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

ABSTRACT: 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.

SUBMITTER: Darvas M

PROVIDER: S-EPMC4001780 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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

Darvas Martin M Henschen Charles W CW Palmiter Richard D RD

Neurobiology of disease 20140201

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 ...[more]

PMID: 24491966

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Project description:Dopamine (DA), a highly significant neurotransmitter in the mammalian central nervous system, operates on multiple time scales to affect a diverse array of physiological functions. The significance of DA in human health is heightened by its role in a variety of pathologies. Voltammetric measurements of electrically evoked DA release have brought to light the existence of a patchwork of DA kinetic domains in the dorsal striatum (DS) of the rat. Thus, it becomes necessary to consider how these domains might be related to specific aspects of DA's functions. Responses evoked in the fast and slow domains are distinct in both amplitude and temporal profile. Herein, we report that responses evoked in fast domains can be further classified into four distinct types, types 1-4. The DS, therefore, exhibits a total of at least five distinct evoked responses (four fast types and one slow type). All five response types conform to kinetic models based entirely on first-order rate expressions, which indicates that the heterogeneity among the response types arises from kinetic diversity within the DS terminal field. We report also that functionally distinct subregions of the DS express DA kinetic diversity in a selective manner. Thus, this study documents five response types, provides a thorough kinetic explanation for each of them, and confirms their differential association with functionally distinct subregions of this key DA terminal field. The dorsal striatum is composed of five significantly different dopamine domains (types 1-4 and slow, average ± SEM responses to medial forebrain bundle (MFB) stimulation are shown in the figure). Responses from each of these five domains exhibit significantly different ascending and descending kinetic profiles and return to a long lasting elevated dopamine state, termed the dopamine hang-up. All features of these responses are modeled with high correlation using first-order modeling as well as our recently published restricted diffusion model of evoked dopamine overflow. We also report that functionally distinct subregions of the dorsal striatum express selective dopamine kinetic diversity.

Dataset Information

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

Publications

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

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