Traumatic Brain Injury (TBI) not only results in immediate neocortex disruption (primary injury), but also damages the surviving cells secondarily by complex mechanisms triggered by the primary event. This secondary injury leads to further cognitive, sensory, and motor dysfunction. At present, there are no clinically proven and FDA approved drug therapies for treatment of TBI patients aimed at reducing the neurological injuries. The functional impairments following TBI were previously thought to result from rapid cell death. Although TBI causes significant cell death in the cortex and hippocampus, most neurons survive the initial insult. The injuries to those spared neurons are not fully studied Mounting evidence shows axonal damage after TBI. Our recent study revealed that a significant number of spared neurons exhibit dramatic dendritic degeneration and synaptic elimination following TBI. The number of neurons that experience dendrite degeneration is hundreds of times greater than the number of neurons lost in the hippocampus following TBI. Since dendrites provide enormous surface area for spine formation and determine the range and scope of synaptic inputs, dendritic degeneration following TBI could cause significant disruption in synaptic transmission between neurons, in turn, contributing to neurological disorders. Thus, neurological disorders due to TBI could be a result of injury-induced neuronal death as well as axonal damage and dendritic atrophy of surviving neurons. While extensive studies have been focused on preventing neuronal death at the acute phase of TBI, the dendritic damage in spared neurons has been largely neglected. Our long-term goal is to identify novel approaches to enhance dendrite regeneration for functional recovery following TBI. Recently, we found that Notch signaling regulates the activity of the mammalian target of rapamycin (mTOR) pathway and plays novel roles in enhancing dendrite arborization of neurons in the postnatal brain. We hypothesize that activation of mTOR pathway enhances dendrite arborization in the neurons of the postnatal brain and accelerates functional recovery following TBI. To provide the evidence to support this novel hypothesis, we will use innovative strategies including conditional transgenic technology and viral-mediated gene knockout in single cells combined with prestigious histological studies to determine 1) the molecular pathway(s) that mediate Notch signaling-enhanced dendrite arborization of postnatally born neurons;and 2) Assess whether activation of mTOR pathway enhances dendrite re-growth in the spared neurons following TBI. The results from this proposal will not only advance the understanding of dendrite plasticity in the postnatal brain, but will also shed light on innovative strategies to promote dendrite regeneration to accelerate functional recovery following TBI.

Public Health Relevance

Traumatic brain injury (TBI) is the leading cause of death in children and young adults. Many patients are left with substantial cognitive impairment, movement disorders, and epilepsy. At present, there is no effective treatment for these TBI-associated disorders. This proposal is designed to determine neural plasticity following TBI and test innovative strategies to encourage neural regeneration for accelerating functional recovery following TBI.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS075733-01A1
Application #
8302015
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Hicks, Ramona R
Project Start
2012-09-01
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
1
Fiscal Year
2012
Total Cost
$195,000
Indirect Cost
$70,000
Name
Indiana University-Purdue University at Indianapolis
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202