Recent studies showing that the injured spinal cord has the capacity to learn motor tasks, suggest that spinal learning is an intrinsic component of functional recovery. The physiological and molecular mechanisms by which repeated activity can enhance locomotor learning in spinal cord injured subjects remain elusive. Our current research clearly indicates that exercise has an effect on select molecular systems involved with synaptic plasticity underlying learning and memory. In particular, exercise elevates BDNF in the spinal cord. Several studies have demonstrated the potent effect of BDNF on synaptic facilitation and neuronal excitability, indicating that BDNF has the capacity to mediate higher order neural function such as learning and memory. In fact, we have recently shown that exercise-induced BDNF production facilitates hippocampal learning. In addition, a large body of work has demonstrated the therapeutic potential of BDNF to attenuate neural loss associated with neural trauma or disease. Therefore, a central theme of this proposal is to examine the relationship between exercise-induced BDNF and learning in the spinal cord. We propose studies to determine how exercise can facilitate learning in the spinal cord by activating signaling systems under the modulation of endogenous BDNF and NT-3. To accomplish this goal, we will rely on our experience gained from pioneering the current understanding of the involvement of exercise-induced BDNF in mediating synaptic plasticity and learning. We will use a well-defined quantitative behavioral paradigm to assess spinal cord learning. We hypothesize that exercise and learning share molecular mechanisms and that BDNF plays a central role in modulating these mechanisms in the injured spinal cord. The highlight of these studies is the possibility to evaluate the effects of exercise on learning, in conjunction with its effects on stepping performance in the same animals. We will take advantage of the pharmacology of the serotonergic system to facilitate locomotion in complete transected animals, and its close interaction with the BDNF system. Success in the proposed investigations should provide new strategies for the development of treatments to improve functional recovery after spinal cord injury.

Public Health Relevance

The potential of the injured spinal cord to learn motor tasks offers the possibility to elaborate programs to enhance functional recovery. Our current research indicates that exercise impacts select molecular systems such as brain-derived neurotrophic factors (BDNF) involved with synaptic plasticity underlying learning and memory. We propose studies to determine how exercise can facilitate learning in the spinal cord by activating BDNF-mediated synaptic plasticity. We will use a well-defined quantitative behavioral paradigm to determine spinal cord learning, and will rely on our experience gained studying the central effects of exercise-induced BDNF. We hypothesize that exercise and learning share molecular mechanisms and that BDNF plays a central role in modulating these mechanisms in the injured spinal cord. The highlight of these studies is the possibility to evaluate the effects of exercise on learning in conjunction with its effects on stepping performance in the same animals. We will make use of the pharmacology of the serotonergic system to facilitate locomotion in complete transected animals, and its close interaction with the BDNF system. Success in the proposed investigations should provide new strategies for the development of treatments to improve functional recovery after spinal cord injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS056413-04
Application #
8197312
Study Section
Special Emphasis Panel (ZRG1-BDCN-Y (06))
Program Officer
Hicks, Ramona R
Project Start
2009-01-01
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
4
Fiscal Year
2012
Total Cost
$394,017
Indirect Cost
$138,162
Name
University of California Los Angeles
Department
Surgery
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Agrawal, Rahul; Zhuang, Yumei; Cummings, Bethany P et al. (2014) Deterioration of plasticity and metabolic homeostasis in the brain of the UCD-T2DM rat model of naturally occurring type-2 diabetes. Biochim Biophys Acta 1842:1313-23
Tyagi, Ethika; Agrawal, Rahul; Ying, Zhe et al. (2014) TBI and sex: crucial role of progesterone protecting the brain in an omega-3 deficient condition. Exp Neurol 253:41-51
Agrawal, Rahul; Tyagi, Ethika; Vergnes, Laurent et al. (2014) Coupling energy homeostasis with a mechanism to support plasticity in brain trauma. Biochim Biophys Acta 1842:535-46
Baruch, Kuti; Ron-Harel, Noga; Gal, Hilah et al. (2013) CNS-specific immunity at the choroid plexus shifts toward destructive Th2 inflammation in brain aging. Proc Natl Acad Sci U S A 110:2264-9
Gomez-Pinilla, Fernando; Hillman, Charles (2013) The influence of exercise on cognitive abilities. Compr Physiol 3:403-28
Gomez-Pinilla, Fernando; Tyagi, Ethika (2013) Diet and cognition: interplay between cell metabolism and neuronal plasticity. Curr Opin Clin Nutr Metab Care 16:726-33
Tyagi, Ethika; Agrawal, Rahul; Zhuang, Yumei et al. (2013) Vulnerability imposed by diet and brain trauma for anxiety-like phenotype: implications for post-traumatic stress disorders. PLoS One 8:e57945
Gomez-Pinilla, Fernando; Ying, Zhe; Zhuang, Yumei (2012) Brain and spinal cord interaction: protective effects of exercise prior to spinal cord injury. PLoS One 7:e32298
Agrawal, Rahul; Gomez-Pinilla, Fernando (2012) 'Metabolic syndrome' in the brain: deficiency in omega-3 fatty acid exacerbates dysfunctions in insulin receptor signalling and cognition. J Physiol 590:2485-99
Wu, Aiguo; Ying, Zhe; Schubert, David et al. (2011) Brain and spinal cord interaction: a dietary curcumin derivative counteracts locomotor and cognitive deficits after brain trauma. Neurorehabil Neural Repair 25:332-42

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