Deep brain stimulation (DBS) is a clinical and investigational treatment for a variety of neuropsychiatric conditions, such as Parkinson’s Disease (PD) and obsessive-compulsive disorder. Despite widespread clinical use, its therapeutic mechanism is unknown. Previous results indicate DBS may produce a complex array of effects, ranging from inhibition in the STN to antidromic stimulation of cortical afferents, but it has proven difficult to establish how these changes interact to alter behavior. Here, we developed a mouse model of subthalamic nucleus (STN) DBS for PD to investigate this question using the mechanistic and cell type-specific tools available in mice.
First, in Chapter 1 we detail the various theories surrounding the mechanism of STN DBS and discuss the technical limitations that have prevented a definitive exploration from taking place.
In Chapter 2, we create a mouse model of electrical STN DBS in parkinsonian mice and demonstrate that it recapitulates many of the salient features of STN DBS in human PD patients. Furthermore, we develop a metric to characterize the behavioral efficacy of various DBS parameters in mice and show that this metric holds when applying it to human data.
In Chapter 3, we use fiber photometry in our STN DBS model to record calcium signals as a surrogate marker of neural activity without DBS-associated electrical artifacts. In concordance with previous electrophysiological studies, we find that in parkinsonian mice, therapeutic levodopa treatment causes large decreases in neural activity at the level of basal ganglia output. In contrast, therapeutic electrical STN DBS increases activity in both the STN and SNr. Furthermore, we find that both optogenetic inhibition of the SNr, imitating the effects of levodopa, and optogenetic excitation of the STN, imitating the effects of STN DBS, are therapeutic in mice.
Finally, in Chapter 4, we discuss the implications of these findings and the role of future studies in further elucidating the mechanism of STN DBS.
|Commitee:||Nelson, Alexandra, Berke, Joshua, Ganguly, Karunesh|
|School:||University of California, San Francisco|
|School Location:||United States -- California|
|Source:||DAI-B 81/12(E), Dissertation Abstracts International|
|Keywords:||Basal ganglia, Deep brain stimulation, Parkinson's disease|
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