Exercise-induced regulation of brain-derived neurotrophic factor (BDNF) gene expression in the rat hippocampus

Exercise is associated with enhanced cognitive function and maintenance of cognitive health. The molecular mechanisms underlying this improved brain functioning are beginning to be identified. Our research suggests that regulation of growth factor expression in the central nervous system may be one mechanism by which exercise can improve brain health and function. Physical activity (exercise) increases gene expression of brain-derived neurotrophic factor (BDNF), and this effect is particularly prominent in the hippocampus, a brain region associated with learning and memory rather than motor function. The goal of my studies has been to characterize the effect of physical activity on regulation of BDNF gene expression in the rat hippocampus, using voluntary wheel running as the exercise model.; The studies presented in this thesis explore variables that influence BDNF gene regulation in response to physical activity. Upregulation of BDNF gene expression in the hippocampus is a reproducible response to exercise across animal strains, sex, and species. BDNF gene upregulation by exercise is consistent under a variety of exercise conditions, such as duration of the exercise period, from hours to days and weeks. The effect is rapid, occurring within hours, and sustained. Voluntary exercise differentially increases the expression of multiple BDNF transcript forms. Exon I-BDNF and exon-II BDNF transcripts are selectively increased after 6 and 12 hours of running. Cholinergic and GABAergic input to the hippocampus from the medial septum provide a tonic regulation of BDNF gene expression in the hippocampus. Removal or reduction of cholinergic and GABAergic septohippocampal input reduces baseline BDNF gene activity, and blocks exercise-dependent increases in BDNF gene expression, particularly in the dentate gyrus and hilus of the hippocampus. Unexpectedly, the GABAergic input appears relatively more important than the cholinergic afferents in this effect. In addition, exercise and estrogen interact to modulate BDNF gene expression. In the absence of estrogen, exercise increases hippocampal BDNF gene expression only during a critical window of time. Finally, the presence of estrogen increases both BDNF gene expression as well as physical activity levels.; These data provide an initial characterization of the exercise-associated regulation of BDNF gene expression, a molecule increasingly recognized for its critical role in neuroprotection and synaptic plasticity.