Traumatic brain injury (TBI) impacts nearly 2% of the population and is a major cause of disability in the Veteran population, often resulting in long-term physical, cognitive and neurobehavioral impairments that prevent return to the workforce and community. It has long been appreciated that poor sleep and excessive daytime sleepiness are common and persistent symptoms after mild TBI. Data suggests that poor sleep interferes with recovery from TBI. What is not known is why sleep-wake disturbances persist after TBI. More effective therapies are needed for the treatment of TBI and associated post-concussive symptoms. Thus, there is an urgent need to understand mechanisms underlying sleep-wake disturbances in order to identify better therapeutic targets. Our long-term goal is to understand why sleep-wake disturbances persist after mild TBI. Our central hypothesis is that TBI disrupts physiological cortical function which in turn alters glutamatergic inputs to hypothalamic sleep-wake circuits, resulting in sleep-wake fragmentation, and subsequently delaying cognitive recovery in individuals with TBI. Our hypothesis was formulated on the basis of our own preliminary data showing decreased excitability of hypothalamic wake-active neurons in a mouse model of TBI, and improved wakefulness with administration of a dietary therapy that is thought to increase synaptic glutamate content. The rationale for the proposed research is that, once it is known how changes in brain glutamate cause sleep-wake fragmentation in TBI, pharmacological manipulation of glutamate in sleep-wake circuits could yield novel approaches for recovery from TBI. We plan to test our central hypothesis by pursuing the following three specific aims: 1. Characterize regional patterns of sleep-wake dysfunction in TBI. 2. Assess glutamate and GABA changes during sleep and wakefulness in TBI. 3. Examine the effect of a dietary therapy on glutamate, GABA, and regional sleep-wake dysfunction in TBI. To accomplish these aims, we will first perform chronic, in vivo electrophysiological recordings across different cortical brin regions in freely behaving, brain-injured mice, analyze quantitative EEG measures in sleep and wakefulness, and correlate these metrics with behavior. Next, we will perform in vivo microdialysis in combination with EEG in brain-injured mice to determine extracellular glutamate and GABA levels in the hypothalamus during sleep and wake states. We will then use quantitative electron microscopy (EM) to confirm synaptic changes in glutamate and GABA in the hypothalamus. Lastly, given the hypothesis that our dietary therapy replenishes glutamate content in nerve terminal inputs onto wake-active neurons in the hypothalamus, dietary therapy will be administered to brain- injured mice to determine the recovery of extracellular glutamate and GABA (microdialysis), synaptic glutamate and GABA (EM), and sleep-wake measures (EEG). With respect to expected outcomes, the work proposed in aims 1, 2 and 3 is expected to identify quantitative EEG metrics of sleep-wake dysfunction in TBI that predict functional recovery, and examine excitatory and inhibitory inputs to sleep-wake circuits in TBI that are amenable to therapeutic intervention. Such results are expected to have a profound impact on our understanding of TBI and post-concussive symptoms, by deepening our understanding of cortico-hypothalamic interactions in TBI-induced sleep-wake disturbances, and evaluating a therapy that has enormous potential to optimize wakefulness, and therefore recovery, from TBI.

Public Health Relevance

Traumatic brain injury (TBI) is a major cause of disability in the Veteran population, often resulting in long-term cognitive and behavioral impairments that prevent return to the workforce and community. Disturbed sleep and excessive daytime sleepiness are among the most pervasive and enduring sequelae after TBI. Mild TBI is a clinical diagnosis, and currently no criteria exist to predict who will continue to experience debilitating neurological symptoms. There is a pressing need for more effective, mechanistic-based therapies for the treatment of TBI and associated post-concussive symptoms. Our research aims to 1) quantify electroencephalographic (EEG)-based markers of sleep and wakefulness in TBI that can aid in the prediction of functional recovery, 2) evaluate brain glutamate changes during wakefulness in TBI, and 3) evaluate the mechanisms by which a promising dietary therapy composed of branched chain amino acids restores glutamate and wakefulness in TBI.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Veterans Administration (IK2)
Project #
5IK2BX002712-02
Application #
9206082
Study Section
Neurobiology R (NURR)
Project Start
2015-10-01
Project End
2020-09-30
Budget Start
2016-10-01
Budget End
2017-09-30
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Portland VA Medical Center
Department
Type
DUNS #
089461255
City
Portland
State
OR
Country
United States
Zip Code
97239