Traumatic brain injury (TBI) is a complex condition with many variables within the human population, both with the parameters of the injury and in the demographics of those affected by it. Some studies have found a neuroprotective effect of female sex hormones, but attempts to translate these findings into human clinical trials have failed. Most pre-clinical TBI studies focus on male animals in order to eliminate variability induced by cycling levels of sex hormones in female animals. The influence of endogenous sex hormone levels on the outcome from TBI is under-studied, particularly within mild TBI (mTBI). Few studies have examined the influence of the estrous cycle by administering injuries at controlled points, and given the high proportion of mTBI within the human TBI population, it is important to understand the effect this may have on the outcome from TBI. Improving our understanding will also inform both past and future pre- clinical experiments that involve a mix of male and female animals. Our group has extensive experience modeling mild TBI in mice, and in our previous studies we have found significant sex-dependent differences in the neurobehavioral and pathological outcomes acutely after TBI. In this study we propose to use the Lee-Boot effect on group housed female mice to produce a prolonged diestrus phase where endogenous levels of progesterone and estradiol are low. The Whitten effect will be used on a separate cohort of group housed females where they will be exposed to male pheromones in their bedding to stimulate a normal estrous cycle. This cohort will be injured at the proestrus phase when progesterone and estradiol levels are high. Male mice will also be included along with sham control mice. Tail vein blood draws will take place at the time of injury in order to quantify endogenous hormone levels. The motor performance and memory of the animals will be tested for two weeks following injury and the pathological outcome will be examined at that time using markers for neuroinflammation, axonal injury and white matter loss. Correlating the endogenous hormone levels to neurobehavioral and pathological outcome from TBI at controlled points in the estrous cycle will provide valuable information on the role of estrous cycle fluctuations in modulating outcome. If elevated levels of endogenous progesterone and estradiol do alter the outcome from TBI it will be important to understand how they may interact with treatment studies before proceeding with future human clinical trials.

Public Health Relevance

Traumatic brain injury (TBI) is a complex condition with serious challenges for attempts to translate therapeutic interventions into the human clinical population. Thus far, all attempts to improve the outcome from TBI with pharmacological compounds have failed. One potential confounder is a poorly understood role of female sex hormones on the secondary injury factors after TBI. Although pre-clinical studies have shown that estrogen and progesterone appear neuroprotective after moderate to severe TBI, attempts at using progesterone as an acute treatment for moderate to severe TBI has failed in humans. The effect of endogenous female sex hormone levels on mild TBI (mTBI) has not been studied in the pre-clinical literature, even though mild TBI has recently become a point of focus and makes up most of the human TBI clinical population. In this study, we propose to examine the effect of endogenous female hormone levels in a mouse model of mTBI by administering a single injury at controlled points in the estrous cycle.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Small Research Grants (R03)
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Brain Injury and Neurovascular Pathologies Study Section (BINP)
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Bellgowan, Patrick S F
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Roskamp Institute, Inc.
United States
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