# Contribution of adult neurogenesis to epileptogenesis and recovery after TBI

> **NIH NIH R01** · COLORADO STATE UNIVERSITY · 2022 · $389,221

## Abstract

Project Summary
More than one million people are treated medically each year in the United States after sustaining a brain
injury and traumatic brain injury (TBI) is often accompanied by the delayed development of posttraumatic
epilepsy (PTE), for which there are few effective therapies. Although clinical association between TBI and
epilepsy is well documented, treatments designed to prevent PTE have been largely unsuccessful. Among the
most promising antiepileptogenic treatments reported to date center on inhibition of the mammalian
(mechanistic) target of rapamycin (mTOR) pathway. mTOR is activated after TBI and seizures, and it's activity
regulates a variety of cellular activities, including growth and proliferation, especially in developing neurons.
Inhibiting mTOR activity has shown promise for altering the progression of epileptogenesis in rodent models of
epilepsy, including PTE, but several caveats have also been acknowledged, specifically: Suppression of
mTOR post-TBI has been proposed to prevent epileptogenesis, whereas mTOR activation has been proposed
as a means of improving cognitive recovery after TBI in patients. The mechanisms by which mTOR
modulation exerts its anti-epileptogenic effects are not known, and the contribution of newborn neurons and
synaptic reorganization in the dentate gyrus to epileptogenesis and cognition are controversial. Preventing
PTE is hampered by these fundamental knowledge gaps. This proposal will use the controlled cortical impact
(CCI) model of TBI, which results in cell loss, increased neurogenesis and synaptic reorganization in the
dentate gyrus, and delayed development of spontaneous seizures (i.e., epileptogenesis) to study the impact of
newborn neurons on synaptic excitability changes in the dentate gyrus. The effects of both negative and
positive regulation of mTOR on epileptogenesis and cognitive recovery will also be determined in the context of
neurogenesis after brain injury. The overarching hypotheses are that adult born neurons contribute to synaptic
reorganization after TBI and that mTOR activity-dependent regulation of neurogenesis alters epileptogenesis
and post-TBI cognitive recovery. A combination of electrophysiological, histological, and behavioral techniques
utilizing optogenetic and chemogenetic modification of adult born neurons will be used to address three aims:
1) Determine the functional synaptic organization of adult born DGCs after TBI; 2) Determine effects of mTOR
modulation on neurogenesis and synaptic connectivity in the dentate gyrus after TBI; and 3) Determine how
adult born DGCs contribute to functional recovery and seizures after TBI. A mechanistic understanding of how
adult born neurons contribute to DGC circuitry and how mTOR modulation alters the circuitry of these neurons
after CCI will be developed in the context of both cognitive recovery after TBI and development of PTE. A
better understanding of the contribution of adult born neurons to recovery and epileptogen...

## Key facts

- **NIH application ID:** 10401446
- **Project number:** 5R01NS092552-06
- **Recipient organization:** COLORADO STATE UNIVERSITY
- **Principal Investigator:** Bret N Smith
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $389,221
- **Award type:** 5
- **Project period:** 2018-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10401446

## Citation

> US National Institutes of Health, RePORTER application 10401446, Contribution of adult neurogenesis to epileptogenesis and recovery after TBI (5R01NS092552-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10401446. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*