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

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.

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Substantia nigra hyperechogenicity and CSF dopamine depletion in HIV

Aktuelle Neurologie ◽

10.1055/s-0028-1086479 ◽

2008 ◽

Vol 35 (S 01) ◽

Author(s):

J Thiermann ◽

M Obermann ◽

M Küper ◽

O Kastrup ◽

Ö Yaldizli ◽

...

Keyword(s):

Substantia Nigra ◽

Dopamine Depletion ◽

Substantia Nigra Hyperechogenicity

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Association of the Non-Motor Burden with Patterns of Striatal Dopamine Loss in de novo Parkinson’s Disease

Journal of Parkinson s Disease ◽

10.3233/jpd-202127 ◽

2020 ◽

Vol 10 (4) ◽

pp. 1541-1549

Author(s):

Seok Jong Chung ◽

Sangwon Lee ◽

Han Soo Yoo ◽

Yang Hyun Lee ◽

Hye Sun Lee ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

De Novo ◽

Early Stage ◽

Striatal Dopamine ◽

Motor Deficits ◽

Dopamine Depletion ◽

Severe Motor ◽

Severe Group ◽

Striatal Dopamine Depletion

Background: Striatal dopamine deficits play a key role in the pathogenesis of Parkinson’s disease (PD), and several non-motor symptoms (NMSs) have a dopaminergic component. Objective: To investigate the association between early NMS burden and the patterns of striatal dopamine depletion in patients with de novo PD. Methods: We consecutively recruited 255 patients with drug-naïve early-stage PD who underwent 18F-FP-CIT PET scans. The NMS burden of each patient was assessed using the NMS Questionnaire (NMSQuest), and patients were divided into the mild NMS burden (PDNMS-mild) (NMSQuest score <6; n = 91) and severe NMS burden groups (PDNMS-severe) (NMSQuest score >9; n = 90). We compared the striatal dopamine transporter (DAT) activity between the groups. Results: Patients in the PDNMS-severe group had more severe parkinsonian motor signs than those in the PDNMS-mild group, despite comparable DAT activity in the posterior putamen. DAT activity was more severely depleted in the PDNMS-severe group in the caudate and anterior putamen compared to that in the PDMNS-mild group. The inter-sub-regional ratio of the associative/limbic striatum to the sensorimotor striatum was lower in the PDNMS-severe group, although this value itself lacked fair accuracy for distinguishing between the patients with different NMS burdens. Conclusion: This study demonstrated that PD patients with severe NMS burden exhibited severe motor deficits and relatively diffuse dopamine depletion throughout the striatum. These findings suggest that the level of NMS burden could be associated with distinct patterns of striatal dopamine depletion, which could possibly indicate the overall pathological burden in PD.

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

Journal of Neurophysiology ◽

10.1152/jn.00441.2013 ◽

2013 ◽

Vol 110 (12) ◽

pp. 2792-2805 ◽

Cited By ~ 10

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.

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Striatal dopamine–glutamate interactions reflected in substantia nigra reticulata firing

Neuroreport ◽

10.1097/00001756-199812010-00012 ◽

1998 ◽

Vol 9 (17) ◽

pp. 3829-3836 ◽

Cited By ~ 5

Author(s):

Wia Timmerman ◽

Fiona Westerhof ◽

Taliet I. C. van der Wal ◽

Ben H. C. Westerink

Keyword(s):

Substantia Nigra ◽

Striatal Dopamine ◽

Substantia Nigra Reticulata

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Neuroprotective Effect of Nortriptyline in Overt Hepatic Encephalopathy Through Attenuation of Mitochondrial Dysfunction

ASN NEURO ◽

10.1177/1759091418810583 ◽

2018 ◽

Vol 10 ◽

pp. 175909141881058 ◽

Cited By ~ 3

Author(s):

Ji Heun Jeong ◽

Do Kyung Kim ◽

Nam-Seob Lee ◽

Young-Gil Jeong ◽

Ho Won Kim ◽

...

Keyword(s):

