Contributions of signaling by dopamine neurons in dorsal striatum to cognitive behaviors corresponding to those observed in Parkinson's disease.
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.
Department of Pathology, University of Washington, Seattle, WA 98195, USA. Electronic address: mdarvas@uw.edu.
Martin
M
Darvas
Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
Charles W
CW
Henschen
Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA.
Richard D
RD
Palmiter
D000818:Animals; D003072:Cognition Disorders / Q000473:pathology*; D003342:Corpus Striatum / Q000473:pathology*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000378:metabolism*; D008568:Memory / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D019957:Motor Skills Disorders / Q000209:etiology; D053580:Muscle Strength / Q000187:drug effects / Q000502:physiology; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000150:complications* / Q000209:etiology / Q000473:pathology*; D011597:Psychomotor Performance / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013565:Sympatholytics / Q000633:toxicity; D014446:Tyrosine 3-Monooxygenase / Q000172:deficiency / Q000235:genetics
D013565:Sympatholytics; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine
6-Hydroxydopamine; Dopamine-deficient mice; Executive function; Neurodegeneration; Tyrosine hydroxylase; Viral inactivation