# Importance of Brain Temperature on the Inflammatory and Microvascular Consequences of Mild TBI

> **NIH NIH R01** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2020 · $335,781

## Abstract

The potentially detrimental effects of concussion or mild traumatic brain injury (mTBI) are a major public health
problem. Although the majority of mTBI patients recover within 1-2 weeks, a subpopulation takes weeks to
months for full recovery and some report symptoms lasting years after the initial trauma. Thus, identification of
clinically relevant factors that alter the brain's recovery after mTBI is an understudied, but much needed research
area. Clinical investigations have reported that strenuous activity and exercise can lead to mild elevations in core
and brain temperature. We now show that a relatively mild brain temperature elevation of only 39oC significantly
aggravates neuropathological and cognitive outcome in two distinct models of mTBI as compared to
normothermic mTBI. These observations suggest that small variations in brain temperature at or around the time
of injury may influence the acute and long term traumatic consequences of mTBI. Novel preliminary results
demonstrate that hyperthermia at the time of mTBI has profound effects on inflammatory, microvascular and
hemodynamic perturbations. The goal of this proposal is to investigate the causal links between temperature-
sensitive inflammatory and cerebrovascular responses and the emergence of structural and behavioral changes
that may underlie the exacerbation of outcome after hyperthermic mTBI. Aim 1 will characterize the inflammatory
responses to mTBI during normothermic or hyperthermic conditions. Flow cytometry will be used to characterize
macrophage/microglia phenotypes and biomarker analysis including cytokine and chemokine signaling
correlated with chronic cognitive outcomes. Complementary rat and transgenic models including CCL2 and
caspase 1 knockout mice will clarify the role of inflammatory cell infiltration on triggering cytotoxic inflammation
after hyperthermic mTBI. Aim 2 will focus on the microvascular permeability patterns following normothermic or
hyperthermic mTBI in concert with tight junctional protein and endothelial adhesion molecule changes. The
cellular identification of macrophage origins on cerebrovascular permeability and integrity will be correlated with
inflammatory responses using ICAM-1 and MMP-9 transgenic models with light sheet fluorescence microscopy
and 3D image visualization and quantitation. Because the hemodynamic state of the posttraumatic brain can
influence secondary injury mechanisms after mTBI, Aim 3 will assess alterations in local cerebral blood flow and
vascular reactivity using autoradiography and two-photon laser scanning microscopy. The underlying
mechanisms of these hemodynamic responses will be tested using eNOS and iNOS knockout mice. Clinically
relevant treatments including minocycline and progesterone targeting microglia and macrophage/endothelial
interactions will be tested in these models of hyperthermic mTBI and concussion. Together, these studies will
clarify the temperature-sensitive inflammatory and cerebrovascular ev...

## Key facts

- **NIH application ID:** 9902551
- **Project number:** 5R01NS042133-15
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** W Dalton Dietrich
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $335,781
- **Award type:** 5
- **Project period:** 2002-04-15 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9902551

## Citation

> US National Institutes of Health, RePORTER application 9902551, Importance of Brain Temperature on the Inflammatory and Microvascular Consequences of Mild TBI (5R01NS042133-15). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9902551. Licensed CC0.

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