Becker-Krail, Darius D.
(2021)
Cell-type Specific Regulation of Reward-Related Behavior: The Interface of Metabolic State and the Circadian Molecular Clock.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Substance use disorder (SUD) is a widely prevalent, devastating, and highly complex disease with limited effective treatment options. Given the lack of successful therapeutics, it is crucial to understand better the cellular and molecular level processes that drive reward and how their disruption may contribute to SUDs development and/or perpetuation. The studies outlined here propose that reward may be regulated within the nucleus accumbens (NAc), a key reward region of the brain, through interactions between cellular metabolic state and the circadian molecular clock, a ubiquitous transcription-translation feedback loop that drives endogenous rhythms in physiology and behavior. Moreover, this interaction is mediated at both the molecular level by circadian interfacing redox sensors, namely Neuronal PAS Domain Protein 2 (NPAS2) and Sirtuin 1 (SIRT1), and at the cellular level by astrocytes, highly abundant glial cells integral for circadian, metabolic, and reward function. In our first study, we utilize both molecular and behavioral techniques to demonstrate the circadian redox sensors NPAS2 and SIRT1 interact in the NAc, together regulating reward and metabolic-relevant processes, and this interaction in the NAc is necessary for cocaine reward. Moreover, this interaction introduces a potential mechanism by which cocaine’s demonstrated effects on circadian and metabolic gene expression may influence reward. In our second study, we utilize time of day and cell-type-specific RNA-sequencing to demonstrate for the first time that astrocytes exhibit robust rhythmicity in the NAc, with approximately ~43% of their transcriptome showing diurnal variation. Remarkably, this circadian astrocyte function in the NAc is also important for regulating reward-related behavior, in that mice with genetically induced loss of NAc astrocyte molecular clock function show increased novelty-induced locomotion, exploratory drive, and operant food self-administration and motivation. Finally, this phenotype is also coupled with significant disruptions to NAc metabolic homeostasis in the form of downregulated lactate and glutathione shuttling. Taken together, these two studies not only underscore the multifaceted and interconnected relationship between circadian rhythms, metabolic state, and reward-regulation in the NAc, but also reveal novel mechanisms by which drugs of abuse may influence reward-circuitry to drive the development of SUDs and addiction-like behavior.
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| Item Type: |
University of Pittsburgh ETD
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| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
27 April 2021 |
| Date Type: |
Publication |
| Defense Date: |
3 December 2020 |
| Approval Date: |
27 April 2021 |
| Submission Date: |
20 December 2020 |
| Access Restriction: |
2 year -- Restrict access to University of Pittsburgh for a period of 2 years. |
| Number of Pages: |
177 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Neurobiology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
circadian rhythms, nucleus accumbens, reward, astrocytes, metabolic state |
| Date Deposited: |
27 Apr 2021 17:24 |
| Last Modified: |
27 Apr 2023 05:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/40126 |
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