Action control is mediated by prefrontal BDNF and glucocorticoid receptor binding
Action control is mediated by prefrontal BDNF and glucocorticoid receptor binding
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DOI：
10.1073/pnas.1208342109
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发表时间：
2012-12-11
影响因子：
11.1
通讯作者：
Taylor, Jane R.
中科院分区：
文献类型：
--
作者：
Gourley, Shannon L.;Swanson, Andrew M.;Taylor, Jane R.
压力源暴露会使决策策略偏离基于行为及其对受刺激-反应关联限制的其他人的后果之间关系的决策策略。慢性压力源暴露也会使糖皮质激素受体（GR）变得不敏感，并降低获得食物强化的动力，尽管因果关系在很大程度上尚未确定。我们发现，长期接触 GR 配体皮质酮的历史或使用 RU38486 进行急性训练后 GR 阻断的历史会使啮齿动物不太能够根据其后果采取行动。因此，最佳的 GR 结合对于巩固新的反应结果学习是必要的。相比之下，内侧前额叶（但不是纹状体）BDNF 可以解释与压力相关的消极动机，因为选择性的内侧前额叶皮层 Bdnf 敲低会降低渐进比率任务中的断点比率。击倒也增加了对 RU38486 的脆弱性。尽管 BDNF 在树突棘重组中发挥作用，但深层树突棘重塑并不明显平行于渐进比率反应模式，但用 Na+ 通道抑制剂利鲁唑治疗可逆转皮质类固醇诱导的动机缺陷，并在皮质酮后恢复前额叶 BDNF 表达。我们认为，当前额神经营养蛋白系统受到损害，并且 GR 介导的下丘脑-垂体-肾上腺轴反馈变得不敏感时（如慢性应激激素暴露的情况），就会导致缺乏动力和不灵活的适应不良反应策略，从而导致与压力相关的情绪障碍。
Stressor exposure biases decision-making strategies from those based on the relationship between actions and their consequences to others restricted by stimulus-response associations. Chronic stressor exposure also desensitizes glucocorticoid receptors (GR) and diminishes motivation to acquire food reinforcement, although causal relationships are largely not established. We show that a history of chronic exposure to the GR ligand corticosterone or acute posttraining GR blockade with RU38486 makes rodents less able to perform actions based on their consequences. Thus, optimal GR binding is necessary for the consolidation of new response-outcome learning. In contrast, medial prefrontal (but not striatal) BDNF can account for stress-related amotivation, in that selective medial prefrontal cortical Bdnf knockdown decreases break-point ratios in a progressive-ratio task. Knockdown also increases vulnerability to RU38486. Despite the role of BDNF in dendritic spine reorganization, deep-layer spine remodeling does not obviously parallel progressive-ratio response patterns, but treatment with the Na+-channel inhibitor riluzole reverses corticosteroid-induced motivational deficits and restores prefrontal BDNF expression after corticosterone. We argue that when prefrontal neurotrophin systems are compromised, and GR-mediated hypo-thalamic-pituitary-adrenal axis feedback is desensitized (as in the case of chronic stress hormone exposure), amotivation and inflexible maladaptive response strategies that contribute to stress-related mood disorders result.