Advisor(s)
Karen Gamble
School
Joint Health Sciences (Interdisciplinary)
Document Type
Dissertation
Department (new version)
Neurobiology
Date of Award
1-7-2025
Abstract
Circadian rhythms are crucial endogenous cycles with period of ~24 hours that evolved to adapt to light – dark driven changes in environmental conditions. At a molecular level, circadian rhythms are generated by the actions of clock genes that form a transcriptional- translational feedback loop and regulate the rhythmic expression of downstream clock-controlled genes. Cumulatively, the actions of these molecular clocks regulate rhythmicity of physiological and behavioral processes and are extensively characterized within the central circadian pacemaker, the suprachiasmatic nucleus (SCN). Like SCN neurons, dopaminergic neurons of the SN are intrinsically pacemaking, though it is unknown if this intrinsic firing is driven by a molecular clock. Importantly, DAN dysfunction underlies the development of several neurological diseases including Parkinson’s disease (PD) wherein DAN neurodegeneration yields motor impairment. Given that circadian disruption (CRD) is a common non-motor symptom of PD, and the molecular clock is key to timing several homeostatic cellular processes, the goal of this dissertation was to characterize rhythms in DANs and study the bidirectional relationship between CRD and PD. Here, we report cell intrinsic molecular clocks in DANs of the midbrain SN pars compacta (SNc) and ventral tegmental area (VTA) and demonstrate that these DAN clocks are necessary for production of motivated locomotor behavior and circadian patterning of electrophysiological output across time of day. Additionally, loss of this cell-intrinsic clock uncovers ultradian rhythms in spike rate and ablates early-night bursting activity in SNc DANs which we found was L-type calcium channel dependent. Next, to study the DAN clock in a disease-context, we utilized the α-synuclein pre-formed fibril mouse model of PD and showed mice lose day night clock gene variation in SNc DANs 1 month after disease induction. In contrast, VTA DANs, which are relatively spared in PD, retained diurnal clock gene variation in the same samples. Lastly, we demonstrate prior circadian disruption exacerbates terminal loss in both SNc and VTA-originating DANs in synucleinopathy. Taken together, these experiments further our understanding of the clock regulation of DANs, which may reveal therapeutic targets to abate neurodegeneration in PD.
ProQuest ID
Recommended Citation
Swaroop, Ananya, "The Dopaminergic Cell-Intrinsic Clock And Bidirectional Relationships Of Circadian Disruption And Synucleinopathy" (2025). All ETDs from UAB. 7323.
https://digitalcommons.library.uab.edu/etd-collection/7323
