# Mechanisms of cognitive dysfunction after repetitive closed head injury in adolescent mice

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2021 · $356,343

## Abstract

Mild traumatic brain injury (TBI), or concussion, is epidemic in the United States affecting at least half a million
adolescent athletes annually. There is now a greater awareness of the possibility of long term neurological
consequences of repeated concussions suffered during a time when the brain is still developing, including the
possibility of long term cognitive and other neurological deficits. Unfortunately, almost nothing is known about
the specific mechanisms leading to brain injury after repeated mild TBI, and no specific therapy other than rest
exists to reduce long-term cognitive and other sequelae. To begin to address these knowledge gaps, we
developed a repetitive closed head injury (rCHI) model in adolescent mice that produces sub-concussive
biomechanical forces, mild histopathology, and long-term deficits in learning and memory, brain connectivity,
cerebrovascular reactivity, and respiratory and heart rate reactivity to carbon dioxide challenge. Our goals are
to examine the relationship between the vulnerable period to repetitive injuries and development of
neurological and physiological deficits in adolescent mice, use fMRI and tests of respiratory and heart rate
reactivity to carbon dioxide challenge to predict the brain's vulnerable period to further injury resulting in
permanent neurological deficits, and test the hypothesis that endothelial interleukin-1 signaling mechanisms in
part mediate outcome in the rCHI model, with the following Specific Aims: Aim 1: Characterize the neurological
deficits of rCHI using a focused battery of tests with known brain circuitry; define electrophysiological correlates
of neurological dysfunction; and perform axon tracing and cFos immunohistochemistry to examine circuit
integrity in injured male and female mice. Aim 2: Using fMRI/BOLD, characterize the effects of single and 3 hit
daily (3HD) vs. 3 hit weekly (3HW) CHI on cerebrovascular reactivity (CVR) at acute and chronic time points
after injury. Characterize respiratory and heart rate reactivity to inhaled CO2 and test the hypothesis that
abnormal reactivity of cerebral blood flow and respiratory and heart rate are physiological biomarkers of closed
head injury (CHI) that can be used to predict safe rest interval between repeated CHIs. Aim 3: Test the
hypothesis that brain endothelial IL-1 signaling mediates postinjury cognitive deficits in adolescent mice using
genetic and pharmacological tools. The proposed studies would lay the groundwork for future
mechanistic/treatment studies of repetitive concussive TBI in adolescents.

## Key facts

- **NIH application ID:** 10130633
- **Project number:** 5R01NS096550-04
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** MICHAEL J WHALEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $356,343
- **Award type:** 5
- **Project period:** 2018-07-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10130633

## Citation

> US National Institutes of Health, RePORTER application 10130633, Mechanisms of cognitive dysfunction after repetitive closed head injury in adolescent mice (5R01NS096550-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10130633. Licensed CC0.

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