# The role of sex- and cell-type specific protein degradation increases in the amygdala in fear memory formation

> **NIH NIH R01** · VIRGINIA POLYTECHNIC INST AND ST UNIV · 2021 · $416,710

## Abstract

Project Summary/Abstract
The broad goal of this proposal is to understand how fear memories are formed and stored in the brain. Post-
traumatic stress disorder (PTSD) affects nearly 5% of the world population, however, current treatments have
limited efficacy in reversing the symptoms of this disorder. Furthermore, females are more likely than males to
develop PTSD, though the mechanisms controlling this sex-dependent predisposition remain equivocal.
Recently, work from our group and others have implicated protein degradation mediated by the ubiquitin-
proteasome system (UPS) in fear memory formation in the amygdala, the primary brain region involved in
emotional processing. However, the functional role of protein degradation in fear memory formation has yet to
be identified. Furthermore, previous studies on UPS-mediated protein degradation have focused exclusively on
males, so little is known about whether similar UPS mechanisms control the formation of fear memories in
females. In our preliminary studies, we found that in males protein degradation was localized to the nucleus of
amygdala cells following fear learning, suggesting a potential role in transcriptional control, though this has
never been directed tested. Surprisingly, females did not show any changes in UPS-mediated protein
degradation in the amygdala following fear learning though did have elevated baseline ubiquitin-proteasome
activity in comparison with males, which was associated with increased DNA 5-hydroxymethylation (5-hmc) of
Uba52, one of the ubiquitin coding genes. This suggests that elevated baseline UPS activity in females could
be regulated by altered DNA methylation of Uba52 and may be sufficient for them to acquire fear memories.
The work in this proposal is designed to answer these important questions about sex-dependent differences in
the role of nuclear protein degradation in transcriptional control during fear memory formation. Using a
combination of pharmacology and sophisticated CRISPR-dCas9 manipulations of proteasome activity in
combination with mass spectrometry and whole genome next generation RNA-seq technology, Aim 1 will test
whether nuclear protein degradation is involved in transcriptional control during fear memory formation and
whether this varies between males and females. Aim 2 will use cutting-edge CRISPR-dCas9 technology to
control the methylation state of Uba52 and will test how this effects baseline differences in ubiquitin-
proteasome activity in the amygdala of males and females. Finally, in Aim 3 we will using CRISPR-dCas9
technology to test whether increased baseline protein degradation in the amygdala of females primes them to
acquire fear memories. Collectively, this study will answer important questions about sex-dependent
differences in the role of protein degradation in fear memory formation. The results obtained from this project
could have important implications for understanding the etiology of sex-related differences in fear memory
...

## Key facts

- **NIH application ID:** 10117396
- **Project number:** 1R01MH122414-01A1
- **Recipient organization:** VIRGINIA POLYTECHNIC INST AND ST UNIV
- **Principal Investigator:** TIMOTHY JOSEPH JAROME
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $416,710
- **Award type:** 1
- **Project period:** 2020-12-01 → 2025-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10117396

## Citation

> US National Institutes of Health, RePORTER application 10117396, The role of sex- and cell-type specific protein degradation increases in the amygdala in fear memory formation (1R01MH122414-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10117396. Licensed CC0.

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