Development of enlarged cerebral ventricles is a hallmark of repeated mild traumatic brain injury (rmTBI). However, the mechanisms leading to ventricle expansion, the progressive nature of expansion and the consequence to important transependymal transport and clearance mechanisms are not understood. Studies are proposed to investigate how acceleration/deceleration and rotational force experienced by the brain in rmTBI results in ventricle enlargement, affects the integrity of the ventricle lining and leads to loss of critical ventricle functions. Using a mouse model of rmTBI, preliminary studies revealed substantial ventricle surface gliosis and ventricle enlargement one-month post-impact and in other studies, a strong correlation between surface gliosis and ventricle expansion in the absence of any neuronal degeneration has been established. To test the hypothesis that the repeated impacts from rmTBI is translated to shear force along the ventricle lining, resulting in tearing, surface gliosis and ventricle enlargement that progresses over time, a time line for surface gliosis and onset of expansion will be determined. Detailed immunohistochemical characterization of cell organization and interactions at the ventricle surface, and the contributions by dividing cells to glial scar formation will establish the sequence of events leading to scarring and expansion. Ventricle volumes will be modeled in 3D and regional surface scarring/edema will be mapped to areas of expansion. To test the hypothesis that loss of areas of ependymal cell coverage to gliosis significantly compromises the barrier and filtration system provided by the ependymal lining, time-lapsed imaging of laminar flow in whole-mount preparations of the ventricle wall will be evaluated based on extent of surface gliosis, and protein aggregation in ependymal and periventricular regions evaluated. In addition, fluorescent tracers will be used to evaluate changes in transependymal transport, and the impact ventricle surface gliosis has on periventricular structures will be investigated. Together, the proposed studies address how loss of transependymal transport and clearance functions may contribute to some of the brain pathology found in rmTBI. Importantly, ventricle enlargement and associated periventricular edema can be tracked over time by fluid attenuated inversion recovery (FLAIR) MRI highlighting how a standard diagnostic tool can be used to assess progressive decline of ventricle system health and inform about the consequences.

Public Health Relevance

Chronic traumatic encephalopathy occurs as a consequence of repeated mild traumatic brain injury and an early hallmark is ventricle enlargement, with astrocytic tangles and aggregation of tau proteins frequently observed in periventricular regions in post-mortem samples. Ventricle system health and function are critical for proper clearance of extracellular solutes from the brain. Examination of the relationship between chronic traumatic encephalopathy, ventricle expansion and compromised ventricular functions may reveal important connections between impairment of the brain's clearance mechanisms, aberrant accumulation of soluble proteins and the frequent association of chronic traumatic encephalopathy with neurodegenerative and neuropsychiatric disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS090092-01
Application #
8805504
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Hicks, Ramona R
Project Start
2014-08-15
Project End
2016-07-31
Budget Start
2014-08-15
Budget End
2015-07-31
Support Year
1
Fiscal Year
2014
Total Cost
$189,048
Indirect Cost
$64,048
Name
University of Connecticut
Department
Physiology
Type
Schools of Arts and Sciences
DUNS #
614209054
City
Storrs-Mansfield
State
CT
Country
United States
Zip Code
06269