Traumatic brain injury (TBI) is associated with long-term deficit in cognitive abilities and elevated risk for psychiatric disorders. The pathology of TBI is very complex involving multiple cascades of molecular and cellular events, which are difficult to target with pharmacological therapies that are too confined. An overlooked aspect of TBI is damage to plasma membranes, which may reduce neuronal excitability and interneuronal signaling, thereby affecting fundamental mechanisms required for processing and storage of information. In turn, the dysfunction in energy management resulting from TBI imposes a heavy toll on the multitude of neuronal processes that rely on energy, and can affect membrane structure and function. Abundant evidence in the human literature emphasizes the importance of dietary omega-3 fatty acids to reduce the incidence of psychiatric disorders. According to our studies, the benevolent action of DHA on rodent TBI seems related to supporting membrane stability. In turn, the curry spice curcumin, traditionally known in Asia for its medicinal power, has been shown in our hands to promote energy homeostasis and reduce the learning impairment after TBI. In addition, our new preliminary data point out the capacities of DHA and curcumin to attenuate anxiety- like behaviors. Although exercise is an excellent therapy to promote cognitive and emotional enhancement across several conditions and ages, its deployment after TBI requires optimization. Our strategy involves the use of the intrinsic capacity of the omega-3 fatty acid DHA to support plasma membranes, and the power of curcumin to support energy metabolism. We expect that this dietary therapy can contribute to the effects of exercise after TBI, and can have long-term consequences for mechanisms responsible for maintaining higher order operations such as learning and memory, and emotions. We will use a rodent model of concussion injury to evaluate crucial mechanisms that can restore membrane function, and assess their effects on reducing anxiety-like behaviors and cognition. Our comprehensive approach based on noninvasive interventions to promote neuronal stability and mental health after TBI has an outstanding safety profile, and information derived from these studies can be readily translatable into human treatments.

Public Health Relevance

We will pursue studies to understand how dietary factors can complement the action of exercise to reduce the consequences of TBI. TBI disrupts molecular systems that maintain membrane function and synaptic plasticity. Our design relies on the powerful action of select dietary factors and exercise to modulate membrane physiology, synaptic function, and to enhance cognitive abilities.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS050465-10
Application #
8660353
Study Section
Acute Neural Injury and Epilepsy Study Section (ANIE)
Program Officer
Bellgowan, Patrick S F
Project Start
2004-12-01
Project End
2015-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
10
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Physiology
Type
Schools of Arts and Sciences
DUNS #
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Meng, Qingying; Zhuang, Yumei; Ying, Zhe et al. (2017) Traumatic Brain Injury Induces Genome-Wide Transcriptomic, Methylomic, and Network Perturbations in Brain and Blood Predicting Neurological Disorders. EBioMedicine 16:184-194
Fernandes, Jansen; Arida, Ricardo Mario; Gomez-Pinilla, Fernando (2017) Physical exercise as an epigenetic modulator of brain plasticity and cognition. Neurosci Biobehav Rev 80:443-456
Krishna, Gokul; Agrawal, Rahul; Zhuang, Yumei et al. (2017) 7,8-Dihydroxyflavone facilitates the action exercise to restore plasticity and functionality: Implications for early brain trauma recovery. Biochim Biophys Acta 1863:1204-1213
Krityakiarana, Warin; Zhao, Paul M; Nguyen, Kevin et al. (2016) Proof-of Concept that an Acute Trophic Factors Intervention After Spinal Cord Injury Provides an Adequate Niche for Neuroprotection, Recruitment of Nestin-Expressing Progenitors and Regeneration. Neurochem Res 41:431-49
Meng, Qingying; Ying, Zhe; Noble, Emily et al. (2016) Systems Nutrigenomics Reveals Brain Gene Networks Linking Metabolic and Brain Disorders. EBioMedicine 7:157-66
Carlin, Jesse L; Grissom, Nicola; Ying, Zhe et al. (2016) Voluntary exercise blocks Western diet-induced gene expression of the chemokines CXCL10 and CCL2 in the prefrontal cortex. Brain Behav Immun 58:82-90
Agrawal, Rahul; Noble, Emily; Vergnes, Laurent et al. (2016) Dietary fructose aggravates the pathobiology of traumatic brain injury by influencing energy homeostasis and plasticity. J Cereb Blood Flow Metab 36:941-53
Yoon, Hyesook; Kleven, Andrew; Paulsen, Alex et al. (2016) Interplay between exercise and dietary fat modulates myelinogenesis in the central nervous system. Biochim Biophys Acta 1862:545-555
Gomes da Silva, Sérgio; Victorino, Angélica Begatti; de Almeida, Alexandre Aparecido et al. (2016) Neural Reserve Induced By Practice Of Physical Activity In Adolescence: A Study Of The Intracellular Signaling Pathways Linked To Cellular Growth And Proliferation: 3023 Board #88 June 3, 2: 00 PM - 3: 30 PM. Med Sci Sports Exerc 48:854
Agrawal, Rahul; Noble, Emily; Tyagi, Ethika et al. (2015) Flavonoid derivative 7,8-DHF attenuates TBI pathology via TrkB activation. Biochim Biophys Acta 1852:862-72

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