This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Traumatic brain injury (TBI) results in significant acute neurobehavioral deficits that, despite some spontaneous recovery persist at more chronic times. At least 5.3 million Americans - 2% of the U.S. population currently lives with disabilities resulting from TBI. However, beyond acute interventions there are currently no generally accepted medical treatments for reducing secondary neuropathology and promoting functional recovery after TBI. The central hypotheses of the proposed research are that: (1) limited functional recovery after TBI is due, at least in part, to inadequate axonal sprouting, (2) limited sprouting is a result of an increase in growth-inhibitory molecules (growth-IMs), (3) treatment to reduce growth-IMs will improve functional outcome, and (4) combined treatments to reduce growth-IMS and to activate cellular growth will further enhance sprouting and functional outcome. We base this hypothesis on observations after controlled-cortical impact (CCI) injury, a clinically relevent model of TBI that: 1) a persistent behavioral deficit occurs, despite functional imaging data showing activation in novel ipsi-lesional regions, 2) spontaneous axon sprouting occurs only in regions of reduced growth-inhibitory chondroitin sulphate proteoglycans (CSPGs), 3) pharmacological reduction of CSPGs increases perilesional sprouting and 4) the same treatment-induced sprouting is the anatomical substrate for enhanced functional outcome after spinal cord injury which also prolongs the critical period for plasticity in dark-reared cats. Based on these observations the focus of this proposal is on the growth-inhibitory activity of the CSPGs and their contribution to failed axon plasticity after TBI.
The specific aims are to: (i) Determine the relationship between CSPG expression and spontaneous axon sprouting after CCI injury. We will examine whether spontaneous axon sprouting occurs only in regions where CSPG expression is low and where perineuronal net organization of CSPGs is reduced, (ii) Determine whether attenuating CSPG protein expression enhances subsequent axonal sprouting. We will use chondroitinase ABC to reduce ipsi-lesional CSPG proteins to enhance and sustain axonal sprouting, (iii) Determine whether axon sprouting is regionally and temporally specific to novel regions of fore-limb evoked functional activation after injury. We will assess whether axonal sprouting provides the anatomical substrate for functional recovery in the same animal, (iv) Determine if attenuating CSPG expression improves functional and neurobehavioural outcome. We will use functional microPET imaging and behavioral tests of fore-limb function to determine if enhancing sprouting improves outcome, (v) Determine if activating cellular growth status by BDNF infusion combined with attenuation of CSPG expression results in further increases in sprouting and improved behavioral outcome.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Biotechnology Resource Grants (P41)
Project #
5P41RR013642-12
Application #
7955835
Study Section
Special Emphasis Panel (ZRG1-SBIB-L (40))
Project Start
2009-08-01
Project End
2010-07-31
Budget Start
2009-08-01
Budget End
2010-07-31
Support Year
12
Fiscal Year
2009
Total Cost
$6,798
Indirect Cost
Name
University of California Los Angeles
Department
Neurology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Green, Shulamite A; Hernandez, Leanna M; Bowman, Hilary C et al. (2018) Sensory over-responsivity and social cognition in ASD: Effects of aversive sensory stimuli and attentional modulation on neural responses to social cues. Dev Cogn Neurosci 29:127-139
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Ordóñez, Anna E; Loeb, Frances F; Zhou, Xueping et al. (2016) Lack of Gender-Related Differences in Childhood-Onset Schizophrenia. J Am Acad Child Adolesc Psychiatry 55:792-9
Green, Shulamite A; Hernandez, Leanna; Bookheimer, Susan Y et al. (2016) Salience Network Connectivity in Autism Is Related to Brain and Behavioral Markers of Sensory Overresponsivity. J Am Acad Child Adolesc Psychiatry 55:618-626.e1
Kodumuri, Nishanth; Sebastian, Rajani; Davis, Cameron et al. (2016) The association of insular stroke with lesion volume. Neuroimage Clin 11:41-45
Kamins, Joshua; Giza, Christopher C (2016) Concussion-Mild Traumatic Brain Injury: Recoverable Injury with Potential for Serious Sequelae. Neurosurg Clin N Am 27:441-52
Agis, Daniel; Goggins, Maria B; Oishi, Kumiko et al. (2016) Picturing the Size and Site of Stroke With an Expanded National Institutes of Health Stroke Scale. Stroke 47:1459-65

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