Activity of Neurochemically Heterogeneous Dopaminergic Neurons in the Substantia Nigra during Spontaneous and Driven Changes in Brain State

Brown, Matthew T.; Henny, Pablo; Bolam, J. Paul; Magill, Peter J.

doi:10.1523/jneurosci.4423-08.2009

Cited by 94 publications

(108 citation statements)

References 65 publications

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“…Dopamine did not inhibit the firing of these classically defined non-dopaminergic or GABAergic neurons (Grace & Onn, 1989;Johnson & North, 1992). A recent study confirmed that almost all electrophysiologically-classified dopaminergic neurons are tyrosine hydroxylasepositive (Brown et al, 2009), despite discrepancies found in some other studies (Margolis et al, 2006;Margolis et al, 2010). "Dopamine neurones" referred to in this study are therefore those that conform to electrophysiological and pharmacological criteria, but not necessarily to the content of dopamine.…”

Section: Vta Slice Preparation and Electrophysiological Recordingssupporting

confidence: 73%

Increased desensitization of dopamine D2 receptor-mediated response in the ventral tegmental area in the absence of adenosine A2A receptors

Al‐Hasani

Metaxas

et al. 2011

Neuroscience

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Section: Vta Slice Preparation and Electrophysiological Recordingssupporting

confidence: 73%

Increased desensitization of dopamine D2 receptor-mediated response in the ventral tegmental area in the absence of adenosine A2A receptors

Al‐Hasani

Metaxas

et al. 2011

Neuroscience

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“…Several lines of evidence suggest that the movementassociated decreases in the firing of SNc neurons that we observed are not related to aversion or a negative prediction error. First, compared with VTA neurons (4,6,(34)(35)(36), SNc neurons exhibit relatively poor encoding of aversive stimuli and negative prediction errors (37)(38)(39). Moreover, we observed movementrelated decreases in the firing of SNc neurons but not of VTA neurons, the opposite of what would be expected if the pauses were encoding aversion.…”

Section: Discussionmentioning

confidence: 51%

Representation of spontaneous movement by dopaminergic neurons is cell-type selective and disrupted in parkinsonism

Dodson

Dreyer

Jennings

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

154

167

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Midbrain dopaminergic neurons are essential for appropriate voluntary movement, as epitomized by the cardinal motor impairments arising in Parkinson's disease. Understanding the basis of such motor control requires understanding how the firing of different types of dopaminergic neuron relates to movement and how this activity is deciphered in target structures such as the striatum. By recording and labeling individual neurons in behaving mice, we show that the representation of brief spontaneous movements in the firing of identified midbrain dopaminergic neurons is cell-type selective. Most dopaminergic neurons in the substantia nigra pars compacta (SNc), but not in ventral tegmental area or substantia nigra pars lateralis, consistently represented the onset of spontaneous movements with a pause in their firing. Computational modeling revealed that the movement-related firing of these dopaminergic neurons can manifest as rapid and robust fluctuations in striatal dopamine concentration and receptor activity. The exact nature of the movement-related signaling in the striatum depended on the type of dopaminergic neuron providing inputs, the striatal region innervated, and the type of dopamine receptor expressed by striatal neurons. Importantly, in aged mice harboring a genetic burden relevant for human Parkinson's disease, the precise movement-related firing of SNc dopaminergic neurons and the resultant striatal dopamine signaling were lost. These data show that distinct dopaminergic cell types differentially encode spontaneous movement and elucidate how dysregulation of their firing in early Parkinsonism can impair their effector circuits.opamine is vital for normal motor function, as exemplified by the motor deficits arising from the dysfunction/degeneration of midbrain dopaminergic neurons in Parkinson's disease (PD). One prevailing view is that midbrain dopaminergic neurons guide purposeful actions through encoding value, for example, by conveying the difference between expected and actual reward (1-3). Although this function has been ascribed to all midbrain dopaminergic neurons, there is considerable functional heterogeneity across different cell populations in the ventral tegmental area (VTA; A10) and the substantia nigra pars compacta (SNc; A9) (4-7). For example, some dopaminergic neurons respond to novel or salient events or during cognitive processes such as decision making and working memory (6,(8)(9)(10). Moreover, although the firing of these dopaminergic neurons generally has been thought not to vary consistently with movement (3, 11), there is evidence that the activity of putatively classified dopaminergic neurons can change during movement execution in a heterogeneous manner (12-16). This evidence, in turn, raises the possibilities that at least some types of movement might be differentially encoded by the firing of distinct populations of dopaminergic neuron and that dysregulation of such activity might contribute to motor impairment in PD before, or commensurate with, frank neurodegeneration.To ...

