcting for nonstationarity in a unit's firing rate (Willard et al, 2019). In brief, we 578 windowed both spike trains into 12-second segments and zeroed the first and last four seconds 579 of the segment taken from the second spike train.…”

Section: Neural Measures 568mentioning

confidence: 99%

“…Full details on the behavioral testing and the principal component analysis (PCA) metric 595 for gradually depleted animals can be found in Willard et al 2019. In brief, PCA was performed 596 on the following metrics from behavioral tests: mean speed in an open field, number of rears in 597 10 minutes in a small enclosure, total time spent traversing a pole task, and latency to fall on a 598 wire hang task.…”

Section: Behavioral Testing and Metric 594mentioning

confidence: 99%

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

Whalen

Willard

Rubin

et al. 2020

Preprint

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1Delta oscillations (0.5-4 Hz) are a robust but often overlooked feature of basal ganglia 2 pathophysiology in Parkinson's disease and their relationship to parkinsonian akinesia has not 3 been investigated. Here, we establish a novel approach to detect spike oscillations embedded in 4 noise to provide the first study of delta oscillations in awake, dopamine depleted mice. We find 5 that approximately half of neurons in the substantia nigra reticulata exhibit delta oscillations in 6 dopamine depletion and that these oscillations are a strong indicator of dopamine loss and 7 akinesia, outperforming measures such as changes in firing rate, irregularity, bursting and 8 synchrony. We further establish that these oscillations are caused by the loss of D2 receptor 9 activation and do not require motor cortex, contrary to previous findings in anesthetized animals. 10These results give insight into how dopamine loss leads to dysfunction and suggest a 11 reappraisal of delta oscillations as a biomarker in Parkinson's disease. 12 models, the link between beta oscillations and motor symptoms is less clear. Beta oscillations Belluscio et al., 2003) and were weakened after cortical ablation (Magill et al., 2001), leading to 53 the conclusion that they merely infiltrate the basal ganglia through M1 and are not relevant to 54 the awake, behaving parkinsonian animal. Experiments investigating the presence of sub-beta 55 band oscillations in awake, behaving animals have, to our knowledge, not been performed. 56One factor limiting these investigations is the high levels of noise that contaminate low 57 frequency signals, particularly during awake recordings. So-called "pink" or "flicker" noise is 58 most prevalent at low frequencies and typically observed in LFP recordings but is also present 59 in the spiking of individual neurons. This complication makes reliable detection of oscillations 60 near or below 2 Hz difficult with current methods. 61Here, we develop a method to reliably distinguish spike oscillations from noise and use 62 this approach to characterize the oscillations in the substantia nigra pars reticulata (SNr) of 63 dopamine depleted mice. We demonstrate that delta, not beta, oscillations are the primary 64 oscillatory feature in SNr neurons after loss of dopamine, and that they correlate strongly with 65 PD-like motor deficits. We show that, contrary to prior reports, delta oscillations in the SNr 66 precede those in M1, and that M1 is not necessary for these oscillations to develop in the SNr. 67We also establish that a loss of D2 receptor activation is sufficient to immediately and reversibly 68 generate both delta oscillations and PD-like akinesia in awake mice, suggesting a direct link 69 between dopamine loss, delta oscillations, and parkinsonian symptoms. This work indicates that 70 delta oscillations in basal ganglia neurons are a critical component of parkinsonian pathology in 71 DD mice and suggests that DD mice may effectively model the low frequency oscillations seen 72 in PD patients. 73 74Results 75 D...

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Section: Of Dysfunction 139supporting

confidence: 71%

mentioning

confidence: 67%

Section: Of Dysfunction 139mentioning

confidence: 99%

Section: Neural Measures 568mentioning

confidence: 99%

Section: Behavioral Testing and Metric 594mentioning

confidence: 99%

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

Whalen

Willard

Rubin

et al. 2020

Preprint

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Aberrant features of in vivo striatal dynamics in Parkinson's disease

Lee

Masmanidis

2019

J of Neuroscience Research

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The striatum plays an important role in learning, selecting, and executing actions. As a major input hub of the basal ganglia, it receives and processes a diverse array of signals related to sensory, motor, and cognitive information. Aberrant neural activity in this area is implicated in a wide variety of neurological and psychiatric disorders. It is therefore important to understand the hallmarks of disrupted striatal signal processing. This review surveys literature examining how in vivo striatal microcircuit dynamics are impacted in animal models of one of the most widely studied movement disorders, Parkinson's disease. The review identifies four major features of aberrant striatal dynamics: altered relative levels of direct and indirect pathway activity, impaired information processing by projection neurons, altered information processing by interneurons, and increased synchrony.

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Substantia Nigra Pars Reticulata Projections to the Pedunculopontine Nucleus Modulate Dyskinesia

Alberico

et al. 2023

Movement Disorders

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BackgroundLong‐term use of levodopa for Parkinson's disease (PD) treatment is often hindered by development of motor complications, including levodopa‐induced dyskinesia (LID). The substantia nigra pars reticulata (SNr) and globus pallidus internal segment (GPi) are the output nuclei of the basal ganglia. Dysregulation of SNr and GPi activity contributes to PD pathophysiology and LID.ObjectiveThe objective of this study was to determine whether direct modulation of SNr GABAergic neurons and SNr projections to the pedunculopontine nucleus (PPN) regulates PD symptoms and LID in a mouse model.MethodsWe expressed Cre‐recombinase activated channelrhodopsin‐2 (ChR2) or halorhodopsin adeno‐associated virus‐2 (AAV2) vectors selectively in SNr GABAergic neurons of Vgat‐IRES‐Cre mice in a 6‐hydroxydopamine model of PD to investigate whether direct optogenetic modulation of SNr neurons or their projections to the PPN regulates PD symptoms and LID expression. The forepaw stepping task, mouse LID rating scale, and open‐field locomotion were used to assess akinesia and LID to test the effect of SNr modulation.ResultsAkinesia was improved by suppressing SNr neuron activity with halorhodopsin. LID was significantly reduced by increasing SNr neuronal activity with ChR2, which did not interfere with the antiakinetic effect of levodopa. Optical stimulation of ChR2 in SNr projections to the PPN recapitulated direct SNr stimulation.ConclusionsModulation of SNr GABAergic neurons alters akinesia and LID expression in a manner consistent with the rate model of basal ganglia circuitry. Moreover, the projections from SNr to PPN likely mediate the antidyskinetic effect of increasing SNr neuronal activity, identifying a potential novel role for the PPN in LID. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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

Cited by 55 publications

References 98 publications

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

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

Aberrant features of in vivo striatal dynamics in Parkinson's disease

Substantia Nigra Pars Reticulata Projections to the Pedunculopontine Nucleus Modulate Dyskinesia

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