Cell Death ◽

Hepatic Encephalopathy ◽

Substantia Nigra ◽

Mitochondrial Dysfunction ◽

Mitochondrial Permeability Transition ◽

Neuroprotective Effect ◽

Motor Deficits ◽

Apoptotic Pathway ◽

Duct Ligation ◽

Overt Hepatic Encephalopathy

Hyperammonemia associated with overt hepatic encephalopathy (OHE) causes excitotoxic neuronal death through activation of the cytochrome C (CytC)-mediated mitochondria-dependent apoptotic pathway. We tested the therapeutic effect of nortriptyline (NT), a mitochondrial permeability transition pore (mPTP) blocker that can possibly inhibit mitochondrial CytC efflux to the cytosol on in vivo and in vitro OHE models. After ensuring the generation of OHE rats, established by bile duct ligation (BDL), they were intraperitoneally administered either 20 mg/kg NT (i.e., BDL+NT) or another vehicle (i.e., BDL+VEH) for 14 days. Compared with the control, BDL+VEH showed an increment of motor deficits, cell death, synaptic loss, apoptosis, and mitochondria with aberrant morphology in substantia nigra compacta dopaminergic (DA-ergic) neurons. However, the extent was significantly reversed in BDL+NT. Subsequently, we studied the neuroprotective mechanism of NT using PC-12 cells, a DA-ergic cell line, which exposed glutamate used as an excitotoxin. Compared with the control, the cells exposed to 15 mM glutamate (i.e., GLU) showed incremental cell death, apoptosis, and demise in mitochondrial respiration. Importantly, efflux of CytC from mitochondria to cytosol and the dissipation of mitochondrial membrane potential (△Ψm), an indicator of mPTP opening, were prominent in GLU. However, compared with the GLU, the cells cotreated with 10 μM NT (i.e., GLU+NT) showed a significant reduction in the aforementioned phenomenon. Together, we concluded that NT can be used for OHE therapeutics, mitigating the excitotoxic death of substantia nigra compacta DA-ergic neurons via mPTP-associated mitochondrial dysfunction inhibition.

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Role of the Subthalamic Nucleus in Cannabinoid Actions in the Substantia Nigra of the Rat

Journal of Neurophysiology ◽

10.1152/jn.1997.77.3.1635 ◽

1997 ◽

Vol 77 (3) ◽

pp. 1635-1638 ◽

Cited By ~ 58

Author(s):

M. Clara Sañudo-Peña ◽

J. Michael Walker

Keyword(s):

Substantia Nigra ◽

Subthalamic Nucleus ◽

Cannabinoid Receptors ◽

Excitatory Input ◽

Physiological Regulation ◽

Cannabinoid Antagonist ◽

Substantia Nigra Reticulata ◽

Cannabinoid Agonist ◽

Stimulation Of

Sañudo-Peña, M. Clara and J. Michael Walker. Role of the subthalamic nucleus in cannabinoid actions in the substantia nigra of the rat. J. Neurophysiol. 77: 1635–1638, 1997. The effect of cannabinoids on the excitatory input to the substantia nigra reticulata (SNr) from the subthalamic nucleus was explored. For this purpose a knife cut was performed rostral to the subthalamic nucleus to isolate the subthalamic nucleus and the SNr from the striatum, a major source of cannabinoid receptors to the SNr. The data showed that the cannabinoid agonist WIN55,212-2 blocked the increase in the firing rate of SNr neurons induced by stimulation of the subthalamic nucleus with bicuculline. Furthermore, the cannabinoid antagonist SR141716A antagonized the effect of the cannabinoid agonist. This study showed that cannabinoids regulate not only the striatonigral pathway, as previously reported, but also the subthalamonigral pathway. The opposite influences of these two inputs to the SNr, inhibitory and excitatory respectively, suggest that endogenous cannabinoids play a major role in the physiological regulation of the SNr.

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Transient dopamine neuron activity precedes and encodes the vigor of contralateral movements

10.1101/2021.04.20.440527 ◽

2021 ◽

Author(s):

Marcelo D Mendonça ◽

Joaquim Alves da Silva ◽

Ledia F. Hernandez ◽

Ivan Castela ◽

José Obeso ◽

...

Keyword(s):

Substantia Nigra ◽

Dopamine Neurons ◽

Substantia Nigra Pars Compacta ◽

Neuron Activity ◽

Similar Proportion ◽

List Type ◽

Dopamine Depletion ◽

Movement Initiation ◽

Transient Activity ◽

Forelimb Movement

SummaryDopamine neurons (DANs) in the substantia nigra pars compacta (SNc) have been related to movement vigor, and loss of these neurons leads to bradykinesia in Parkinson’s disease. However, it remains unclear whether DANs encode a general motivation signal or modulate movement kinematics. We imaged activity of SNc DANs in mice trained in a novel operant task which relies on individual forelimb movement sequences. We uncovered that a similar proportion of SNc DANs increased their activity before ipsi- vs. contralateral forelimb movements. However, the magnitude of this activity was higher for contralateral actions, and was related to contralateral but not ipsilateral action vigor. In contrast, the activity of reward-related DANs, largely distinct from those modulated by movement, was not lateralized. Finally, unilateral dopamine depletion impaired contralateral, but not ipsilateral, movement vigor. These results indicate that movement-initiation DANs encode more than a general motivation signal, and invigorate kinematic aspects of contralateral movements.HighlightsDeveloped a freely-moving task where mice learn rapid individual forelimb sequences.Movement-related DANs encode contralateral but not ipsilateral action vigor.The activity of reward-related DANs is not lateralized.Unilateral dopamine depletion impaired contralateral, but not ipsilateral, movement vigor.eTOC summary: Mendonça et al. show that transient activity in movement-related dopamine neurons in substantia nigra pars compacta encodes contralateral, but not ipsilateral action vigor. Consistently, unilateral dopamine depletion impaired contralateral, but not ipsilateral, movement vigor.

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