Impaired glucose utilization and behavior in a mouse model of chronic, mild TBI

U.S. Dept/Vets Affairs Medical Center, San Juan DC

Investigators

Abstract

DESCRIPTION (provided by applicant): Mild-moderate traumatic brain injury (mTBI) is the signature injury of both Iraq and Afghanistan conflicts and leads to significant disability. During the chronic phase of mTBI, a consistent funding is a decreased cerebral glucose utilization in both humans and animals. Glucose and its intermediate metabolites are essential fuels to maintain neuronal cell function. The decreased supply of glucose and its intermediary metabolite in the brain also lead to memory loss, a common findings in patients with mTBI. To date, strategies that target improvements in brain glucose utilization have not been employed in paradigms for mTBI rehabilitation. Objective: using mouse model of mTBI to study long-term effects of mTBI on brain glucose utilization, neurobehavioral recovery, and their inter-relationships. Specific aims: (1) to longitudinally characterize and modify an established mouse mTBI model that demonstrates persistent neurobehavioral impairments, (2) to determine whether such impairments are associated with altered expression of proteins and genes related to glucose utilization in discrete brain areas, and (3) to assess as a proof of concept whether augmenting endogenous incretin hormone, GLP-1, via a specific dietary intervention ameliorates these chronic neurobehavioral and biomarker abnormalities. Hypothesis: (1) Chronic mTBI decreases expression of glucose utilization related transporters and enzymes in specific brain regions, in association with impaired neurobehavioral functions. (2) Augmentation of endogenous GLP- 1during the post-acute phase of TBI improves expression of brain glucose utilization related transporters/enzymes and related neurobehavioral outcomes in the above mTBI model. Methods: The repetitive mild closed-skull traumatic brain injuries within 24 or 96 hours will be used to generate mouse model of mTBI. This mouse mTBI model will be used for three experiments proposed: (1) determining the time course of chronic (> 7 weeks) neurobehavioral impairments in this mouse mTBI model: Morris water maze for learning and memory test; the rotarotor for motor coordination; and 2-bottle sucrose/water preference test for anhedonia; (2) measuring the temporal relationships between neurobehavioral impairments and expression of glucose utilization related transporters and enzymes in discrete brain regions, such as cortex (frotal lobe, parietal lobe, temporal lobe and occipital lobe), corpus callosum, hippocampus, thalamus, and hypothalamus; (3) examining whether increasing endogenous GLP-1 by a specific dietary intervention enhances expression of glucose utilization related biomarkers and neurobehavioral recovery in mTBI mice. The results from proposed studies will provide necessary data for further collaborative researches that will inform additional basic science and translational investigations on chronic phase of mTBI; and for more detailed cellular and molecular mechanistic studies on prolonged decreased brain glucose utilization following mTBI. Our long term goal is to improve the management of mTBI in both Veterans and non-Veterans, based upon reversing their impaired brain glucose metabolism.