Department of Pharmacology.
Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, North Carolina 07141.
J Neurosci. 2018 Oct 10;38(41):8845-8859. doi: 10.1523/JNEUROSCI.1116-18.2018. Epub 2018 Aug 27.
Deficits in motivation and cognition are hallmark symptoms of multiple psychiatric diseases. These symptoms are disruptive to quality of life and often do not improve with available medications. In recent years there has been increased interest in the role of the immune system in neuropsychiatric illness, but to date no immune-related treatment strategies have come to fruition. The cytokine granulocyte-colony stimulating factor (G-CSF) is known to have trophic and neuroprotective properties in the brain, and we recently identified it as a modulator of neuronal and behavioral plasticity. By combining operant tasks that assess discrete aspects of motivated behavior and decision-making in male mice and rats with subsecond dopamine monitoring via fast-scan cyclic voltammetry, we defined the role of G-CSF in these processes as well as the neural mechanism by which it modulates dopamine function to exert these effects. G-CSF enhanced motivation for sucrose as well as cognitive flexibility as measured by reversal learning. These behavioral outcomes were driven by mesolimbic dopamine system plasticity, as systemically administered G-CSF increased evoked dopamine release in the nucleus accumbens independent of clearance mechanisms. Importantly, sustained increases in G-CSF were required for these effects as acute exposure did not enhance behavioral outcomes and decreased dopamine release. These effects seem to be a result of the ability of G-CSF to alter local inflammatory signaling cascades, particularly tumor necrosis factor α. Together, these data show G-CSF as a potent modulator of the mesolimbic dopamine circuit and its ability to appropriately attend to salient stimuli. Emerging evidence has highlighted the importance of the immune system in psychiatric diseases states. However, the effects of peripheral cytokines on motivation and cognitive function are largely unknown. Here, we report that granulocyte-colony stimulating factor (G-CSF), a pleiotropic cytokine with known trophic and neuroprotective properties in the brain, acts directly on dopaminergic circuits to enhance their function. These changes in dopaminergic dynamics enhance reward learning and motivation for natural stimuli. Together, these results suggest that targeting immune factors may provide a new avenue for therapeutic intervention in the multiple psychiatric disorders that are characterized by motivational and cognitive deficits.
动机和认知缺陷是多种精神疾病的标志性症状。这些症状会破坏生活质量，而且往往不会因现有药物而改善。近年来，人们对免疫系统在神经精神疾病中的作用越来越感兴趣，但迄今为止，没有任何与免疫相关的治疗策略取得成果。细胞因子粒细胞集落刺激因子 (G-CSF) 已知在大脑中具有营养和神经保护特性，我们最近发现它是神经元和行为可塑性的调节剂。通过结合评估雄性小鼠和大鼠离散动机行为和决策方面的操作性任务以及通过快速扫描循环伏安法进行亚秒级多巴胺监测，我们确定了 G-CSF 在这些过程中的作用以及它调节多巴胺功能以发挥这些作用的神经机制。G-CSF 增强了蔗糖的动机以及通过反转学习测量的认知灵活性。这些行为结果是由中脑边缘多巴胺系统可塑性驱动的，因为系统给予的 G-CSF 增加了伏隔核中诱导的多巴胺释放，而与清除机制无关。重要的是，这些效应需要持续增加 G-CSF，因为急性暴露不会增强行为结果并减少多巴胺释放。这些效应似乎是 G-CSF 改变局部炎症信号级联的能力的结果，特别是肿瘤坏死因子 α。总之，这些数据表明 G-CSF 是中脑边缘多巴胺回路的有效调节剂，并且能够适当地关注显著刺激。新出现的证据强调了免疫系统在精神疾病状态中的重要性。然而，外周细胞因子对动机和认知功能的影响在很大程度上尚不清楚。在这里，我们报告粒细胞集落刺激因子 (G-CSF)，一种具有已知在大脑中的营养和神经保护特性的多效细胞因子，直接作用于多巴胺能回路以增强其功能。这些多巴胺动力学的变化增强了奖励学习和对自然刺激的动机。总之，这些结果表明，靶向免疫因子可能为以动机和认知缺陷为特征的多种精神障碍提供新的治疗干预途径。
