# Molecular and Cellular Correlates of Plasticity in Hippocampal-Prefrontal Circuitry

> **NIH NIH R01** · LIEBER INSTITUTE, INC. · 2022 · $67,675

## Abstract

Summary of funded grant
The hippocampal-prefrontal circuit is implicated in many neuropsychiatric illnesses. This circuit is critically
involved in cognition and emotional regulation, and is particularly vulnerable to stress, which is a key precipitating
factor for these disorders. Chronic stress has deleterious effects on neuronal structure and physiological function
in the hippocampus, and impairs hippocampal-dependent behavior, including processing of contextual fear. The
hippocampus (HPC) and prefrontal cortex (PFC) communicate during cognitive and emotional tasks by altering
the coherence of oscillatory activity between the two regions. However, the cellular and molecular events that
drive changes in HPC-PFC synchrony are not well understood. Neurons projecting from the ventral CA1 region
of the HPC provide the major monosynaptic input to the PFC. Many of the risk factors for neuropsychiatric
disorders, including stress, affect genes that play important roles in synapse development and plasticity, and
disruptions in synaptic connections of the neuronal projections between the HPC and PFC could contribute to
impairments in HPC-PFC synchrony. The central hypothesis of this proposal is that cellular and molecular
signaling in HPC-PFC projection neurons control their structure and function, and that these signaling pathways
regulate patterns of neural activity between the HPC and PFC that influence their connectivity. The goals of this
application are to 1) understand how stress drives molecular and cellular signaling in HPC-PFC projection cells
to control their physiological function; and 2) determine how plasticity in HPC-PFC projection neurons impacts
functional connectivity to control fear-related behavior. The funded application has three aims, designed to reveal
fundamental information about molecular and cellular signaling programs in HPC-PFC projection neurons. Aim
1: Identify how stress impacts neural activity in hippocampal-prefrontal circuitry to drive enhanced fear recall;
Aim 2: Determine how manipulation of plasticity in hippocampal-prefrontal projection neurons mediates
functional connectivity between the HPC and PFC; Aim 3: Define how stress impacts molecular and structural
correlates of plasticity in hippocampal-prefrontal projection neurons. We made substantial progress on Aims 2
and 3. Specifically, we successfully and stably overexpressed BDNF in HPC-PFC projectors, and acquired LFPs
in HPC and PFC from implanted stereotrodes to assess how BDNF expression impacted connectivity in this
circuit, and in parallel, assessed calcium activity in individual PFC neurons during fear recall. Towards the goals
of Aim 3 we conducted single-nuclei RNA sequencing (snRNA-seq) in PFC following selective stimulation of both
HPC-PFC projection neurons and a comparator projection neuron type - locus coeruleus (LC)-PFC neurons. A
key, unexpected finding from these studies, which we validated at cellular resolution with RNAscope techn y,
is select...

## Key facts

- **NIH application ID:** 10518191
- **Project number:** 3R01MH105592-08S1
- **Recipient organization:** LIEBER INSTITUTE, INC.
- **Principal Investigator:** Keri Martinowich
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $67,675
- **Award type:** 3
- **Project period:** 2015-06-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10518191

## Citation

> US National Institutes of Health, RePORTER application 10518191, Molecular and Cellular Correlates of Plasticity in Hippocampal-Prefrontal Circuitry (3R01MH105592-08S1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10518191. Licensed CC0.

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