Traumatic brain injury (TBI) accounts for more than 90,000 newly disabled persons annually in the USA with the upsurge in metabolic neuropathologies increasingly recognized to worsen outcomes. It is an alarming public health issue that more than 40% of the American population is affected by some metabolic disorder such as diabetes and obesity. Metabolic disorders are a risk factor for increased morbidity and predictors of death of TBI patients, and high sugar consumption, particularly fructose, is emerging as a main cause of metabolic disorders. Our preliminary results indicate that consumption of fructose disturbs important parameters of brain plasticity and can worsen the pathology of TBI. We would like to pursue these findings further to determine mechanisms by which fructose influences the capacity of the brain to cope with trauma. For example, the question as to whether fructose has direct effects on brain metabolism and cognitive function is largely uncharted, but the implications are paramount to employing strategies to enhance TBI recovery. Currently, insufficient understanding of how altered cellular metabolism affects brain function has limited the development of preventive programs and treatments. We have embarked on studies in rodents to determine crucial mechanisms by which metabolic perturbations disrupt the substrates for brain plasticity and function, underlying cognition. We will investigate the hypothesis that metabolic alterations carried by fructose impact important aspects of neuronal function and plasticity, which underlie cognitive performance (learning and memory) and emotional health (anxiety-like behaviors). Studies are also intended to obtain novel information how TBI influences main aspects of the metabolism of fructose in the brain, including fructose transporter, enzymatic activity, and metabolites. Although oxidative metabolism and plasma membrane homeostasis are inter-related events, this interaction is often overlooked. We will examine the concept that the plasma membrane is the main gate for transmission of information across the CNS, which can be damaged by the effects of fructose thereby reducing the threshold for the negative consequences of TBI. We will determine the capacity of dietary docosahexaenoic acid (DHA) to counteract the effects of fructose on synaptic plasticity and membrane function after TBI. DHA is a main component of the membrane; therefore, DHA has the magnificent power to regulate all forms of interneuronal signaling and the course of TBI. The successful completion of this proposal relies on our unique expertise in mechanisms by which metabolic challenges affect the substrates of brain plasticity and repair. We expect that mechanistic information provided by these interdisciplinary studies can nurture a new line of thought with regards to the menace of metabolic challenges on TBI and other neurological disorders, and foster new potential treatments.

Public Health Relevance

The increasing consumption of fructose in the modern society poses a heavy threat to brain function, repair and the capacity to resist neurological disorders. We propose to determine mechanisms by which fructose consumption can worsen the outcome of TBI over time by integrating concepts of cellular bioenergetics, synaptic plasticity, and behavior. We also propose the use of omega-3 fatty acids to counteract the effects of fructose on TBI.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Bellgowan, Patrick S F
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University of California Los Angeles
Schools of Arts and Sciences
Los Angeles
United States
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Gomez-Pinilla, Fernando; Yang, Xia (2018) System biology approach intersecting diet and cell metabolism with pathogenesis of brain disorders. Prog Neurobiol 169:76-90
Hall, Joseph M; Gomez-Pinilla, Fernando; Savage, Lisa M (2018) Nerve Growth Factor Is Responsible for Exercise-Induced Recovery of Septohippocampal Cholinergic Structure and Function. Front Neurosci 12:773
Jiménez-Maldonado, Alberto; Ying, Zhe; Byun, Hyae Ran et al. (2018) Short-term fructose ingestion affects the brain independently from establishment of metabolic syndrome. Biochim Biophys Acta Mol Basis Dis 1864:24-33
Arneson, Douglas; Zhang, Guanglin; Ying, Zhe et al. (2018) Single cell molecular alterations reveal target cells and pathways of concussive brain injury. Nat Commun 9:3894
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 Mol Basis Dis 1863:1204-1213
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
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
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
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

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