ORCID
0000-0002-3392-5654
Date of Award
5-3-2024
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
During the pursuit of basic needs, animals sometimes fail to suppress actions that are maladaptive and counterproductive to their survival. In humans, these actions are often called impulsive because they can incur negative consequences. Impulsivity is ubiquitous across psychiatric disorders and related to debilitating outcomes such as substance abuse, crime and suicidality. Despite its risks, a lack of a neural mechanism understanding of impulsive actions impedes the development of effective treatments.In this dissertation, I set out to bridge the knowledge gained from the parallel fields of neuropsychopharmacology, experimental psychology, and systems neuroscience to uncover neural mechanisms of impulsive actions. Clinicians and scientists have produced mounting evidence of the involvement of the neuromodulator, dopamine (DA), but variability in the conceptualization and assessment of impulsivity have precluded a granular understanding akin to that of DA’s role in optimal behavior in classical conditioning paradigms, which is accounted for by reinforcement learning frameworks to a remarkable degree. Nonetheless, this framework fails to explain the counterintuitive phenomenon of negative auto-maintenance - that when reward is contingent on inaction, animals persistently fail to suppress approach behaviors and undermine the reinforcement learning tenet of reward optimization. I argue that we are now poised to exploit this phenomenon to uncover DA’s role in impulsive actions in light of recent insights on DA’s role in optimal behavior. To achieve this, I designed the cued reward approach suppression task, a twist on classical conditioning paradigms that pits reward pursuit against behavioral suppression in mice. The task provides quantitative real-time measurements of impulsive actions that were precisely related to mesolimbic DA activity, recorded with bulk imaging of midbrain DA cell activity and striatal DA release. I found that two features of DA activity predict distinct behavioral modes. The first is the canonical “phasic” activation, or synchronous bursts of activity, known to encode errors in reward prediction. The second is asynchronous population activity in between task related events, which I argue is suggestive of the elusive “tonic” DA, continuous levels of DA hypothesized to underlie many psychiatric disorders involving impulsivity. I found that phasic DA evoked by reward predicting cues reflected reward expectation and underlying motivational state. In contrast, variability in asynchronous DA activity prior to the trial start independently predicted vigor of adaptive and impulsive reward approach and tracked the local reward rate that drove moment-to-moment changes in action impulsivity. Furthermore, the rate of DA decay during reward approach specifically predicted the suppression of impulsive actions, highlighting a potential target for the exertion of behavioral control. Therefore, these results provide evidence that distinct facets of DA activity are related to dissociable aspects of impulsive actions with implications for refining the field’s current conception of mesolimbic DA’s role across a wider range of behavior.
Language
English (en)
Chair and Committee
Adam Kepecs
Recommended Citation
Pinkhasov, Tzvia, "Dual Modes of Dopamine Underly Distinct Facets of Impulsive Actions" (2024). Arts & Sciences Electronic Theses and Dissertations. 3053.
https://openscholarship.wustl.edu/art_sci_etds/3053