Date of Award

Summer 7-13-2023

Embargo Period

7-30-2025

Document Type

Dissertation - MUSC Only

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience

College

College of Graduate Studies

First Advisor

Mark George

Second Advisor

Catrina Robinson

Third Advisor

Dorothea Jenkins

Fourth Advisor

Heather Boger

Fifth Advisor

Adviye Ergul

Abstract

Neonatal hypoxic-ischemic brain injury (HI) is an acute neurologic syndrome where decreased blood flow and oxygen to the brain cause acute and chronic brain dysfunction. The only proven neuroprotective intervention for HI is therapeutic hypothermia (TH); however, 50% of survivors still have long-term deficits. Pre-clinical studies on adult ischemic brain injury models demonstrate that vagus nerve stimulation (VNS) has anti-inflammatory effects and attenuates brain damage. In HI infants, a non-invasive VNS called transcutaneous auricular VNS (taVNS) is safe and may improve motor skills for bottle feeding. Our objective was to determine if a combination of TH and taVNS treatment in neonatal rats shortly after HI can reduce brain injury and behavioral deficits in neonatal rats compared to TH treatment alone.

The HI model involved ligating the right common carotid artery (CCA) in postnatal day 7 (P7) rats, followed by 2.5 hours of hypoxia and 2 hours of TH. For sham surgery, we explored the CCA without ligation, hypoxia, and TH. taVNS was administered for 30 minutes in awake rats using a bipolar electrode on the auricular concha region. The active-taVNS intensity was kept below the perceptual threshold (PT) as per clinical protocol, while inactive-taVNS was administered at 0 mA. The experimental groups included HI/active, HI/inactive, sham/active, and sham/inactive.

We found taVNS was feasible when delivered below PT in awake rat pups up to P13. taVNS acutely decreased HR, suggesting parasympathetic activation by the vagus fibers. We assessed the acute effects of a single taVNS treatment and the chronic effects of repeated taVNS on HI brain injury and behavior. TH-only treated HI pups had acute and chronic brain injuries and behavior deficits. A single taVNS-TH treatment reduced the number of HI male pups with acute brain injury. However, repeated taVNS after HI and TH did not attenuate chronic brain injury or behavior deficits compared to TH-only.

Overall, this study demonstrates that taVNS is feasible in brain-injured rat pups and may have acute neuroprotection in males. These first pre-clinical studies of a non-invasive brain stimulation technique provided valuable information for further development of taVNS in neonatal HI and other developmental disorders.

Rights

Copyright is held by the author. All rights reserved.

Download

Available for download on Wednesday, July 30, 2025

Share

COinS