Dopaminergic control of individual variability in risk preference
Abstract/Contents
- Abstract
- This thesis consists of two main sections.The first is dedicated to the development of enabling technologies for optogenetic experimentation in rats. In this section, I provide an overview of opsin selection and targeting in rat models and review the state of the literature in terms of applying these technologies to neuroscientific questions in rats. In the second chapter, I discuss the development of the first cre-driver rat lines, allowing for genetic access to dopaminergic, cholinergic, and noradreneric neural populations in rats. Finally, in the third chapter of this section, I utilize the tyrosine hydroxlase cre-driver line to examine the effect of VTA dopamine neuron stimulation and inhibition, in combination with systemic pharamacological manipulations, on the brain-wide BOLD signal. This description of the BOLD response to dopamine neuron activity will, hopefully, inform human fMRI studies in behaviors where dopamine effects on the BOLD signal are suspected, including studies of reward, decision making, learning, and neuroeconomics. The second section of this thesis is devoted to my primary scientific project, examining the role of dopamine signaling in risk-preference. Risk aversion is fundamental to most human decision making and has been described in even evolutionarily-distant animals, including honeybees, stickleback fish, songbirds, and shrews. Such enduring evolutionary conservation implies both strong selection for this phenotype and the potential for conserved neural mechanism. Given this strong selection, it is interesting that variation persists; some individuals consistently prefer uncertainty. One fundamental and fascinating goal of neuroscience is to describe the neural basis for naturally-occurring individual variation, and I hope to address this goal in this work in the context of risk-preference. Dopamine neurons project to many areas of the brain, including nucleus accumbens, striatum, prefrontal cortex, and amygdala. Those neurons that project to the nucleus accumbens have been implicated in substance abuse and behavioral addictions. These cells fire in synchronized bursts in response to unexpected rewards and pause their firing in response to withheld rewards or unpredictable punishments. Postsynaptically, in the nucleus accumbens (NAc), this univariate signal is parsed into two distinct streams. The first pathway is reward-responsive. NAc cells expressing the D1-type dopamine receptor are excited by dopamine bursts and increase their firing in response to reward. The second pathway is loss-responsive. Cells expressing D2-type receptors are inhibited by dopamine and are thought to increase their firing when dopamine neurons pause in response to losses. Evidence from clinical populations suggests that disruption of encoding in the loss pathway may contribute to problem gambling behavior. In the first segment of this section, I describe a novel behavioral model for risk-preference in rats, in which rats repeatedly chose between a ``safe" lever, which yields the same volume of sucrose reward on every trial, and a ``risky" lever, which yields a small reward on 75\% of trials (a ``loss") and a large reward on 25\% of trials (a ``win"). The expected value of choosing either lever was the same. I found that most rats exhibit stable risk-averse behavior, but some smaller subset of rats are consistently risk-seeking. This long-term behavioral difference seems to be driven by a highly-local behavioral phenomenon: if a risk-averse rat ``loses" on the risky lever, they are much more likely to switch to the safe lever, as compared to risk-seeking rats. They are more ``loss sensitive". In the next segment, I discuss a pharmacological investigation of neural populations that might be driving individual variability in risk-preference. Concordant with human clinical literature, I find that a D2-agonist drug (loss pathway) but not a D1 agonist drug (win pathway) dramatically and reversibly increases risk-seeking choices in rats. By infusing the drug directly into the brain through permanently-implanted cannulas, I found that I could recapitulate this effect by administering the drug only into the nucleus accumbens (NAc), but not into other likely targets, such as the orbitofrontal cortex. This experiment strongly implicated dopamine D2 receptor (D2R) expressing cells in the NAc in driving risk preference. I then optically recorded from these cells during the behavior. I found that the D2R cells are more active during the decision period following a loss than following other trial types. This ``loss sensitivity" signal was largest in the most risk-averse animals. A correlation between the size of this effect and the degree of risk-aversion explains the vast majority of the rat-by-rat variance in risk-preference. Finally, I used optogenetic manipulation of D2R NAc cells to determine whether this increased activity was sufficient to drive risk-preference. By driving increased activity in those cells during the decision period of the task, I reasoned I could mimic the ``loss sensitivity" effect observed in the recordings, and attempt to decrease risk-seeking behavior. I found that driving firing in D2R cells during the decision period does, in fact, decrease risk-seeking choices, both on a trial-by-trial basis and on average, across an entire session of behavior. These findings together suggest that natural individual variation in risk preference can be largely explained by loss-related activity of D2R-expressing NAc cells during decision-making.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2016 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Zalocusky, Kelly Anne |
|---|---|
| Associated with | Stanford University, Neurosciences Program. |
| Primary advisor | Deisseroth, Karl |
| Thesis advisor | Deisseroth, Karl |
| Thesis advisor | Knutson, Brian |
| Thesis advisor | Malenka, Robert C |
| Thesis advisor | Shenoy, Krishna V. (Krishna Vaughn) |
| Advisor | Knutson, Brian |
| Advisor | Malenka, Robert C |
| Advisor | Shenoy, Krishna V. (Krishna Vaughn) |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Kelly Anne Zalocusky. |
|---|---|
| Note | Submitted to the Program in Neurosciences. |
| Thesis | Thesis (Ph.D.)--Stanford University, 2016. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2016 by Kelly Anne Zalocusky
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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