Dissertation
Dorsal striatal dopamine and interval timing
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2026
DOI: 10.25820/etd.008368
Abstract
Dopamine-related disorders like Parkinson’s disease, schizophrenia, and substance use disorder display robust sex differences in prevalence, symptom progression, and treatment response. These disorders exhibit cognitive impairments which remain difficult to treat, and the neural mechanisms underlying these deficits are not fully understood. Dopamine within the dorsal striatum plays a critical role in cognitive function, yet it remains unclear whether dopamine dynamics during cognition differ between males and females. The objective of this dissertation was to determine whether sex influences dopaminergic regulation of cognition at baseline and during dopaminergic manipulation.
To measure cognition, we used an interval timing “switch” task in humans and mice. Interval timing requires attention to the passage of time and working memory for temporal rules and is strongly modulated by dopamine. In Chapter 2, we demonstrate that timing accuracy and precision do not differ between females and males in either species. In female mice, estrus cycle stage did not alter timing performance. Pharmacological manipulation of dopamine receptors revealed that D2 receptor agonists and antagonists, as well as D1 receptor antagonists, shifted timing similarly in males and females. However, a D1 receptor agonist produced a sex-specific behavioral effect, altering timing in males but not females. These findings indicate that baseline performance can be similar across sexes while underlying dopaminergic mechanisms may differ.
In Chapter 3, we recorded dorsal striatal dopamine dynamics using fiber photometry with the fluorescent dopamine sensor dLight1.3b while mice performed the interval timing task. At baseline, males and females exhibited similar dopamine dynamics during the timing task. Across trials, the dLight signal changed over time by decreasing across the trial, suggesting that dorsal striatal dopamine is tracking time by steadily decreasing during timing behaviors. These temporal dynamics of dopamine signaling were similar between sexes, indicating conserved baseline dopaminergic activity during timing.
In Chapter 4, we recorded dorsal striatal dopamine dynamics with dLight following administration of amphetamine, which increases synaptic dopamine, and GBR 12909, which blocks the dopamine transporter (DAT). These manipulations altered how the dLight signal changed across the trial interval in a sex-dependent manner. Amphetamine significantly disrupted the pattern of decreasing the dLight signal across the trial in females and not males, whereas GBR 12909 altered these temporal dynamics in males. These findings suggest that while baseline dopamine dynamics during timing are similar across sexes, perturbations of dopaminergic signaling reveal sex-dependent differences in how dopamine is regulated across time.
Together, this work demonstrates that dorsal striatal dopamine dynamically regulates time-based decisions and that sex-dependent effects can emerge after dopamine is dysregulated. These findings provide mechanistic insight into dopamine’s role in cognition and inform our understanding of sex differences in dopamine-related neuropsychiatric disorders.
Details
- Title: Subtitle
- Dorsal striatal dopamine and interval timing
- Creators
- Hannah R Stutt
- Contributors
- Nandakumar S Narayanan (Advisor)Rory Fisher (Committee Member)Rainbo Hultman (Committee Member)Hanna Stevens (Committee Member)Adele Stewart (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Neuroscience
- Date degree season
- Spring 2026
- DOI
- 10.25820/etd.008368
- Publisher
- University of Iowa
- Number of pages
- xiii, 103 pages
- Copyright
- Copyright 2026 Hannah R Stutt
- Language
- English
- Date submitted
- 04/24/2026
- Description illustrations
- Illustrations, tables, graphs
- Description bibliographic
- Includes bibliographical references (pages 91-103).
- Public Abstract (ETD)
Parkinson’s disease, schizophrenia, and substance use disorder are brain disorders that affect dopamine, a brain chemical, and often show important differences between males and females. These disorders also include cognitive symptoms, problems with attention, working memory, and decision-making, that are difficult to treat. Although dopamine is known to regulate these cognitive processes, it is not clear whether dopamine functions differently in males and females during cognitive behaviors.
In this thesis, I studied dopamine in the dorsal striatum, a brain region strongly implicated in disorders involving dopamine disruptions. I investigated how this region regulates a specific cognitive behavior called interval timing, the ability to use an internal sense of time to guide decisions. I used both human participants and mice to determine whether males and females perform differently on this task. I found that males and females performed similarly in timing accuracy and consistency. Normal hormonal fluctuations in female mice also did not disrupt performance.
I then tested how manipulating dopamine receptors altered timing behavior. Most dopamine-targeting drugs affected males and females similarly. However, one drug that stimulates D1 dopamine receptors altered timing in males but not females, revealing a sex-specific effect. I also examined how amphetamine, a drug that strongly increases dopamine and is relevant to substance use disorder, altered dopamine signaling and behavior. Amphetamine changed dorsal striatal dopamine fluctuations and disrupted the normal relationship between dopamine activity and timing decisions. By measuring dopamine fluctuations in real time in the brains of mice while they performed the task, I found that under baseline, dopamine activity decreased across the trial in a consistent pattern, suggesting that dopamine signals track the passage of time as animals approach a decision. This pattern was similar in both males and females. However, when dopamine was increased using amphetamine, this normal pattern of change across the trial was disrupted in a sex-dependent manner. Dopamine signals were altered differently in females compared to males, indicating that dopamine regulation can diverge between sexes when the system is challenged.
Overall, this work shows that males and females often behave similarly during cognitive tasks, but differences in dopamine signaling can emerge when the system is pharmacologically challenged. Understanding these mechanisms is important for improving treatments for dopamine-related brain disorders that affect men and women differently.
- Academic Unit
- Interdisciplinary Graduate Program in Neuroscience
- Record Identifier
- 9985177272002771
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