Abstract

The goal of this project is to use a combination of genetically engineered mice and virus-mediated gene transfer in conjunction with mouse behavioral tests of learning and memory to identify the neural circuits that may underlie the cognitive decline in PD patients. We will develop two novel transgenic mouse lines that will allow us either to block genetically the production of dopamine in discrete dopaminergic projection regions by viral-mediated recombination of the tyrosine hydroxylase gene or to ablate completely dopamine neurons. We will determine whether the loss of dopamine signaling (by inactivation of tyrosine hydroxylase) or dopamine neuron death (by action of diphtheria toxin) leads to cognitive impairment and morphological changes within the striatum and/or prefrontal cortex (in conjunction with project 2).

Public Health Relevance

Parkinson's disease (PD) is caused by dopamine neuron cell death, but it is unclear if PD-related cognitive impairment is due to the loss of dopamine signaling, or to the secondary effects of dopamine neuron degeneration. We will develop 2 novel mouse models of PD to distinguish between the effects of loss of dopamine signaling and dopamine neuron degeneration on cognitive abilities.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center (P50)
Project #
5P50NS062684-05
Application #
8535834
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2013
Total Cost
$188,627
Indirect Cost
$57,181

  Institution

Name
University of Washington
Department
Type
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195

  Publications

Flanagan, Margaret E; Cholerton, Brenna; Latimer, Caitlin S et al. (2018) TDP-43 Neuropathologic Associations in the Nun Study and the Honolulu-Asia Aging Study. J Alzheimers Dis 66:1549-1558
Gray, Shelly L; Anderson, Melissa L; Hanlon, Joseph T et al. (2018) Exposure to Strong Anticholinergic Medications and Dementia-Related Neuropathology in a Community-Based Autopsy Cohort. J Alzheimers Dis 65:607-616
Moreno, Monica A; Or-Geva, Noga; Aftab, Blake T et al. (2018) Molecular signature of Epstein-Barr virus infection in MS brain lesions. Neurol Neuroimmunol Neuroinflamm 5:e466
Condello, Carlo; Lemmin, Thomas; Stöhr, Jan et al. (2018) Structural heterogeneity and intersubject variability of A? in familial and sporadic Alzheimer's disease. Proc Natl Acad Sci U S A 115:E782-E791
Locke, Timothy M; Soden, Marta E; Miller, Samara M et al. (2018) Dopamine D1 Receptor-Positive Neurons in the Lateral Nucleus of the Cerebellum Contribute to Cognitive Behavior. Biol Psychiatry 84:401-412
Cholerton, Brenna; Johnson, Catherine O; Fish, Brian et al. (2018) Sex differences in progression to mild cognitive impairment and dementia in Parkinson's disease. Parkinsonism Relat Disord 50:29-36
Blue, Elizabeth E; Bis, Joshua C; Dorschner, Michael O et al. (2018) Genetic Variation in Genes Underlying Diverse Dementias May Explain a Small Proportion of Cases in the Alzheimer's Disease Sequencing Project. Dement Geriatr Cogn Disord 45:1-17
Houser, Madelyn C; Chang, Jianjun; Factor, Stewart A et al. (2018) Stool Immune Profiles Evince Gastrointestinal Inflammation in Parkinson's Disease. Mov Disord 33:793-804
Wile, Daryl J; Agarwal, Pankaj A; Schulzer, Michael et al. (2017) Serotonin and dopamine transporter PET changes in the premotor phase of LRRK2 parkinsonism: cross-sectional studies. Lancet Neurol 16:351-359
Dublin, Sascha; Walker, Rod L; Gray, Shelly L et al. (2017) Use of Analgesics (Opioids and Nonsteroidal Anti-Inflammatory Drugs) and Dementia-Related Neuropathology in a Community-Based Autopsy Cohort. J Alzheimers Dis 58:435-448

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