Background: Parkinson's disease (PD) is a chronic, progressive, neurodegenerative disorder with currently no known cure. PD has a significant impact on quality of life of the patients, as well as, the caregivers and family members. It is the second most common cause of chronic neurological disability in US and Europe. According to National Parkinson's Foundation, there are almost 1 million patients in the Unites States and 50,000 to 60,000 new cases of PD are diagnosed each year. The total number of cases of PD is predicted to double by 2030. The annual cost associated with this disease is estimated to be $10.8 billion in the United States, including the cost of treatment and the cost of the disability. Although it is primarily thought of as a movement-disorder and is clinically diagnosed based on motor symptoms, non-motor symptoms such as cognitive and emotional deficits are thought to precede the clinical diagnosis by almost 20 years. By the time of clinical diagnosis, there is 80% loss in the dopamine content in the striatum and 50% degeneration of the substantia nigra dopamine cells. The research presented in this thesis was an attempt to develop an animal model of PD in its pre-motor stages. Such a model would allow us to develop pre-clinical markers for PD, and facilitate the development and testing of potential treatment strategies for the non-motor symptoms of the disorder. Specific Aims: There were five specific aims for this research: * The first specific aim dealt with development of a rat model of PD with slow, progressive onset of motor deficits, determination of timeline for future studies, and quantification the dopamine depletion in this model at a pre-motor stage. * The second and the third specific aims focused on testing for emotional (aversion) deficits and cognitive (executive functioning) deficits in this rat model at the 3 week timepoint determined during specific aim 1. * The fourth specific aim was to determine the brain network changes associated with the behavioral changes observed our rat model using resting state connectivity as a measure. * The fifth and the final specific aim was to test sodium butyrate, a drug from the histone deacetylase inhibitor family, as a potential treatment option for cognitive deficits in PD. Results: The 6-hydroxy dopamine based stepwise striatal lesion model of pre-motor PD, developed during this research, exhibits delayed onset of Parkinsonian gait like symptoms by week 4 after the lesions. At 3 weeks post lesion (3WKPD), the rats exhibit 27% reduction in striatal dopamine and 23%reduction in substantia nigra dopamine cells, with lack of any apparent motor deficits. The 3WKPD rats also exhibited changes in aversion. The fMRI study with the aversive scent pointed towards possible amygdala dysfunction sub-serving the aversion deficits. The executive function deficits tested using a rat analog of the Wisconsin card sorting test, divulged an extra-dimensional set shifting deficit in the 3WKPD rats similar to those reported in PD patients. The resting state connectivity study indicated significant changes in the 3WKPD rats compared to age matched controls. We observed increased overall connectivity of the motor cortex and increased CPu connectivity with prefrontal cortex, cingulate cortex, and hypothalamus in the 3WKPD rats compared to the controls. These observations parallel the observations in unmedicated early-stage PD patients. We also observed negative correlation between amygdala and prefrontal cortex as reported in humans. This negative correlation was lost in 3WKPD rats. Sodium butyrate treatment, tested in the cognitive deficit study, was able to ameliorate the extra-dimensional set shifting deficit observed in this model. This treatment also improved the attentional set formation. Conclusion: Taken together, our observations indicate that, the model of pre-motor stage PD developed during this research is a very high face validity rat model of late Braak stage 2 or early Braak stage 3 PD. Sodium butyrate was able to alleviate the cognitive deficits observed in our rat model. Hence, along with the prior reports of anti-depressant and neuroprotective effects of this drug, our results point towards a possible treatment strategy for the non-motor deficits of PD.
Worcester Polytechnic Institute
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Rane, P. S. (2011). Rat Model of Pre-Motor Parkinson's Disease: Behavioral and MRI Characterization.. Retrieved from https://digitalcommons.wpi.edu/etd-dissertations/114
aversion, cognition, resting state connectivity, animal model, Parkinson's disease, MRI