All ETDs from UAB

Advisory Committee Chair

Mark Bolding

Advisory Committee Members

Lucas Pozzo-Miller

Lawrence Sincich

Eugenia Kharlampieva

Lawrence Ver Hoef

Document Type

Dissertation

Date of Award

2020

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Fundamental neuroscience research has provided a deeper understanding of the genes, molecules and cellular circuitry involved in neurological disorders, however translating discovery into clinical application remains a major challenge. This bench to bedside gap is in part due to the discrepancy in techniques used in the laboratory vs. the clinic for targeting the mechanisms that underlie disease. Ideally this discrepancy would be resolved not only by implementing novel clinical techniques to provide more precise targeting of disease foci, but also by using the same techniques in the clinic that are used at the lab bench to provide a direct bench to bedside approach. Focused ultrasound (FUS) in combination with circulating microbubbles can be used to provide highly localized openings in the blood brain barrier (BBB) and has recently been used in clinical trials for a number of neurological disorders. If this technique can replace the very routine stereotactic surgeries performed in the laboratory on model systems, then subsequent findings would inherently be highly translational. This dissertation is focused on investigating the use of FUS BBB opening to provide a noninvasive alternative to stereotactic surgery. First, we established a protocol for a benchtop approach to FUS BBB opening that can be easily adapted by other laboratories. Next, we investigated whether this technique could be used for three different routine neuroscience research methods that rely heavily on stereotactic surgery; location specific drug delivery, optogenetics, and chemogenetics. Using our benchtop approach to FUS BBB opening we were able to target MRI-visible drug carriers to the hippocampus and release glutamate causing activation of local neurons. In addition, we were able to deliver radioluminescent nanoparticles that emit light upon external x-ray exposure therefore potentially providing a noninvasive alternative to optogenetics. Lastly, we were able to noninvasively deliver adeno associated virus (AAV) for the expression of designer receptors exclusively activated by designer drugs (DREADDs) that could later be targeted by their designer ligand to modulate hippocampal activity. In conclusion, FUS BBB opening can provide a noninvasive alternative to stereotactic surgery for routine laboratory methods potentially transforming basic science findings into translational applications.

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