Gourley Shannon L, Zimmermann Kelsey S, Allen Amanda G, Taylor Jane R
Department of Pediatrics, Graduate Program in Neuroscience, and Yerkes National Primate Research Center, Emory University, Atlanta, Georgia 30329, and,
Department of Pediatrics, Graduate Program in Neuroscience, and Yerkes National Primate Research Center, Emory University, Atlanta, Georgia 30329, and.
J Neurosci. 2016 Apr 20;36(16):4600-13. doi: 10.1523/JNEUROSCI.4253-15.2016.
An essential component of goal-directed decision-making is the ability to maintain flexible responding based on the value of a given reward, or "reinforcer." The medial orbitofrontal cortex (mOFC), a subregion of the ventromedial prefrontal cortex, is uniquely positioned to regulate this process. We trained mice to nose poke for food reinforcers and then stimulated this region using CaMKII-driven Gs-coupled designer receptors exclusively activated by designer drugs (DREADDs). In other mice, we silenced the neuroplasticity-associated neurotrophin brain-derived neurotrophic factor (BDNF). Activation of Gs-DREADDs increased behavioral sensitivity to reinforcer devaluation, whereas Bdnf knockdown blocked sensitivity. These changes were accompanied by modifications in breakpoint ratios in a progressive ratio task, and they were recapitulated in Bdnf(+/-)mice. Replacement of BDNF selectively in the mOFC in Bdnf(+/-)mice rescued behavioral deficiencies, as well as phosphorylation of extracellular-signal regulated kinase 1/2 (ERK1/2). Thus, BDNF expression in the mOFC is both necessary and sufficient for the expression of typical effort allocation relative to an anticipated reinforcer. Additional experiments indicated that expression of the immediate-early gene c-fos was aberrantly elevated in the Bdnf(+/-)dorsal striatum, and BDNF replacement in the mOFC normalized expression. Also, systemic administration of an MAP kinase kinase inhibitor increased breakpoint ratios, whereas the addition of discrete cues bridging the response-outcome contingency rescued breakpoints in Bdnf(+/-)mice. We argue that BDNF-ERK1/2 in the mOFC is a key regulator of "online" goal-directed action selection.
Goal-directed response selection often involves predicting the consequences of one's actions and the value of potential payoffs. Lesions or chemogenetic inactivation of the medial orbitofrontal cortex (mOFC) in rats induces failures in retrieving outcome identity memories (Bradfield et al., 2015), suggesting that the healthy mOFC serves to access outcome value information when it is not immediately observable and thereby guide goal-directed decision-making. Our findings suggest that the mOFC also bidirectionally regulates effort allocation for a given reward and that expression of the neurotrophin BDNF in the mOFC is both necessary and sufficient for mice to sustain stable representations of reinforcer value.
目标导向决策的一个关键组成部分是根据给定奖励或“强化物”的价值保持灵活反应的能力。内侧眶额皮质（mOFC）是腹内侧前额叶皮质的一个亚区域，在调节这一过程中具有独特的地位。我们训练小鼠通过鼻触获取食物强化物，然后使用由钙调蛋白激酶II驱动的、仅由设计药物（DREADDs）激活的Gs偶联设计受体刺激该区域。在其他小鼠中，我们使与神经可塑性相关的神经营养因子脑源性神经营养因子（BDNF）沉默。激活Gs-DREADDs增加了行为对强化物贬值的敏感性，而敲低Bdnf则阻断了这种敏感性。这些变化伴随着渐进比率任务中断点比率的改变，并且在Bdnf(+/-)小鼠中也得到了重现。在Bdnf(+/-)小鼠的mOFC中选择性地替换BDNF挽救了行为缺陷以及细胞外信号调节激酶1/2（ERK1/2）的磷酸化。因此，mOFC中BDNF的表达对于相对于预期强化物的典型努力分配的表达既是必要的也是充分的。额外的实验表明，Bdnf(+/-)背侧纹状体中即早基因c-fos的表达异常升高，而在mOFC中替换BDNF可使表达正常化。此外，全身给予丝裂原活化蛋白激酶激酶抑制剂会增加断点比率，而添加连接反应-结果偶联的离散线索可挽救Bdnf(+/-)小鼠的断点。我们认为，mOFC中的BDNF-ERK1/2是目标导向“在线”行动选择的关键调节因子。
目标导向的反应选择通常涉及预测自身行为的后果和潜在回报的价值。大鼠内侧眶额皮质（mOFC）的损伤或化学遗传学失活会导致在检索结果身份记忆方面出现失败（Bradfield等人，2015年），这表明健康的mOFC在结果价值信息无法立即观察到时用于获取该信息，从而指导目标导向的决策。我们的研究结果表明，mOFC还双向调节对给定奖励的努力分配，并且mOFC中神经营养因子BDNF的表达对于小鼠维持强化物价值的稳定表征既是必要的也是充分的。
