? DESCRIPTION (provided by applicant): DBS is known to be highly effective for conditions such as Parkinson's disease and essential tremor, but its mechanisms are not well understood. Its therapeutic success in movement disorders has led to its consideration for a rapidly expanding set of neurologic and psychiatric conditions from obsessive compulsive disorder to depression and memory loss. The pressure to expand DBS applications makes it all the more critical that we improve understanding of its underlying mechanisms and that all potential molecular and physiologic processes that bear on its therapeutic action be investigated. To date, basic science research has focused on DBS-driven changes in neurons and their projections around the DBS lead. And, while the physiological actions of astrocytes, the most numerous cell type in the brain, have been extensively investigated, little attention has been paid to their functional role in therapeutic DBS. We know that astrocytes play a significant role i neurotransmission, chemical homeostasis, synaptic plasticity, and control of blood flow. We also know that they respond to high frequency stimulation (HFS), conditions similar to those of therapeutic DBS, by altering important regulators of neuronal network activity, inducing the release of glutamate, ATP, and adenosine. Thus, the role of astrocytes in DBS warrants investigation. Our main hypothesis is that astrocytes make local and distal contributions to the therapeutic effects of DBS. Not intended as an alternative to theories of neuronal modulation during DBS, but rather a critical refinement, this application can be seen as deepening our understanding of those changes and more accurately reflecting their complexity. The overall plan for this investigation is to characterize the effects of in vivo HFS-driven astrocyte activatin on local adenosine release, on distal neural circuitry activation, and on tremor reduction. Tremor was chosen as a representative disorder that is easy to measure and known to be successfully treated by DBS. Aim 1, will characterize HFS-driven astrocytic function at the ventrolateral (VL) thalamus, a clinically effective DBS target for tremor, by examining local adenosine release, electrophysiology, and neural network activation effects during DBS and during selective astrocytic activation using an optogenetic approach in subject groups that vary according to selective cell type (neuronal versus astrocytic) activation. Aim 2 will use a swine harmaline- tremor model to characterize the differential effects on tremor of HFS-driven astrocytic or neuronal activation in subjects infected with optogenetic vectors. To further validate the findings the effects on tremor during DBS will be investigated in a group of pigs with selectively blockage of SNARE protein activity using shRNA, which can inhibit astrocytic gliotransmitter release. Ultimately, characterization of the as yet unidentified DBS-related functions of astrocytes should impact DBS therapy, providing key information for target selection, the development of closed-loop stimulation devices and other individualized interventions for neurologic and psychiatric conditions that are treated by DBS, now and in the future.
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