Date of Award
Master of Science (MS)
Donna L. Korol
Cognitive changes accompany and often precede the onset of classic motor deficits typical of Parkinson&;#8217;s disease. A current focus of Parkinson&;#8217;s research has become understanding the development and progression of pre-motor cognitive changes. Based on previous research showing that hippocampus-sensitive spatial learning can be enhanced at the cost of impaired striatum-sensitive response learning, we hypothesized that changes in the balance between these two cognitive systems could be used as a proxy for the relative strength or health of their associated brain regions. Because non-motor symptoms of Parkinson&;#8217;s disease can precede the onset of the diagnostic motor dysfunction, changes in the balance between distinct learning strategies may represent an early marker of Parkinson’s-related neurodegeneration. Two rat models were used to assess the relationship between Parkinson’s disease-related motor dysfunction and changes in cognition. In the first study, a 6-OHDA rat model of Parkinson’s disease was used to generate a partial lesion of dopaminergic neurons in the nigrostriatal pathway. Despite the probable depletion of dopamine in the nigrostriatal pathway of lesioned rats that presented as impairment in two motor tasks, rats showed enhanced performance on the cognitive spontaneous alternation task, a test of spatial working memory. However, recent data suggest that multiple brain regions, including both the hippocampus and striatum, are activated during performance of the spontaneous alternation task; Parkinson’s-induced enhancements on this task may not be due solely to a shift in cognitive balance. Previous data show that inactivation of the hippocampus can enhance striatum-sensitive learning; however, it is unclear if inactivation of the striatum enhances hippocampus-sensitive functions. Prior to determining the effect of a 6-OHDA-induced lesion on hippocampus-sensitive learning, we wanted first to assess how impairing striatum function modulated place learning to determine cognitive shifts in rats with an intact brain. The second study uses two single-solution cognitive tasks that may link more closely to activation of separate neural systems. Temporary inhibition of the dorsal striatum by the GABAA receptor agonist, muscimol, produced deficits in motor function similar to those seen in the 6-OHDA model of Parkinson’s. Intrastriatal muscimol also impaired learning on a striatum-sensitive response learning task, suggesting that striatum-sensitive motor processes may overlap with striatum-sensitive cognitive processes. However, muscimol-induced striatum dysregulation did not produce enhancements on a hippocampus-sensitive spatial learning task. It is possible that the cognitive enhancements in hippocampus-sensitive processes are maximized when only specific neurotransmitter systems are dampened, such as the loss of dopaminergic signaling seen in Parkinson’s disease. Unlike 6-OHDA, which targets dopaminergic neurons, muscimol activates GABAA receptors, leading to the opening of Cl- channels, altering membrane potentials, and changing the likelihood of neurotransmitter release. Thus, activation of GABAA receptors by muscimol will alter neuron activity regardless of neurotransmitter system while 6-OHDA must initially affect dopaminergic neurons. Consequently, it is possible that muscimol decreases activity in neurotransmitter systems that play a compensatory role following 6-OHDA-induced dopaminergic degeneration. As such, a generalized inhibitor of neural activity like muscimol, may disrupt neural processes that are integral for seeing the Parkinson’s disease-related cognitive enhancements.
Mitterling, Katherine Lee, "Assessing motor and cognitive function to detect shifts in brain function in two models of Parkinson's disease" (2015). Dissertations - ALL. 282.