Our long term goals are to develop effective pharmacological and rehabilitative treatment strategies that promote adaptive reorganization of brain-injured circuits to mitigate neurological dysfunction (morbidity) after diffuse traumatic brain injury (TBI). To achieve these goals, we will exploit a novel, reproducible, late-onset neurological deficit that we have observed in the diffuse brain-injured rat, analogous to agitation in brain injury survivors. In contrast to the soothing and pacifying nature of facial whisker stimulation in uninjured rats, brain- injured rats react to whisker stimulation by cowering, freezing and guarding the mystacial pads. This aberrant behavior is concomitant with axonal damage, neuronal atrophy, persistent inflammation and neuroplasticity, such that whisker stimulation activates brain regions outside the conventional somatosensory whisker circuit. The current proposal tests the hypothesis that diffuse brain injury-induced inflammation drives the maladaptive structural plasticity responsible for aberrant behavioral responses to whisker stimulation. The model system afforded by the brain-injured somatosensory whisker circuit provides a reductionistic approach to the complexity of diffuse TBI, to address pathological and reparative mechanisms associated with post-traumatic morbidity. This circuit in diffuse brain-injured adult male rats will be evaluated for (Aim 1) aberrant behaviors elicited by whisker stimulation, (Aim 2) chronic neuropathology, neuronal activation and circuit reorganization, and (Aim 3) neuroinflammation-driven neuroplastic responses that contribute to circuit reorganization and morbidity. An anti-inflammatory therapeutic regimen may provide a clinically relevant intervention to prevent circuit rewiring and the onset of morbidity. The innovative combination of behavioral, anatomical, functional and therapeutic approaches directed at the brain-injured somatosensory whisker circuit addresses the underlying mechanisms associated with unregulated structural plasticity in the injured brain. Uncovering these processes can direct treatments to mitigate the onset, reduce the duration and/or promote the resolution of neurological dysfunction. Results from this circuit can ultimately be expanded to other circuits in rodents and then man to improve quality of life for millions of TBI survivors and potentially others suffering from progressive neurodegenerative diseases.

Public Health Relevance

The present proposal focuses on the persistent morbidity experienced by diffuse brain injury survivors, for whom treatment options are limited. In diffuse brain-injured rats, aberrant responses to whisker stimulation will be employed as a tool to identify pathological and reparative mechanisms associated with somatosensory whisker circuit disruption. By developing, validating and implementing an animal model of one discrete post-traumatic morbidity, significant advancements can be made towards reshaping first one, then other, brain- injured circuits in rodents and man.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS065052-01A2
Application #
7899513
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Hicks, Ramona R
Project Start
2010-02-01
Project End
2015-01-31
Budget Start
2010-02-01
Budget End
2011-01-31
Support Year
1
Fiscal Year
2010
Total Cost
$321,152
Indirect Cost
Name
University of Kentucky
Department
Neurology
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Thomas, Theresa Currier; Ogle, Sarah B; Rumney, Benjamin M et al. (2018) Does time heal all wounds? Experimental diffuse traumatic brain injury results in persisting histopathology in the thalamus. Behav Brain Res 340:137-146
Hoffman, Ann N; Paode, Pooja R; May, Hazel G et al. (2017) Early and Persistent Dendritic Hypertrophy in the Basolateral Amygdala following Experimental Diffuse Traumatic Brain Injury. J Neurotrauma 34:213-219
Ziebell, Jenna M; Ray-Jones, Helen; Lifshitz, Jonathan (2017) Nogo presence is inversely associated with shifts in cortical microglial morphology following experimental diffuse brain injury. Neuroscience 359:209-223
Rowe, Rachel K; Ellis, Gavin I; Harrison, Jordan L et al. (2016) Diffuse traumatic brain injury induces prolonged immune dysregulation and potentiates hyperalgesia following a peripheral immune challenge. Mol Pain 12:
Ziebell, Jenna M; Rowe, Rachel K; Harrison, Jordan L et al. (2016) Experimental diffuse brain injury results in regional alteration of gross vascular morphology independent of neuropathology. Brain Inj 30:217-24
Lifshitz, Jonathan; Rowe, Rachel K; Griffiths, Daniel R et al. (2016) Clinical relevance of midline fluid percussion brain injury: Acute deficits, chronic morbidities and the utility of biomarkers. Brain Inj 30:1293-1301
Ziebell, Jenna M; Adelson, P David; Lifshitz, Jonathan (2015) Microglia: dismantling and rebuilding circuits after acute neurological injury. Metab Brain Dis 30:393-400
Evilsizor, Megan N; Ray-Jones, Helen F; Lifshitz, Jonathan et al. (2015) Primer for immunohistochemistry on cryosectioned rat brain tissue: example staining for microglia and neurons. J Vis Exp :e52293
Khodadad, Aida; Adelson, P David; Lifshitz, Jonathan et al. (2015) The time course of activity-regulated cytoskeletal (ARC) gene and protein expression in the whisker-barrel circuit using two paradigms of whisker stimulation. Behav Brain Res 284:249-56
Harrison, Jordan L; Rowe, Rachel K; Ellis, Timothy W et al. (2015) Resolvins AT-D1 and E1 differentially impact functional outcome, post-traumatic sleep, and microglial activation following diffuse brain injury in the mouse. Brain Behav Immun 47:131-40

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