# Structural and Functional Dysconnectivity in Dopamine/Acetylcholine Circuitry in Repetitive Mild TBI

> **NIH NIH R21** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $430,375

## Abstract

Traumatic brain injury (TBI) of all severities can result in chronic disturbances of cognitive, behavioral, emotional,
and physical functioning. Recovery of cognitive function after TBI is a dynamic process in which alterations in
neurotransmitter systems do not likely occur in isolation. Numerous studies have demonstrated that the
dopaminergic (DA) innervation of medial septum and diagonal band of broca (medial septal area [MSA]) regions
that are dense with cholinergic neurons can affect hippocampal acetylcholine (ACh) release. The goal of this
R21 grant is to evaluate mild repetitive TBI-induced changes in the integrity of dopaminergic/cholinergic
connectivity using contemporary tools including diffusion MRI tractography with network analysis, transgenic
human tyrosine hydroxylase GFP expressing rats, and Fluorescence activated synaptosomal sorting (FASS)
analysis. The overall hypothesis is that TBI produces a loss of DA fiber connectivity, including DAergic
innervation of the MSA, which contributes to cholinergic deficits. Aim 1 will determine the effects of repeated mild
fluid percussion TBI (rmTBI) on the connectivity of the nigrostriatal pathway using high-definition fiber tracking
in conjunction with network topology analysis. Complimentary immunohistochemistry in hTH-GFP rats will be
compared to the imaging tractography to enhance specificity to DA circuits. Aim 2 will determine if rmTBI results
in a loss of DAergic innervation in the MSA, which is a region of cholinergic nuclei that project to the
hippocampus. Changes in DA innervation will be determined by a novel florescence-activated synaptosome
sorting (FASS) process to quantitate hTH-GFP-positive synaptosomes in the MSA. To determine if the loss of
DAergic innervation of cholinergic systems is functionally significant, we will use microdialysis to measure
hippocampal ACh levels evoked by electrical stimulation of the medial forebrain bundle. If successful, this project
will demonstrate the use of contemporary and novel methods to evaluate the degree and consequences of
DAergic dysconnectivity after TBI.

## Key facts

- **NIH application ID:** 9916055
- **Project number:** 1R21NS115440-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** C EDWARD DIXON
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $430,375
- **Award type:** 1
- **Project period:** 2020-02-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9916055

## Citation

> US National Institutes of Health, RePORTER application 9916055, Structural and Functional Dysconnectivity in Dopamine/Acetylcholine Circuitry in Repetitive Mild TBI (1R21NS115440-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/9916055. Licensed CC0.

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