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

Abstract

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 ...

Retracted: Downregulated expression of microRNA‐329 inhibits apoptosis of nigral dopaminergic neurons by regulating CDKN2D expression via the FoxO3a signaling pathway in rats with Parkinson's disease

“…The pairing of miRs base to the 3′‐UTR of their target mRNAs can cause mRNA destabilization or translation repression, which consequently inhibits mRNA expression (Fabian et al, ). Dopaminergic neurons in the nigral dopaminergic neurons are crucial to appropriate voluntary movement like the impairment of cardinal motor in PD (Dodson et al, ). Progressive, selective, and irreversible loss of these neurons in brain substantia nigra of rats will result in PD (Zhang et al, ).…”

Differential Control of Dopaminergic Excitability and Locomotion by Cholinergic Inputs in Mouse Substantia Nigra

“…Dodson and colleagues reported that most DA neurons in the SNc had a pause in activity during onset of movement [29]. Others have shown that increased SNc activity is critical for initiation and acceleration of movement [2,30–32].…”

The missing, the short, and the long: Levodopa responses and dopamine actions

“…This work associates dorsal striatal phasic dopamine signaling with specific kinematic features of movement, consistent with other reports of movement-related phasic changes in nigrostriatal dopamine neuron firing. 43,44,45 …”

“…This work associates dorsal striatal phasic dopaminergic signaling with specific kinematic features of movement, consistent with other reports of movement-related phasic changes in nigrostriatal dopamine neuron firing. [43][44][45] Phasic dorsal nigrostriatal dopaminergic signaling likely plays a critical role in important aspects of fine motor performance distinct from its well-established role in reinforcement learning based on primary rewards. Some conceptual models of nigrostriatal phasic signaling in motor performance suggest that dopaminergic signaling is involved in control of motor performance by matching sensory feedback about motor performance to internal representations of desired actions.…”