# Molecular, Cellular and Circuit Mechnisms for Memory-linking deficits in Psychiatric Disorders

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2021 · $445,881

## Abstract

PROJECT SUMMARY
 Molecular, cellular and circuit mechanisms for memory-linking deficits in psychiatric disorders
 Source and relational memory problems are commonly associated with a number of psychiatric conditions,
including schizophrenia [1, 2], and major depression [3]. A key component of these complex cognitive problems
is the inability to properly link information about items and events acquired at different times. Unfortunately, very
little is known about how the brain routinely links and integrates information across time. Additionally, abnormal
levels of Chemokine (C-C motif) ligand 5 (CCL5, also known as RANTES), a ligand for the C-C chemokine
receptor type 5 (CCR5), have been found in association with major depression [4], and schizophrenia[5], but it
is unclear whether and how changes in this cytokine signaling system affects the complex cognitive phenotypes
associated with these disorders. Recent studies in our laboratory revealed that CCR5 in neurons negatively
regulates MAPK/CREB signaling, and that this modulates not only memory formation[6], but also how memories
are linked across time, a mechanism that could contribute to source and relational memory problems in
schizophrenia [1, 2], and major depression [3]. Results from recent studies, including those from our laboratory
[7-18], suggest that learning triggers CREB activation and a subsequent temporary increase in neuronal
excitability[19-21], that for a time biases the allocation of a subsequent memory to the neuronal ensemble
encoding the first memory. We just reported that the resulting overlap between neuronal ensembles encoding
both memories could link these memories across time, such that the recall of one memory leads to the recall of
the other [22]. Here, we propose to use state-of-the-art tools, such as a new generation of head-mounted
fluorescent microscopes developed in our lab, TetTag mice, a new optogenetic tool, and chemogenetics,
to test the novel hypothesis that a) the opposing roles of CCL5/CCR5 and CREB signaling modulate
neuronal excitability in CA1 (Aim 1), b) and consequently memory allocation in this structure (Aim 2), c)
that memory allocation mechanisms determine the overlap between neuronal ensembles encoding
distinct memories (Aim 2), and therefore, d) supports memory linking across time (Aim 3). Importantly,
the highly mechanistic experiments proposed here will also include an FDA approved drug known to inhibit
CCR5, and that could be used to help treat possible memory linking problems caused by deregulation of CCR5
in psychiatric conditions. These studies will focus on CA1 since this structure has been implicated in human
relational memory[23], and the hippocampus is involved in cognitive deficits associated with schizophrenia [1,
24], and major depression [25]. Thus, the studies proposed will not only further our understanding of how memory
allocation affects memory linking across time, a novel concept in memory research, they will address a possibl...

## Key facts

- **NIH application ID:** 10167784
- **Project number:** 5R01MH113071-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** ALCINO J. SILVA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $445,881
- **Award type:** 5
- **Project period:** 2017-06-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10167784

## Citation

> US National Institutes of Health, RePORTER application 10167784, Molecular, Cellular and Circuit Mechnisms for Memory-linking deficits in Psychiatric Disorders (5R01MH113071-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10167784. Licensed CC0.

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