Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
J Neurosci. 2010 Nov 17;30(46):15585-99. doi: 10.1523/JNEUROSCI.2871-10.2010.
Recent studies show that glutamate and orexin (ORX, also known as hypocretin) inputs to the ventral tegmental area (VTA) dopamine (DA) cell region are essential for conditioned behavioral responses to reward-associated stimuli. In vitro experiments showed that ORX inputs to VTA potentiate responses of DA neurons to glutamate inputs, but it has remained unclear which glutamate inputs are modulated by ORX. The medial prefrontal cortex (mPFC) is a good candidate, given its role in processing complex stimulus-response information and its reciprocal connections with VTA DA neurons. Here we used in vivo recordings in anesthetized rats to investigate the responses of VTA DA neurons to mPFC stimulation, and how these responses are modulated by ORX. We demonstrate that mPFC stimulation evokes short- and long-latency excitation and inhibition in DA neurons. Maximal short-latency excitatory responses originated from stimulation sites in ventral prelimbic/infralimbic cortex, and were significantly more frequent during the active than during the rest period of the diurnal cycle. Application of ORX onto VTA DA neurons increased baseline activity and augmented or revealed excitatory responses to mPFC stimulation independent of changes in baseline activity, and without consistently affecting inhibitory responses. Moreover, orexin-1 receptor antagonism decreased tonic DA cell activity in active- but not rest-period animals, confirming a diurnal influence of ORX. These results indicate that ORX potently influences DA neuron activity, in part by modulating responses to mPFC inputs. By regulating prefrontal control of DA release, ORX projections to VTA may shape motivated behaviors in response to conditioned stimuli.
最近的研究表明，谷氨酸和食欲素（ORX，也称为下丘脑泌素）对腹侧被盖区（VTA）多巴胺（DA）细胞区域的输入对于与奖励相关的刺激的条件行为反应至关重要。体外实验表明，ORX 对 VTA 的输入增强了 DA 神经元对谷氨酸输入的反应，但 ORX 调节哪些谷氨酸输入仍不清楚。鉴于其在处理复杂刺激-反应信息中的作用及其与 VTA DA 神经元的相互联系，内侧前额叶皮层（mPFC）是一个很好的候选者。在这里，我们使用麻醉大鼠的体内记录来研究 VTA DA 神经元对 mPFC 刺激的反应，以及 ORX 如何调节这些反应。我们证明，mPFC 刺激会引起 DA 神经元的短潜伏期和长潜伏期兴奋和抑制。最短潜伏期的兴奋反应起源于腹侧前扣带回/下边缘皮层的刺激部位，并且在昼夜周期的活动期比休息期更为频繁。ORX 施加到 VTA DA 神经元上会增加基础活动，并增强或揭示对 mPFC 刺激的兴奋性反应，而与基础活动的变化无关，并且不会一致影响抑制性反应。此外，orexin-1 受体拮抗剂在活动期而非休息期动物中降低了紧张性 DA 细胞活动，证实了 ORX 的昼夜影响。这些结果表明，ORX 强烈影响 DA 神经元活动，部分是通过调节对 mPFC 输入的反应。通过调节前额叶对 DA 释放的控制，ORX 对 VTA 的投射可能会塑造对条件刺激的动机行为。
