In this study we propose to use immediate-early gene (IEG) expression imaging to assess the age-related long-term effects of traumatic brain injury (TBI) on the posttranscriptional infrastructure of gene expression involved in synaptic plasticity and memory. TBI is the leading cause of neurological disability in the world;the critical changes that affect cognition take place over a long period of time the initial injury, and age is a substantial factor in both the risk of and the incidence of acquired brain injury. While the pathogenesis of TBI- related cognitive impairment is uncertain, it is likely multifaceted involving diffuse axonal injury, altered neuronal integrity, imbalances in neurotransmitters, changes on brain metabolism, hippocampal vulnerability;these pathophysiological factors might ultimately alter neuronal plasticity and cause memory deficits. The goal of this proposal is to advance our limited knowledge of the age-related changes in the cellular mechanisms controlling hippocampal neuronal plasticity and memory after TBI. Our working hypothesis is that the long term cognitive dysfunctions resulting from TBI are mediated through altered de novo synthesis of plasticity-related IEGs and consequent disruption of hippocampal network activity. Our hypothesis is based on our recent published data demonstrating that dysregulation of the plasticity-related IEG Arc (activity-regulated cytoskeleton-associated protein) expression parallels cognitive dysfunctions observed two months after TBI. The IEG Arc is expressed in response to synaptic activity and is required for engaging durable plasticity processes that underlie memory;Arc is the only known activity-induced gene that correlates both temporally and spatially with the stimulus that induced its transcription. Given its critical role on synaptic plasticity and its well defined kinetics Arc represents the best candidate to study altered synapti plasticity and to test our hypothesis. Using imaging method called catFISH (cellular compartment analysis of temporal activity with fluorescence in situ hybridization) it is possible t detect the sub-cellular localization (nucleus and cytoplasm) of Arc mRNA in response to synaptic activity in a time-dependent manner. This technique provides excellent temporal and cellular resolution and facilitates mapping of neuronal activity;furthermore, it provides an innovative way to evaluate hippocampal networks mediating contextual and spatial information processing. Based upon our data on TBI, combined with our previous findings on hippocampal network activity we are proposing to use catFISH to: 1) identify the dynamics of the post transcriptional infrastructure of gene expression involved in synaptic plasticity and memory after TBI in behaviorally characterized young and old mice;2) determine how age at the time of TBI affects hippocampal networks mediating contextual and spatial information processing. From these studies we will establish the role and the effect of age on the progression of TBI-related cognitive impairments from a behavioral, cellular and network prospective. These types of data are currently unavailable and are essential for the development of treatments and strategies to manage TBI- mediated neurocognitive dysfunctions.

Public Health Relevance

Traumatic brain injury (TBI) is often characterized by prolonged and permanent neurocognitive dysfunctions that can have a substantial impact on performance and/or quality of life particularly in young and elderly people. The proposed study will advance our current knowledge of the age-related changes in the cellular mechanisms controlling cognitive functions after TBI. These types of data are currently unavailable and are essential for the development of treatments and strategies to manage TBI-mediated neurocognitive dysfunctions.

Agency
National Institute of Health (NIH)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AG042016-02
Application #
8669899
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Wise, Bradley C
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Physical Medicine & Rehab
Type
Schools of Medicine
DUNS #
City
San Francisco
State
CA
Country
United States
Zip Code
94143