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Dissertation Defense: Molecular and epigenetic mechanisms of fear memory

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Shaga Navabpour

Dissertation Defense: Molecular and epigenetic mechanisms of fear memory

Shaghayegh Navabpour

Graduate Student, Translational Biology, Medicine, and Health
Graduate Research Assistant, Jarome Lab
June 13, 2023 at 9:30 a.m.,  Life Science 1

About this Dissertation

Numerous memory studies have demonstrated that epigenetic-mediated transcriptional regulation, such as post-translational histone modifications, is essential to memory formation and maintenance. Moreover, many studies on the mechanisms of memory have focused on fear memories underlying traumatic events, which helps to understand post-traumatic stress disorder (PTSD). However, these mainly focus on individuals directly experiencing the event, while different species have shown the ability to learn fear indirectly by observing a conspecific experiencing a trauma. Thus, our understanding of indirect fear learning (IFL)’s characteristics is very limited.
The trimethylation of histone 3 lysine 4 (H3K4me3) is an essential regulator of active gene transcription in cells and has been shown to be critical for memory formation in the hippocampus, a major site of memory storage. However, it is unknown how H3K4me3 is coordinated to target genes during memory formation. Monoubiquitination of histone H2B (H2Bubi) is critical for recruiting H3K4me3 to DNA in a gene-specific manner during memory formation in the hippocampus. Furthermore, there is a great overlap between H3K4me3 and phosphorylation of histone H2A.X at serine 139 (H2A.XpS139), a marker to study DNA double-strand break (DSB) loci. DSB is a critical mechanism for solving DNA-related topological issues during transcription and replication, which could be triggered in some immediate early genes (IEGs) by neuronal activity, such as memory consolidation.
Here, we used rat fear conditioning paradigms in combination with quantitative molecular assays, such as chromatin immunoprecipitation (ChIP), and gene editing techniques, like siRNAs and CRISPR-dCas9 manipulations, to study the role of hippocampal 1) H2Bubi and 2) DSBs in contextual fear memory consolidation and reconsolidation, respectively. Additionally, we behaviorally and molecularly characterized IFL and compared it to directly acquired fear subjects. We found that contextual fear conditioning changed the expression of 86 genes in the hippocampus one hour after training. Remarkably, siRNA knockdown of the H2Bubi ligase, Rnf20, abolished changes in all but one of these genes, Per1. Additionally, we report that the loss of Rnf20 in neurons, but not astrocytes, of the hippocampus impaired long-term memory formation.
We next found an increase in H2A.XpS139 and H3K4me3 levels in the Npas4, an IEG important for contextual fear memory, promoter region 5 minutes after retrieval. In vivo siRNA-mediated knockdown of the enzyme responsible for DSB, topoisomerase II β, prior to retrieval, decreased Npas4 promoter-specific H3K4me3 and H2A.XpS139 levels and impaired long-term memory. Lastly, our data show that both sexes can indirectly acquire fear from either sex using the auditory-cued IFL model. Moreover, our data show that molecular profiles in the amygdala are largely unique to direct or indirect fear learning and vary by sex. Collectively, this data reveals novel roles for histone phosphorylation and ubiquitination in regulating H3K4me3 and memory formation and shows behavioral and molecular differences in each sex based on the way they acquire fear. 

More About the Candidate and Project


Virginia Tech, Translational Biology, Medicine, and Health, Ph.D. Candidate

University of Tehran, B.S., Biology, & M.S., Physiology


Graduate Research Assistant, Jarome Lab



Timothy Jarome, Ph.D., Assistant Professor, Department of Animal and Poultry Sciences

Committee Members

  • Michelle Olsen, Ph.D., Professor, School of Neuroscience
  • Michael Fox, Ph.D., Professor, Director, School of Neuroscience
  • Amiel Rosenkranz, Ph.D., Professor, Rosalind Franklin University
  • Angela Mabb, Ph.D., Associate Professor, Georgia State University
  • Best talk (1st place) in 38th Graduate and Professional Students Senate (GPSS) Research Symposium at Virginia Tech (2022)
  • Society for Neuroscience Trainee Professional Development Award (TPDA) (2021)
  • Selected as a Diversity Scholar, for Diversity Scholar Program at Virginia Tech, Project’s title: What does it mean to hold an F2 visa? (2022)

Peer-reviewed publications

Devulapalli, R. K., Nelsen, J. L., Orsi, S. A., McFadden, T., Navabpour, S., Jones, N., ... & Jarome, T. J. (2019). Males and females differ in the subcellular and brain region dependent regulation of proteasome activity by CaMKII and protein kinase A. Neuroscience, 418, 1-14.

Navabpour, S., Kwapis, J. L., & Jarome, T. J. (2020). A neuroscientist’s guide to transgenic mice and other genetic tools. Neuroscience & Biobehavioral Reviews, 108, 732-748.

Mulholland, M. M., Navabpour, S. V., Mareno, M. C., Schapiro, S. J., Young, L. J., & Hopkins, W. D. (2020). AVPR1A variation is linked to gray matter covariation in the social brain network of chimpanzees. Genes, Brain and Behavior, 19(4), e12631.

Musaus, M., Navabpour, S., & Jarome, T. J. (2020). The diversity of linkage-specific polyubiquitin chains and their role in synaptic plasticity and memory formation. Neurobiology of learning and memory, 174, 107286.

