Skip to main content
eScholarship
Open Access Publications from the University of California

Scholarly Works (3 results)

  • Thesis
  • Peer Reviewed
UC Irvine Electronic Theses and Dissertations (2024)

Exposure to drugs of abuse, such as cocaine, engages transcriptional machinery to alter gene expression profiles, ultimately giving rise to long-term changes in cellular function, synaptic plasticity, and drug-related behavior. Previous work from our lab has identified glucocorticoid-induced leucine zipper (Gilz) as an epigenetically regulated gene that may be responsible for orchestrating long-term transcriptional adaptations underlying such behaviors. However, it remains unknown whether the distinct mRNA splice variants encoded by the Gilz gene play unique roles in this context. It is also unclear whether Gilz splice variants in the brain differentially respond to stress-related events, despite the body of literature demonstrating Gilz as a downstream transcriptional regulator of glucocorticoid-signaling. In the present dissertation, we investigated whether Gilz splice variants exhibit differential responses to cocaine- or stress-exposure, and we investigated whether Gilz is necessary for (1) long-term potentiation (LTP) in the nucleus accumbens (NAc), (2) cocaine-conditioned place preference, and (3) cocaine self-administration behaviors. We demonstrate that Gilz acts in the NAc to regulate LTP, in the VTA to regulate CPP, and that Gilz is necessary for reinstatement of cocaine-seeking behavior in male mice. We also demonstrate that Gilz splice variants differentially respond to a variety of stress-related stimuli. Overall, this work illustrates how cocaine or stress may engage Gilz in distinct brain regions to regulate cellular and behavioral responses to maladaptive experiences.

    Cover page: Investigating the Role of Gilz in Regulating Cocaine-Induced Cellular Activity and Cocaine-Associated Behaviors
    • Article
    • Peer Reviewed
    UC Irvine Previously Published Works (2024)
    A self-cleaving ribozyme that maps to an intron of the cytoplasmic polyadenylation element-binding protein 3 (Cpeb3) gene is thought to play a role in human episodic memory, but the underlying mechanisms mediating this effect are not known. We tested the activity of the murine sequence and found that the ribozymes self-scission half-life matches the time it takes an RNA polymerase to reach the immediate downstream exon, suggesting that the ribozyme-dependent intron cleavage is tuned to co-transcriptional splicing of the Cpeb3 mRNA. Our studies also reveal that the murine ribozyme modulates maturation of its harboring mRNA in both cultured cortical neurons and the hippocampus: inhibition of the ribozyme using an antisense oligonucleotide leads to increased CPEB3 protein expression, which enhances polyadenylation and translation of localized plasticity-related target mRNAs, and subsequently strengthens hippocampal-dependent long-term memory. These findings reveal a previously unknown role for self-cleaving ribozyme activity in regulating experience-induced co-transcriptional and local translational processes required for learning and memory.
      Cover page: Inhibition of Cpeb3 ribozyme elevates CPEB3 protein expression and polyadenylation of its target mRNAs and enhances object location memory.
      • Article
      • Peer Reviewed
      UC Irvine Previously Published Works (2024)
      Exercise has beneficial effects on cognition throughout the lifespan. Here, we demonstrate that specific exercise patterns transform insufficient, subthreshold training into long-term memory in mice. Our findings reveal a potential molecular memory window such that subthreshold training within this window enables long-term memory formation. We performed RNA-seq on dorsal hippocampus and identify genes whose expression correlate with conditions in which exercise enables long-term memory formation. Among these genes we found Acvr1c, a member of the TGF ß family. We find that exercise, in any amount, alleviates epigenetic repression at the Acvr1c promoter during consolidation. Additionally, we find that ACVR1C can bidirectionally regulate synaptic plasticity and long-term memory in mice. Furthermore, Acvr1c expression is impaired in the aging human and mouse brain, as well as in the 5xFAD mouse model, and over-expression of Acvr1c enables learning and facilitates plasticity in mice. These data suggest that promoting ACVR1C may protect against cognitive impairment.
        Cover page: Specific exercise patterns generate an epigenetic molecular memory window that drives long-term memory formation and identifies ACVR1C as a bidirectional regulator of memory in mice.Creative Commons 'BY' version 4.0 license
        Top