# The role of linear ubiquitination in memory formation

> **NIH NIH R21** · VIRGINIA POLYTECHNIC INST AND ST UNIV · 2020 · $191,233

## Abstract

Project Summary/Abstract
 The broad goal of this proposal is to understand how memories are formed and stored in the brain.
Pavlovian fear conditioning has proven to be a useful paradigm in elucidating the molecular mechanisms
underlying memory formation and storage in cells. Indeed, good evidence now exists suggesting that
memories formed using this paradigm require dynamic post-translational modification of proteins in neurons.
Recently, evidence has emerged demonstrating that protein ubiquitination is critically involved in memory
formation in the brain, primarily through targeting proteins for degradation by the proteasome. However, much
remains unknown about how other ubiquitin marks which are independent of the proteasome are involved in
the memory storage process. In our preliminary studies, we found that in the amygdala fear learning increased
the levels of linear ubiquitinated proteins, an atypical ubiquitin modification that is not targeted for degradation
by the proteasome complex. Importantly, these increases occurred selectively in the nucleus, but not the
cytoplasm or at synapses, and targeted the transcription factor p65, suggesting that linear ubiquitination may
be involved in transcriptional control during memory formation. The work in this proposal is designed to answer
important questions about whether linear ubiquitination is involved in gene transcription critical for fear memory
formation in the amygdala. Using a combination of protein purification methods and mass spectrometry, Aim 1
will identify what proteins are targeted by linear ubiquitination following learning. Additionally, this aim will
correlate these identified proteins with next generation RNA-seq data obtained following siRNA-mediated
reductions in linear ubiquitination within the amygdala, which will allow an unbiased, whole genome analysis of
how this ubiquitin mark is involved in transcriptional processes during the process of memory formation. Aim 2
directly tests the functional role of linear ubiquitination in memory formation by reducing or enhancing this
ubiquitin mark in the amygdala via in vivo siRNA or CRISPR-dCas9 manipulations, respectively, and testing
memory retention for a contextual fear conditioning task. Collectively, this research will provide critical
information regarding how linear ubiquitination is involved in transcriptional regulation during memory formation
and whether it is critical for learning-dependent synaptic plasticity. This could provide potentially useful
information on how memories are stored in the brain which could have important implications for the treatment
of memory impairments associated with a variety of psychiatric disorders.

## Key facts

- **NIH application ID:** 9977384
- **Project number:** 1R21MH120569-01A1
- **Recipient organization:** VIRGINIA POLYTECHNIC INST AND ST UNIV
- **Principal Investigator:** TIMOTHY JOSEPH JAROME
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $191,233
- **Award type:** 1
- **Project period:** 2020-02-05 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9977384

## Citation

> US National Institutes of Health, RePORTER application 9977384, The role of linear ubiquitination in memory formation (1R21MH120569-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9977384. Licensed CC0.

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