Navabpour, S., Rogers, J., McFadden, T., & Jarome, T. J. (2020). Dna double-strand breaks are a critical regulator of fear memory reconsolidation. International Journal of Molecular Sciences, 21(23), 8995.

Devulapalli, R., Jones, N., Farrell, K., Musaus, M., Kugler, H., McFadden, T., ... & Jarome, T. J. (2021). Males and females differ in the regulation and engagement of, but not requirement for, protein degradation in the amygdala during fear memory formation. Neurobiology of learning and memory, 180, 107404.

Jarome, T. J., Perez, G. A., Webb, W. M., Hatch, K. M., Navabpour, S., Musaus, M., ... & Lubin, F. D. (2021). Ubiquitination of histone H2B by proteasome subunit RPT6 controls histone methylation chromatin dynamics during memory formation. Biological psychiatry, 89(12), 1176-1187.

Musaus, M., Farrell, K., Navabpour, S., Ray, W. K., Helm, R. F., & Jarome, T. J. (2021). Sex-specific linear polyubiquitination is a critical regulator of contextual fear memory formation. Frontiers in Behavioral Neuroscience, 15, 709392.

Martin, K., Musaus, M., Navabpour, S., Gustin, A., Ray, W. K., Helm, R. F., & Jarome, T. J. (2021). Females, but not males, require protein degradation in the hippocampus for contextual fear memory formation. Learning & Memory, 28(8), 248-253.

Farrell, K., Musaus, M., Navabpour, S., Martin, K., Ray, W. K., Helm, R. F., & Jarome, T. J. (2021). Proteomic analysis reveals sex-specific protein degradation targets in the amygdala during fear memory formation. Frontiers in Molecular Neuroscience, 14, 716284.

Navabpour, S., Rezayof, A., & Ghasemzadeh, Z. (2021). Activation of VTA/CeA/mPFC cannabinoid CB1 receptors induced conditioned drug effects via interacting with hippocampal CAMKII-CREB-BDNF signaling pathway in rats. European Journal of Pharmacology, 909, 174417.

Maity, S., Farrell, K., Navabpour, S., Narayanan, S. N., & Jarome, T. J. (2021). Epigenetic mechanisms in memory and cognitive decline associated with aging and Alzheimer’s disease. International Journal of Molecular Sciences, 22(22), 12280.

Gustin, A., Navabpour, S., Farrell, K., Martin, K., DuVall, J., Ray, W. K., ... & Jarome, T. J. (2022). Protein SUMOylation is a sex-specific regulator of fear memory formation in the amygdala. Behavioural Brain Research, 430, 113928.

Farrell, K., Musaus, M., Auerbach, A., Navabpour, S., Ray, W. K., Helm, R. F., & Jarome, T. J. (2023). Proteasome-independent K63 polyubiquitination selectively regulates ATP levels and proteasome activity during fear memory formation in the female amygdala. Molecular Psychiatry, 1-12.

Navabpour, S., Patrick, M., Omar, N., McGrew, J., Musaus, M., Ray, W., Helm, R., Jarome, T. J. (2023). Indirectly acquired fear memories have distinct, sex-specific behavioral and molecular signatures. Neuropsychopharmacology, Under revision.

Navabpour, S., Farrell, K., Omar, N., Musaus, M., Lin, Y., Xie, H., and J. Jarome, T. J. (2023). Neuron-specific monoubiquitination of histone H2B is a master regulator of the transcriptome during memory formation. Molecular Neurobiology, In prepration


Shaghayegh Navabpour, Kayla Farrell, Aubrey Auerbach, Timothy J. Jarome. Neuronspecific H2B monoubiquitination is a master regulator of the transcriptome in the hippocampus during memory formation. Oral presentation, Fear and Aversive Learning and Memory: Mechanisms. Neuroscience Meeting Planner. San Diego, CA: Society for Neuroscience, 2022

Shaghayegh Navabpour, Madeline Musaus, Timothy Jarome. Fmr1 knockout rats show social interaction deficits but enhancement in observationally learned cued fear conditioning. Poster session presented, Fragile X: Behavior. Neuroscience Meeting Planner. Chicago, IL: Society for Neuroscience, 2021

Shaghayegh Navabpour, Jessie Rogers, Taylor Marie McFadden, Timothy Jarome. A role for double-strand DNA breaks in epigenetic-mediated transcriptional control during memory reconsolidation. Poster session presented at: 49th Society for Neuroscience (SfN); 2019 Oct 19-23; Chicago, US

S. Navabpour, A. Rezayof, M. Sardari, Z. Ghasemzadeh. Rewarding effect of the ventral tegmental area CB1 receptor activation associated with the hippocampal CaMKII signaling, Poster session presented at: 10th Forum of Neuroscience (FENS), 2016 July 2-6; Copenhagen, Denmark

Women in Learning (WIL) Research symposium, as a part of the annual
Pavlovian Society meeting. Oral presentation (2020)

Rosalind and Franklin University Neuroscience Research Symposium, Oral presentation (2020)

  • Vice President of Council of International Student Organizations (CISO) at
    Virginia Tech (2021-2022)
  • Senator at Graduate and Professional Student Senate (GPSS) at Virginia
    Tech (2021-2022)
  • Co-leader of Iranian Neuroscientists society (IRNSC) (2020-2022)
  • Reviewing manuscripts for Communications Biology (Nature), Journal of Molecular Biology, International Journal of Molecular Science, Neuropsychopharmacology, and Neurobiology of Learning and Memory Journal
  • Founder and member of Art for Environmental Justice organization at VT, 2021-2023