Hippocampal brain‐derived neurotrophic factor gene regulation by exercise and the medial septum
Tóm tắt
Brain‐derived neurotrophic factor (BDNF) enhances synaptic plasticity and neuron function. We have reported that voluntary exercise increases BDNF mRNA levels in the hippocampus; however, mechanisms underlying this regulation have not been defined. We hypothesized that medial septal cholinergic and/or gamma amino butyric acid (GABA)ergic neurons, which provide a major input to the hippocampus, may regulate the baseline gene expression and exercise‐dependent gene upregulation of this neurotrophin. Focal lesions were produced by medial septal infusion of the saporin‐linked immunotoxins 192‐IgG‐saporin or OX7‐saporin. 192‐IgG‐saporin produced a selective and complete loss of medial septal cholinergic neurons with no accompanying GABA loss. Baseline BDNF mRNA was reduced in the hippocampus of sedentary animals, but exercise‐induced gene upregulation was not impaired, despite complete loss of septo‐hippocampal cholinergic afferents. OX7‐saporin produced a graded lesion of the medial septum characterized by predominant GABA neuron loss with less reduction in the number of cholinergic cells. OX7‐saporin lesion reduced baseline hippocampal BDNF mRNA and attenuated exercise‐induced gene upregulation, in a dose‐dependent manner. These results suggest that combined loss of septal GABAergic and cholinergic input to the hippocampus may be important for exercise‐dependent BDNF gene regulation, while cholinergic activity on its own is not sufficient. These results are discussed in relation to their implications for aging and Alzheimer's disease. © 2002 Wiley‐Liss, Inc.
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Alreja M, 2000, Muscarinic tone sustains impulse flow in the septohippocampal GABA but not cholinergic pathway: implications for learning and memory, J Neurosci, 20, 8103, 10.1523/JNEUROSCI.20-21-08103.2000
da Penha Berzaghi M, 1993, Cholinergic regulation of brain‐derived neurotrophic factor (BDNF) and nerve growth factor (NGF) but not neurotrophin‐3 (NT‐3) mRNA levels in the developing rat hippocampus, J Neurosci, 13, 3818, 10.1523/JNEUROSCI.13-09-03818.1993
Ip NY, 1993, Cultured hippocampal neurons show responses to BDNF, NT‐3, and NT‐4, but not NGF, J Neurosci, 13, 3394, 10.1523/JNEUROSCI.13-08-03394.1993
Mizuno M, 2000, Involvement of brain‐derived neurotrophic factor in spatial memory formation and maintenance in a radial arm maze test in rats, J Neurosci, 201, 7116, 10.1523/JNEUROSCI.20-18-07116.2000
Nonner D, 1996, Neurotrophin effects on survival and expression of cholinergic properties in cultured rat septal neurons under normal and stress conditions, J Neurosci, 16, 6665, 10.1523/JNEUROSCI.16-21-06665.1996
Pellegrino L, 1979, A stereotaxic atlas of the rat brain