# The dCA1-LS-VTA Pathway in 14-3-3 Deficiency Induced Hyperlocomotor Behavior and Overactive Dopamine Signaling

> **NIH NIH F31** · FLORIDA STATE UNIVERSITY · 2024 · $40,970

## Abstract

Project Summary / Abstract
An estimated 3% of the population will experience psychosis at some point in their lifetime, yet
we know little about the altered neural circuitry underlying psychosis. To address this gap in
knowledge, our lab created a mouse model in which region-specific functional knockout (FKO) of
the 14-3-3 protein family is achieved through the viral delivery of a small peptide inhibitor called
difopein. These 14-3-3 FKO mice display several phenotypes that are thought to correlate to
symptoms of psychosis, including novelty-induced locomotor hyperactivity. This phenotype was
further shown to be mediated by both hippocampal hyperactivity and overactive dopamine
signaling, leading to our recent discovery of a dorsal hippocampus CA1 (dCA1) – lateral septum
(LS) - ventral tegmental area (VTA) pathway. The goal of this project is to further characterize the
synaptic and functional connectivity of this neural circuitry: which cell types are connected, and
how neuronal excitability at each level of the circuit influences the observed phenotypes. Based
on our findings and the known organization of these brain regions, we hypothesize that the dCA1-
LS-VTA pathway is composed of a dCA1glutamate– LSGABA – VTAGABA – VTAdopamine circuit by which
14-3-3 inhibition induced CA1 hyperactivity ultimately leads to the dis-inhibition of VTA dopamine
neurons. Our first aim is to identify the synaptic connectivity within the dCA1-LS-VTA pathway,
and determine whether GABA or dopamine neurons in the VTA receive direct synaptic input from
LS GABA neurons. To do this we will use the viral-genetic tracing methods known as TRIO and
cTRIO in wildtype and transgenic mice. Our second aim is understand how signaling at each level
of this circuit functionally modulates downstream neural activity and psychosis-related
phenotypes. We will virally deliver inhibitory or excitatory chemogenetic channels that allow for
the manipulation of the neuronal activity of specific sets of neurons within the dCA1-LS-VTA
circuit. We will then measure the effect of these manipulations on novelty-induced locomotor
behavior and mesolimbic dopamine signaling. The proposed studies will allow for the deeper
understanding of a novel neural circuit that correlates to key symptoms of psychosis, contributing
valuable knowledge to the field that may be used in the development of more targeted treatments.

## Key facts

- **NIH application ID:** 10902933
- **Project number:** 1F31MH136804-01
- **Recipient organization:** FLORIDA STATE UNIVERSITY
- **Principal Investigator:** Meaghan Navarrete Mathews
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $40,970
- **Award type:** 1
- **Project period:** 2024-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10902933

## Citation

> US National Institutes of Health, RePORTER application 10902933, The dCA1-LS-VTA Pathway in 14-3-3 Deficiency Induced Hyperlocomotor Behavior and Overactive Dopamine Signaling (1F31MH136804-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10902933. Licensed CC0.

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