Advisory Committee Chair
Jeremy Day
Advisory Committee Members
Andrew Hardaway
Erik Roberson
Farah Lubin
Jeremy Herskowitz
Linda Overstreet-Wadiche
Document Type
Dissertation
Date of Award
1-1-2025
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Drugs of abuse activate defined neuronal populations in brain reward structures such as the nucleus accumbens (NAc), which are thought to promote the enduring synaptic, circuit, and behavioral consequences of drug exposure. While the molecular and cellular effects arising from experience with drugs like cocaine are increasingly well understood, the mechanisms that sculpt NAc neuron participation are largely unknown. Here, we leveraged unbiased single-nucleus transcriptional profiling to identify expression of the secreted glycoprotein Reelin (encoded by the Reln gene) as a marker of cocaine-activated neurons within the rat NAc. Multiplexed in situ detection confirmed selective expression of the immediate early gene Fos in Reln+ neurons after cocaine experience, and also revealed enrichment of Reln mRNA in Drd1+ medium spiny neurons (MSNs) in both the rat and human brain. Using a novel CRISPR interference strategy enabling selective Reln knockdown in the adult NAc, we observed altered expression of genes linked to calcium signaling, emergence of a transcriptional trajectory consistent with loss of cocaine sensitivity, and a striking decrease in MSN intrinsic excitability. At the behavioral level, loss of Reln prevented cocaine locomotor sensitization, abolished cocaine place preference memory, and decreased cocaine self-administration behavior. Together, these results identify Reelin as a critical mechanistic link between ensemble participation and cocaine-induced behavioral adaptations. Reelin also plays a critical role in brain development, though a role in striatal development specifically remains unexplored despite links to neurodevelopmental and neurological disorders with striatal pathology. Using a rat model system and publicly available human striatum data, we demonstrate relative conservation of dynamic temporal RELN expression patterns in the developing striatum. We applied our novel CRISPR-based strategies to either knockdown or overexpress Reln in embryonically derived striatal cells to investigate a role for Reelin striatal neuron development at transcriptional and electrophysiological levels. Our findings indicate a likely role for Reelin in regulating functional maturation of developing striatal neurons.
Recommended Citation
Brida, Kasey Lynn, "Reelin Regulation Of Striatal Physiology And Cocaine Reward" (2025). All ETDs from UAB. 6820.
https://digitalcommons.library.uab.edu/etd-collection/6820
Comments
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