(from Abstract) Neurotrophins are involved in a variety of processes that are responsible for the integrity, growth and physiology of cells in the brain. Direct and indirect evidence supports the contention that neurotrophins, which includes NGF and BDNF have a critical role in maintaining the health of the nervous system, and are important in the continuous modification of neural circuits throughout development and aging. The expression of and responsiveness to NGF and BDNF by the brain may underlie subtle and dramatic structural changes associated with behavior. Trophic factors may be involved in a series of events that modify the CNS. The biological activity associated with neurotrophins are mediated by tyrosine kinase receptors (trks) activation. The regional distribution of neurotrophins and their receptors, and the functional activity of neural circuits should also be taken into consideration. A plethora of research indicates that defined neural circuits are involved in specific behaviors, which can be compromised by age. Maintenance and modification of these neural circuits may rely on NGF and BDNF activity; however, it is not clear how aging affects the neurotrophins or their receptors. If NGF and BDNF are necessary for the health of the brain, then deficits in the neurotrophins could result in neural degeneration and dysfunction. Neurotrophin expression is part of a cascade of events that also relies on binding of the proteins to the appropriate trk receptor. The first two objectives of this proposal are, in young, middle age and old rats, characterize the regional levels of NGF,BDNF, trk A and trk B mRNA in relation to a comprehensive battery of behavioral tests. As age increases there are changes in the brain that can produce successful aging or dementia, and the neurotrophins may be an integral component of that aging process. The third objective of the proposal is to induce higher levels of NGF,BDNF, trk A and trk B mRNA expression in young, middle age and old rats by behavioral interventions. General motor activity can increase neurotrophin levels in the brain, and preliminary data indicate that learning can further elevate neurotrophin levels in excess of activity alone. Implications for these results are significant in that they suggest physical and mental activity facilitates maintenance of a healthy nervous system throughout life. Although this may seem common sense, this proposal will elucidate possible mechanisms responsible for the successful maturation of the nervous system. Direct, optimized stimulation of neurotrophin expression opens new avenues for the development of behavioral interventions. Compromised or at risk neural circuits could benefit from programs designed to stimulate activity and promote neurotrophin expression. Thus, the localization and expression of NGF, BDNF, trk A and trk B mRNA can be an essential factor in aging.
