Walters, Seth
(2016)
DEVELOPMENT, VALIDATION, AND USE OF A QUANTITATIVE THEORY OF IN VIVO DOPAMINE DYNAMICS.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
This is the latest version of this item.
Abstract
Since the early 1980s, fast scan cyclic voltammetry (FSCV) has been used to detect changes in dopamine's presence in the brain's extracellular space. The dopamine signals detected result from several simultaneous biophysical processes. Because these processes currently cannot be directly measured, a mathematical model which quantitatively explains FSCV data is necessary to describe their natures and magnitudes. I have created a simple mathematical model which posits that diffusion of dopamine in the brain follows a unidirectional first order kinetic scheme from its source. The model, using just three parameters, produces excellent fits to dopamine responses evoked by short electrical stimuli. These parameters are: Rp (release), kU (fuptake) and kT (mass transport). When longer stimulations are performed, the addition of a term kR, which modifies Rp by an exponential, is adequate to fit nearly all observed dopamine responses in the anaesthesized rat brain.
To complement this work, I have determined that the ubiquitous failure of dopamine concentration changes as measured by FSCV to return to baseline, called hang-up, is an artifact caused by a form of long duration adsorption to the carbon fiber electrodes commonly used to measure dopamine. I have developed a mathematical correction for this artifact. In addition, I have experimentally determined that the observed first order behavior of the mass transport parameter kT arises essentially entirely from the brain itself, rather than the adsorption kinetics of dopamine at the electrode. Finally, having established a sound theoretical framework for understanding the biological and instrumental origins of dopamine signals in the brain, I have used this model to study both anatomical differences in dopamine signaling, as well as the biophysical effects of the drug buproprion, an antidepressant. These studies have found that the density of dopamine signaling is greatest in the dorsolateral striatum, and that this high density of signaling is enabled by high rates of dopamine uptake, which attenuate the spatial range of dopamine signaling. I anticipate that this work is a necessary step towards the comprehensive mechanistic dissection of cellular signaling, and I hope it will prove invaluable to future progress.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
3 October 2016 |
| Date Type: |
Publication |
| Defense Date: |
11 August 2016 |
| Approval Date: |
3 October 2016 |
| Submission Date: |
28 July 2016 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
144 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
Dietrich School of Arts and Sciences > Chemistry |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
dopamine, "mathematical model", model, "fast scan cyclic voltammetry" |
| Date Deposited: |
03 Oct 2016 19:37 |
| Last Modified: |
19 Dec 2016 14:43 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/29297 |
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DEVELOPMENT, VALIDATION, AND USE OF A QUANTITATIVE THEORY OF IN VIVO DOPAMINE DYNAMICS. (deposited 03 Oct 2016 19:37)
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