# Sculpting the brain: High-resolution spatiotemporally-controlled modulation of memories

> **NIH NIH DP2** · UNIVERSITY OF CALIFORNIA-IRVINE · 2020 · $353,379

## Abstract

ABSTRACT
AD is characterized by a progressive loss of memories over time. This has been hypothesized to be due to a
loss of long-term potentiation (LTP) and other learning and memory mechanisms in neurons affected during
Alzheimer’s Disease (AD) pathogenesis, a result observed both in rodent AD models as well as humans1,2. Much
like AD patients lose the ability to recall former memories, AD model rodents also show deficits in memory
recall3,4. This is presumably due to a destabilization of existing memories, though this has not been directly
examined. If we could stabilize plasticity against destabilization that occurs during AD pathogenesis, we could
prolong the persistence of adaptive memories, thus substantially reducing the symptomatic burden of AD
patients and their caregivers.
As LTP is thought to be a molecular substrate of memories, loss of LTP should be shortly followed by a loss of
associated behavioral memories. Indeed, evidence suggests that this is the case; we find that deterioration of
LTP in the hippocampus in the 5xFAD rodent model starts at roughly 4-6 months of age, followed closely by the
loss of previously established hippocampal memories3,4. In our funded NIH Director’s Innovator Award
(DP2AG067666), we proposed to develop a suite of molecular methods to modulate plasticity in a
spatiotemporally-defined fashion. These approaches are based on the elucidation of the molecular mechanism
of the small peptide ZIP, which we have found to work through macropinocytosis, as ZIP’s behavioral effects
could be blocked by prior administration of amiloride. Importantly, we showed that amiloride not only blocks ZIP-
induced destabilization of LTP, but also natural processes that remove AMPAR receptors, such as are required
for long-term depression (LTD)-induced behavioral extinction. This raises the possibility that our methods for
plasticity modulation, including amiloride administration and molecularly-defined variants, could be used as a
therapeutic strategy to prevent destabilization of LTP that occurs during AD pathogenesis. This in turn could
slow the development of AD-associated cognitive and behavioral deficits.
In this administrative supplement application, we will test the ability of our approaches to slow the AD-associated
loss of contextual and auditory fear conditioning memories, as well as conditioned place preference memories.
Contextual fear memories can be disrupted by modulating LTP in the hippocampus5,6, and we show in our
preliminary data that auditory fear conditioning memories are stored in the basolateral amygdala (BLA), and
conditioned place preference memories are stored in the nucleus accumbens (NAc). We show that injection of
ZIP or the small cationic peptide TAT into the BLA or NAc eliminates the associated memory, and the effects of
ZIP/TAT were blocked by prior amiloride infusion. Here we will test the maintenance of these three memories in
the 5xFAD AD model mice at two different ages following 1 month of eit...

## Key facts

- **NIH application ID:** 10123379
- **Project number:** 3DP2AG067666-01S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** KEVIN T BEIER
- **Activity code:** DP2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $353,379
- **Award type:** 3
- **Project period:** 2019-09-15 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10123379

## Citation

> US National Institutes of Health, RePORTER application 10123379, Sculpting the brain: High-resolution spatiotemporally-controlled modulation of memories (3DP2AG067666-01S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10123379. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*