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“…Extracellular recordings of singleunit activity in the SNc were made using glass electrodes (10-25 MΩ in situ; tip diameter ∼1.5 μm) containing 0.5 M NaCl solution and Neurobiotin (1.5% wt/vol; Vector Laboratories). An electrocorticogram was also recorded above the frontal cortex (18). Following electrophysiological characterization, single neurons were juxtacellularly labeled with Neurobiotin for post hoc verification of location and neurochemical identity (18).…”

Section: Methodsmentioning

confidence: 99%

“…An electrocorticogram was also recorded above the frontal cortex (18). Following electrophysiological characterization, single neurons were juxtacellularly labeled with Neurobiotin for post hoc verification of location and neurochemical identity (18). We focused our analysis on single-unit activity recorded during robust slow-wave activity, as quantitatively defined from the simultaneous electrocorticogram recordings.…”

Section: Methodsmentioning

confidence: 99%

Deficits in dopaminergic transmission precede neuron loss and dysfunction in a new Parkinson model

Janezic

Threlfell

Dodson

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

271

275

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The pathological end-state of Parkinson disease is well described from postmortem tissue, but there remains a pressing need to define early functional changes to susceptible neurons and circuits. In particular, mechanisms underlying the vulnerability of the dopamine neurons of the substantia nigra pars compacta (SNc) and the importance of protein aggregation in driving the disease process remain to be determined. To better understand the sequence of events occurring in familial and sporadic Parkinson disease, we generated bacterial artificial chromosome transgenic mice (SNCA-OVX) that express wild-type α-synuclein from the complete human SNCA locus at disease-relevant levels and display a transgene expression profile that recapitulates that of endogenous α-synuclein. SNCA-OVX mice display age-dependent loss of nigrostriatal dopamine neurons and motor impairments characteristic of Parkinson disease. This phenotype is preceded by early deficits in dopamine release from terminals in the dorsal, but not ventral, striatum. Such neurotransmission deficits are not seen at either noradrenergic or serotoninergic terminals. Dopamine release deficits are associated with an altered distribution of vesicles in dopaminergic axons in the dorsal striatum. Aged SNCA-OVX mice exhibit reduced firing of SNc dopamine neurons in vivo measured by juxtacellular recording of neurochemically identified neurons. These progressive changes in vulnerable SNc neurons were observed independently of overt protein aggregation, suggesting neurophysiological changes precede, and are not driven by, aggregate formation. This longitudinal phenotyping strategy in SNCA-OVX mice thus provides insights into the region-specific neuronal disturbances preceding and accompanying Parkinson disease.dopamine transmission | in vivo electrophysiology | voltammetry | neurodegeneration | behavioral phenotyping T he development of new disease-modifying therapies for Parkinson disease (PD) is critically dependent on animal models that accurately recapitulate pathophysiological sequelae in an age-dependent manner. The generation of such models using genetically altered animals has proved challenging. The traditional use of heterologous gene promoters in the generation of transgenic mouse models precluded an endogenous transgene expression profile and produced additional phenotypes that are not characteristic of PD (1). In contrast, bacterial artificial chromosome (BAC) technology can enable expression of a desired transgene under the control of its native promoter and regulatory elements to achieve a correct spatiotemporal expression profile, thereby providing a more physiological model for investigating molecular mechanisms of the disease.The α-synuclein gene (SNCA) has been implicated in PD through three dominant point mutations (2-4) and locus multiplication (5, 6). SNCA duplications and triplications cause autosomal-dominant PD in which the age of onset and disease severity are related in a gene dosage-dependent manner (5, 6). More recently, genome-wide associatio...

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Activity of Neurochemically Heterogeneous Dopaminergic Neurons in the Substantia Nigra during Spontaneous and Driven Changes in Brain State

Cited by 94 publications

References 65 publications

Increased desensitization of dopamine D2 receptor-mediated response in the ventral tegmental area in the absence of adenosine A2A receptors

Increased desensitization of dopamine D2 receptor-mediated response in the ventral tegmental area in the absence of adenosine A2A receptors

Representation of spontaneous movement by dopaminergic neurons is cell-type selective and disrupted in parkinsonism

Deficits in dopaminergic transmission precede neuron loss and dysfunction in a new Parkinson model

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