Kv7.4在中脑VTA多巴胺神经环路兴奋性调控中的作用及生理病理学意义

Mesocorticolimbic dopaminergic circuit play critical roles in brain functions including rewad and emotion behaviors such as depression. Alteration of dopamine (DA) neuron activity and metabolism are involved in many neuropsychiatric disorders including drug addiction, Parkinson’s disease and schizophrenia. The function of DA circuitry is directed related with DA neuron excitability. However, many unanswered questions remain regarding the intrinsic and the regulatory mechanisms of DA neuron excitability, as such presenting to be a bottle neck for our understanding of DA neuron function and should be a priority for future study. In our earlier work, we found Kv7.4 potassium channels are selectively expressed in VTA DA neurons and play an important role in regulation of the neuronal excitability, and furthermore Kv7.4 is involved in the development of depression behavior in an animal model and is an effective target in alleviating the depression behavior. Based on these results, this application is intended to study Kv7.4 and other factors involved in the regulation of DA neuron excitability under the context of VTA DA-corticolimbic projection specificity. And under the same context, the Kv7.4 modulation by D2 and GABAB receptors will also be studied. Finally the role of Kv7.4 and its modulation in drug addiction and Kv7.4's potential as treatment target for drug addiction will be evaluated.

中脑-皮层及边缘系统的多巴胺（DA）神经环路系统在众多脑功能中发挥重要作用，如奖赏行为及情绪相关行为如抑郁。而DA神经元活性及代谢方式的改变则参与众多神经精神疾病的发生，如药物成瘾、帕金森氏病、精神分裂症等。DA神经环路的功能与其兴奋性直接相关。然而，对于决定DA神经元兴奋性的内在及调控机制仍有许多不明之处，是我们了解DA神经环路功能的瓶颈之一，亟需加强研究。我们前期工作发现Kv7.4钾通道在VTA DA神经元的选择性表达并在其兴奋性调节中发挥重要作用，而且参与动物抑郁样行为的发生且是抗抑郁作用的新靶点。本申请将在前期研究基础之上，以DA神经元向皮层及边缘系统的投射特异性为基础，研究Kv7.4及其它调控因素影响VTA DA神经元的兴奋性的投射特异性机制，以及D2受体及GABAB受体调节Kv7.4功能的机制，在此基础上探讨Kv7.4在药物成瘾中的作用及作为治疗药物成瘾靶点的潜能。

中脑腹侧被盖区(ventral tegmental area，VTA)多巴胺（DA）神经元编码与奖赏和药物成瘾的行为学，以及情感行为异常。VTA DA这些功能与其神经元兴奋性直接相关。本项目聚焦Kv7.4钾离子通道在VTA DA神经元兴奋性调控中的作用，具体研究Kv7.4在投向不同脑区（mPFC、NAC、BLA）的 VTA DA神经元上的功能性表达及异同、Kv7.4在D2多巴胺受体调控VTA DA神经元兴奋性中的作用及机制、Kv7.4在与VTA DA神经元相关的药物成瘾中的作用。项目利用了体内及体外电生理技术、单细胞PCR、免疫荧光、动物行为观察等方法开展研究。结果表明，Kv7.4功能性表达于投向不同脑区（mPFC、NAC、BLA）的 VTA DA神经元上；激活D2受体可以激活Kv7.4通道并由此抑制VTA DA神经元兴奋性，激活机制与细胞内Gi蛋白、ROS系统激活有关；调控Kv7.4 通道功能可以影响由可卡因诱发的动物成瘾样行为。本项目的结果提供了调控VTA DA神经元兴奋性的新机制，为了解与VTA DA神经元兴奋性相关的药物成瘾、抑郁症等行为和疾病的发生机制提供新的视野，为发现新的相关治疗靶点及药物提供新的证据。