# Systems and molecular mechanisms of retrieval-dependent memory destabilization

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN MILWAUKEE · 2020 · $369,369

## Abstract

Fear conditioning is an excellent model system for understanding how the brain responds to
threat. When organisms learn that an auditory cue predicts danger, the formation of this
emotional memory requires plastic changes at synapses in the amygdala. Importantly, the
subsequent retrieval and use of this memory involves activity-dependent synaptic
destabilization. The functional significance of memory destabilization at retrieval is yet to be fully
understood, but this process is likely to be important for memory updating and flexibility under
normal conditions. Understanding and control of memory destabilization may open new
avenues for clinical interventions in anxiety disorders. Our recent work has focused on the
critical role of the ubiquitin-proteasome system (UPS) in controlling synaptic stability when
existing memories are recalled. While destabilization is well documented at amygdala synapses,
very few data exist related to the factors that control this process. In this project we use
optogenetic silencing and stimulation to control neural activity during memory retrieval in
behaving animals while quantifying biochemical signals related to destabilization in the
amygdala. These signals include proteasome activity and activity-driven phosphorylation of
Rpt6 regulatory subunits. Aim 1 is focused on altering activity within specific amygdala nuclei or
connections. Studies in Aim 2 assess the role of prelimbic medial prefrontal cortex (PL) activity
in triggering memory destabilization and address functional interactions between PL and the
amygdala. In Aim 3 we address the role of the ventral periaqueductal gray and some of its
reciprocal connections with the amygdala. The knowledge gained here may ultimately be
applied to the targeted destabilization and erasure of traumatic memories.

## Key facts

- **NIH application ID:** 9972754
- **Project number:** 5R01MH112141-05
- **Recipient organization:** UNIVERSITY OF WISCONSIN MILWAUKEE
- **Principal Investigator:** FRED J HELMSTETTER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $369,369
- **Award type:** 5
- **Project period:** 2016-09-16 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9972754

## Citation

> US National Institutes of Health, RePORTER application 9972754, Systems and molecular mechanisms of retrieval-dependent memory destabilization (5R01MH112141-05). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/9972754. Licensed CC0.

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