# Mild TBI Alters Axonal Structure and Neuronal Electrophysiology

> **NIH NIH R01** · VIRGINIA COMMONWEALTH UNIVERSITY · 2020 · $588,177

## Abstract

Abstract
This application seeks to better understand the pathophysiology of mild traumatic brain injury (mTBI) in a well-
characterized and well-controlled mouse model, incorporating multiple transgenic, structural, optogenetic and
electrophysiological approaches. While our previously funded efforts focused on mTBI-induced diffuse axonal
injury (DAI) occurring within Lamina V neurons, together with the generalized excitation of the non DAI injured
axons, the current application turns its attention to multiple forms of cortical circuit disruption, in which the
interneurons play a major role. The premise of this application is that the parvalbumin (PV) and somatostatin
(SS) expressing interneurons, which are major regulators of cortical inhibitory/excitatory balance, undergo DAI,
creating synaptic and network dysfunction. A specific effect of interneuron DAI to be investigated is PV
deafferentation of intact pyramidal neurons’ perisomatic and axonal initial segments (AIS), which may
contribute to network hyperexcitability. These structural and functional studies will be accomplished by multiple
transgenic approaches relying upon the use of YFP-H mice in concert with interneuron-specific cre mice
crossed with either RFP reporter mice or mice with floxed Channelrhodopsin. Confocal and EM analyses will
be used to detect the potential for DAI within the RFP-labeled PV and SS interneuronal populations, while
electrophysiological recordings will determine whether these same neurons have altered intrinsic or synaptic
input properties. The synaptic terminal distribution from these interneurons onto specific postsynaptic partners
will be assessed to determine whether deafferentation in the perisomatic, AIS and pyramidal dendritic domains
occurs. Correlate optogenetic electrophysiological studies will be used to assess whether the output from the
SS and PV interneurons is functionally altered, while additional electrophysiological measures, including focal
GABA uncaging will determine if the AIS and GABAergic receptors at the AIS are affected by the mTBI. All
measures will be examined over a time course from 1 to 60 days after injury to determine not only initial
dysfunction, but also the potential for recovery over time. We believe that these studies will help to completely
reshape our understanding of mTBI, emphasizing the concept of neocortical circuit disruption and highlighting
the involvement of cortical interneurons. These findings should move the field away from its current emphasis
on mTBI-induced white matter change as the sole contributor to mTBI associated morbidity.

## Key facts

- **NIH application ID:** 9852582
- **Project number:** 5R01NS077675-09
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** KIMBERLE Mae JACOBS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $588,177
- **Award type:** 5
- **Project period:** 2011-09-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9852582

## Citation

> US National Institutes of Health, RePORTER application 9852582, Mild TBI Alters Axonal Structure and Neuronal Electrophysiology (5R01NS077675-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9852582. Licensed CC0.

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