Dopaminergic neurones: much more than dopamine?

Seutin, Vincent

doi:10.1038/sj.bjp.0706328

Cited by 30 publications

(14 citation statements)

References 30 publications

(35 reference statements)

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“…These factors could be (1) loss of physiological DA clearance due to reduction of striatal DAT expression after destruction of DA terminals, (2) loss of co-transmitters or modulators, like glutamate, serotonin, GABA or cholecystokinin, that have been reported to be released from DA terminals, (3) loss of trophic factors, e.g. brain-derived neurotrophic factor, that are produced by DA neurons, or (4) processes related to inflammation and/or gliosis that follow loss of DA neurons (Altar et al, 1997; Hnasko et al, 2010; Hokfelt et al, 1980; Nagatsu and Sawada, 2006; Seroogy et al, 1988; Seutin, 2005; Tritsch et al, 2012; Wallen-Mackenzie et al, 2010; Zhou et al, 2005). …”

Section: Discussionmentioning

confidence: 99%

“…This has important implications for understanding the development of cognitive and motor deficits in late-stage PD, as the actual loss of SNpc DA neurons observed in advanced PD might have effects beyond the mere loss of DA, including inflammatory responses, gliosis and loss of co-transmitter release from DA neurons (Nagatsu and Sawada, 2006; Seutin, 2005; Whitton, 2007). Thus, effective treatment of late-stage, PD-associated deficits may require targeting these processes as well as the loss of DA.…”

Section: Introductionmentioning

confidence: 99%

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Relative contributions of severe dopaminergic neuron ablation and dopamine depletion to cognitive impairment

Morgan

Gibbs

Melief

et al. 2015

Experimental Neurology

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Parkinson’s disease (PD) is characterized by the loss of dopaminergic neurons and produces a movement disorder and cognitive impairment that becomes more extensive with the duration of the disease. To what extent cognitive impairment in advanced PD can be attributed to severe loss of dopamine (DA) signaling is not well understood. Furthermore, it is unclear if the loss of DA neurons contributes to the cognitive impairment caused by the reduction in DA signaling. We generated genetic mouse models with equally severe chronic loss of DA achieved by either extensive ablation of DA neurons or inactivation of DA synthesis from preserved neurons and compared their motor and cognitive performance. Motor behaviors were equally blunted in both models, but we observed that DA neuron ablation caused more severe cognitive deficits than DA depletion. Both models had marked deficits in cue-discrimination learning. Yet, deficits in cue-discrimination learning were more severe in mice with DA neuron ablation and only mice with DA neuron ablation had drastically impaired performance in spatial learning, spatial memory and object memory tests. These results indicate that while a severe reduction in DA signaling results in motor and cognitive impairments, the loss of DA neurons promotes more extensive cognitive deficits and suggest that a loss of additional factors that depend on DA neurons may participate in the progressive cognitive decline found in patients with PD.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Relative contributions of severe dopaminergic neuron ablation and dopamine depletion to cognitive impairment

Morgan

Gibbs

Melief

et al. 2015

Experimental Neurology

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“…The challenge will be to discriminate between secondary processes of DA neuron degeneration like inflammation and gliosis and the loss of other signaling molecules (e.g. brain-derived neurotrophic factor, cholecystokinin, glutamate, serotonin and GABA) that are known to be released by DA neurons (Seutin, 2005; Tritsch et al, 2012). …”

Section: Discussionmentioning

confidence: 99%

Contributions of signaling by dopamine neurons in dorsal striatum to cognitive behaviors corresponding to those observed in Parkinson's disease

Darvas¹,

Henschen²,

Palmiter³

2014

Neurobiology of Disease

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Although the cardinal features of Parkinson’s disease (PD) are motor symptoms, PD also causes cognitive deficits including cognitive flexibility and working memory, which are strongly associated with prefrontal cortex (PFC) functions. Yet, early stage PD is not characterized by pathology in the PFC but by a loss of dopaminergic (DA) projections from the substantia nigra to the dorsal striatum. Moreover, the degree to which PD symptoms can be ascribed to the loss of DA alone or to the loss of DA neurons is unknown. We addressed these issues by comparing mouse models of either chronic DA depletion or loss of DA projections to the dorsal striatum. We achieved equal levels of striatal DA reduction in both models which ranged from mild (~ 25%) to moderate (~ 60%). Both models displayed DA concentration-dependent reductions of motor function as well as mild deficits of cognitive flexibility and working memory. Interestingly, whereas both motor function and cognitive flexibility were more severely impaired after mild ablation of DA neurons as compared to mild loss of DA alone, both models had equal deficits after moderate loss of DA. Our results confirm contributions of nigro-striatal dopamine signaling to cognitive behaviors that are affected in early stage PD. Furthermore, our findings suggest that the phenotype after ablation of DA neurons accrues from factors beyond the mere loss of DA.

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“…While formally possible, it is unlikely that this discrepancy reflects a difference in the role of dopamine neurons that project to the NAc in mice and rats. Another possibility is that the vrDDfs mice have intact dopamine neurons (compared to 6-OHDA-lesioned rats), and hence, they could continue to release other neurotransmitters including neuropeptides (cholecystokinin and neurotensin) and glutamate (Chuhma et al 2004;Seutin 2005). These signaling molecules would be lost along with dopamine after 6-OHDA lesions.…”

Section: Discussionmentioning

confidence: 99%

Viral restoration of dopamine signaling to the dorsal striatum restores instrumental conditioning to dopamine-deficient mice

et al. 2006

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Dopaminergic neurones: much more than dopamine?

Cited by 30 publications

References 30 publications

Relative contributions of severe dopaminergic neuron ablation and dopamine depletion to cognitive impairment

Relative contributions of severe dopaminergic neuron ablation and dopamine depletion to cognitive impairment

Contributions of signaling by dopamine neurons in dorsal striatum to cognitive behaviors corresponding to those observed in Parkinson's disease

Viral restoration of dopamine signaling to the dorsal striatum restores instrumental conditioning to dopamine-deficient mice

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