ABSTRACT
Exercise-induced improvements in learning are associated with neurotrophic and neurogenic changes in the dentate gyrus, but the intracellular signalling mechanisms that may mediate these improvements remain unknown. In the current study we investigate the effects of one week of forced exercise on spatial memory and analyse in parallel BDNF-stimulated signalling pathways in cells of the dentate gyrus. Additionally, we test whether a single intracerebroventricular (i.c.v.) injection of BDNF can mimic the observed cognitive and signalling changes. Male Wistar rats were assigned to exercised and sedentary groups and tested in a spatial task post-exercise. Tissue from the dentate gyrus was assessed for expression and release of BDNF, and for changes in expression and activation of TrkB, ERK and synapsin-1. In a separate set of experiments, male Wistar rats received a single i.c.v. injection of BDNF and were then tested in the same spatial learning task. Exercised and BDNF-treated (but not control) rats could successfully complete an object displacement task that tests spatial learning. Exercised rats and BDNF-treated rats displayed increases BDNF expression and ERK1 activation, while exercised rats showed increases in cell division, stimulated BDNF release, TrkB activation, and synapsin-1 expression in the dentate gyrus. We conclude that exercise-induced increases in BDNF in the dentate gyrus are sufficient to cause improvements in spatial memory by activating signalling cascades that enhance synaptic transmission in the hippocampus.
Subject(s)
Brain-Derived Neurotrophic Factor/pharmacology , Physical Conditioning, Animal , Signal Transduction/drug effects , Spatial Memory/drug effects , Spatial Memory/physiology , Analysis of Variance , Animals , Brain-Derived Neurotrophic Factor/metabolism , Bromodeoxyuridine/metabolism , Cell Division/drug effects , Dentate Gyrus/cytology , Dentate Gyrus/drug effects , Dentate Gyrus/metabolism , Enzyme-Linked Immunosorbent Assay , Male , Potassium Chloride/pharmacology , RNA, Messenger/metabolism , Rats , Rats, Wistar , Receptor, trkB/genetics , Receptor, trkB/metabolism , Signal Transduction/physiology , Spatial Learning , Synapsins/metabolismABSTRACT
As an antidiabetic agent, rosiglitazone (ROSI) binds and activates peroxisome proliferator-activator receptor gamma (PPARγ), altering the expression of genes involved in glucose uptake and disposal, ultimately affecting glucose regulation. ROSI might therefore be a potential treatment to ameliorate age-related decline in cognitive function, particularly on an insulin-resistant background, where improvements in peripheral insulin sensitivity and central nervous system (CNS) glucose utilization may facilitate recovery of cognitive function. We therefore examined the amelioration potential of ROSI for neurocognitive deficits resulting from aging in an animal model. Behaviorally, acute and chronic ROSI treatments enhanced acquisition of learning in the water plus maze, a modified version of the Morris water maze task. In parallel, restoration of synaptic plasticity in the dentate gyrus of ROSI-treated middle-aged rats was evident after a single dose intake. Additionally, the spatial receptive fields of hippocampal CA1 place cells were significantly improved by chronic ROSI administration. ROSI treatment reversed basal plasma insulin abnormalities and increased hippocampal glucose transporter (GLUT)-3 expression in middle-aged rats. Taken together, these results suggest that ROSI modulates hippocampal circuitry effectively to promote an improvement in cognitive function, possibly via a glucose transporter-3 mechanism.
Subject(s)
Hippocampus/cytology , Hypoglycemic Agents/pharmacology , Long-Term Potentiation/drug effects , Memory Disorders/drug therapy , Neurons/drug effects , Thiazolidinediones/pharmacology , Aging/drug effects , Analysis of Variance , Animals , Biophysics , Electric Stimulation , Enzyme-Linked Immunosorbent Assay , Excitatory Postsynaptic Potentials/drug effects , Gene Expression Regulation/drug effects , Glucose Transporter Type 3/genetics , Glucose Transporter Type 3/metabolism , Hippocampus/drug effects , Long-Term Potentiation/physiology , Male , Maze Learning/drug effects , RNA, Messenger/metabolism , Rats , Rats, Wistar , Rosiglitazone , Time FactorsABSTRACT
Short periods of forced exercise have been reported to selectively induce enhancements in hippocampal-dependent cognitive function, possibly via brain-derived neurotrophic factor (BDNF)-mediated mechanisms. In this study, we report that 1 week of treadmill running significantly enhanced both object displacement (spatial) and object substitution (nonspatial) learning. These behavioral changes were accompanied by increased expression of BDNF protein in the dentate gyrus, hippocampus, and perirhinal cortex. The effects of exercise on object substitution were mimicked by intracerebroventricular injection of BDNF protein. These data are consistent with the hypothesis that exercise has the potential to enhance cognitive function in young healthy rats, possibly via a mechanism involving increased BDNF expression in specific brain regions.
