Hunsberger Joshua G, Newton Samuel S, Bennett Alicia H, Duman Catharine H, Russell David S, Salton Stephen R, Duman Ronald S
Department of Psychiatry, Yale University, 34 Park Street, New Haven, Connecticut 06508 USA.
Nat Med. 2007 Dec;13(12):1476-82. doi: 10.1038/nm1669. Epub 2007 Dec 2.
Exercise has many health benefits, including antidepressant actions in depressed human subjects, but the mechanisms underlying these effects have not been elucidated. We used a custom microarray to identify a previously undescribed profile of exercise-regulated genes in the mouse hippocampus, a brain region implicated in mood and antidepressant response. Pathway analysis of the regulated genes shows that exercise upregulates a neurotrophic factor signaling cascade that has been implicated in the actions of antidepressants. One of the most highly regulated target genes of exercise and of the growth factor pathway is the gene encoding the VGF nerve growth factor, a peptide precursor previously shown to influence synaptic plasticity and metabolism. We show that administration of a synthetic VGF-derived peptide produces a robust antidepressant response in mice and, conversely, that mutation of VGF in mice produces the opposite effects. The results suggest a new role for VGF and identify VGF signaling as a potential therapeutic target for antidepressant drug development.
运动对健康有诸多益处，包括对抑郁的人类受试者具有抗抑郁作用，但这些作用背后的机制尚未阐明。我们使用定制的微阵列来鉴定小鼠海马体中一组先前未被描述的运动调节基因，海马体是一个与情绪和抗抑郁反应有关的脑区。对这些受调节基因的通路分析表明，运动上调了一个与抗抑郁药作用相关的神经营养因子信号级联。运动和生长因子通路中调控程度最高的靶基因之一是编码VGF神经生长因子的基因，VGF神经生长因子是一种肽前体，先前已证明它会影响突触可塑性和新陈代谢。我们发现，给予合成的VGF衍生肽会在小鼠中产生强烈的抗抑郁反应，相反，小鼠中VGF基因的突变则会产生相反的效果。这些结果表明VGF有一个新的作用，并确定VGF信号传导是抗抑郁药物开发的一个潜在治疗靶点。
