# Hippocampal mechanisms of cocaine-memory reconsolidation

> **NIH NIH R01** · WASHINGTON STATE UNIVERSITY · 2024 · $578,713

## Abstract

PROJECT SUMMARY/ABSTRACT
Pathologically strong or intrusive cocaine memories elicit uncontrollable drug craving and can trigger drug
relapse in cocaine-predictive environments even after protracted abstinence, yet the contributions of long-term
memory maintenance mechanisms to substance use disorders have been understudied. Cocaine memories are
not necessarily retained over time; they become destabilized upon retrieval (memory reactivation) and need to
be reconsolidated into long-term memory stores to be maintained, updated, and potentially strengthened. Thus,
interference with memory reconsolidation weakens cocaine memories in animal models of drug relapse and
reduces craving in individuals suffering from substance use disorders. The long-term goal of this proposal is to
advance our understanding of the neural basis of cocaine-memory reconsolidation so that cellular/molecular
processes and neural circuits suitable for effective therapeutic targeting can be identified in the future. We have
discovered that the CA3 region of the dorsal hippocampus (dCA3) plays a critical role in the reconsolidation of
cocaine memories. Building on this finding and strong preliminary data, Specific Aim 1 will be to identify cellular
and synaptic-plasticity mechanisms of cocaine-memory reconsolidation within the dCA3. We will test the
hypothesis that reconsolidation requires glutamatergic pyramidal neuronal activity in the dCA3 stratum
pyramidale (SP) cell layer and GABAergic interneuronal activity in the dCA3 SP and stratum lucidum (SL) cell
layers. We will identify and phenotype engram cells in the SP and SL and, also, evaluate the hypothesis that the
maintenance of cocaine-memory strength via reconsolidation is associated with lasting plasticity in dentate gyrus
mossy fiber (MF)dCA3 engram cell synapses, but not in dCA3 non-engram cell synapses. Specific Aim 2 will
be to map dCA3 efferent circuits that regulate cocaine-memory strength during reconsolidation and determine
related synaptic plasticity mechanisms. Based on extant literature and strong preliminary data, we will test the
hypothesis that direct dCA3dCA1 intra-hippocampal and dCA3dorsolateral septum (dlS) extra-hippocampal
circuits regulate cocaine-memory strength in an opposite manner during reconsolidation. Further, we will
examine the hypothesis that cocaine-memory maintenance after reconsolidation is associated with increased
polysynaptic transmission (MFdCA3dCA1/dlS) and excitatory synaptic plasticity in dCA3dCA1/dlS
engram cell synapses. The proposed studies will utilize an instrumental model of drug-memory reconsolidation
and relapse, engram cell tagging using Targeted Recombination in Active Population protocols, cell type- and
pathway-specific in vivo and ex vivo optogenetics, pharmacology, multi-label immunohistochemistry, and whole
cell patch-clamp electrophysiology to increase our understanding of how hippocampal-memory reconsolidation
processes regulate cocaine memory strength and drug...

## Key facts

- **NIH application ID:** 10847515
- **Project number:** 5R01DA057330-02
- **Recipient organization:** WASHINGTON STATE UNIVERSITY
- **Principal Investigator:** Rita A Fuchs Lokensgard
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $578,713
- **Award type:** 5
- **Project period:** 2023-06-01 → 2028-03-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10847515

## Citation

> US National Institutes of Health, RePORTER application 10847515, Hippocampal mechanisms of cocaine-memory reconsolidation (5R01DA057330-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10847515. Licensed CC0.

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