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Abstract：
Our recent study demonstrated the critical role of the mesolimbic dopamine (DA) circuit and its brain-derived neurotropic factor (BDNF) signaling in mediating neuropathic pain. The present study aims to investigate the functional role of GABAergic inputs from the lateral hypothalamus (LH) to the ventral tegmental area (VTA; LHGABA→VTA) in regulating the mesolimbic DA circuit and its BDNF signaling underlying physiological and pathologic pain. We demonstrated that optogenetic manipulation of the LHGABA→VTA projection bidirectionally regulated pain sensation in naive male mice. Optogenetic inhibition of this projection generated an analgesic effect in mice with pathologic pain induced by chronic constrictive injury (CCI) of the sciatic nerve and persistent inflammatory pain by complete Freund\'s adjuvant (CFA). Trans-synaptic viral tracing revealed a monosynaptic connection between LH GABAergic neurons and VTA GABAergic neurons. Functionally, in vivo calcium/neurotransmitter imaging showed an increased DA neuronal activity, decreased GABAergic neuronal activity in the VTA, and increased dopamine release in the NAc, in response to optogenetic activation of the LHGABA→VTA projection. Furthermore, repeated activation of the LHGABA→VTA projection was sufficient to increase the expression of mesolimbic BDNF protein, an effect seen in mice with neuropathic pain. Inhibition of this circuit induced a decrease in mesolimbic BDNF expression in CCI mice. Interestingly, the pain behaviors induced by activation of the LHGABA→VTA projection could be prevented by pretreatment with intra-NAc administration of ANA-12, a TrkB receptor antagonist. These results demonstrated that LHGABA→VTA projection regulated pain sensation by targeting local GABAergic interneurons to disinhibit the mesolimbic DA circuit and regulating accumbal BDNF release.SIGNIFICANCE STATEMENT The mesolimbic dopamine (DA) system and its brain-derived neurotropic factor (BDNF) signaling have been implicated in pain regulation, however, underlying mechanisms remain poorly understood. The lateral hypothalamus (LH) sends different afferent fibers into and strongly influences the function of mesolimbic DA system. Here, utilizing cell type- and projection-specific viral tracing, optogenetics, in vivo calcium and neurotransmitter imaging, our current study identified the LHGABA→VTA projection as a novel neural circuit for pain regulation, possibly by targeting the VTA GABA-ergic neurons to disinhibit mesolimbic pathway-specific DA release and BDNF signaling. This study provides a better understanding of the role of the LH and mesolimbic DA system in physiological and pathological pain.
摘要：
我们最近的研究证明了中脑边缘多巴胺（DA）回路及其脑源性神经营养因子（BDNF）信号在介导神经性疼痛中的关键作用。本研究旨在研究从下丘脑外侧到腹侧被盖区（LHGABA→VTA）的GABA能输入在调节中脑边缘DA回路及其在生理和病理性疼痛中的BDNF信号传导中的功能作用。我们证明了LHGABA→VTA投影的光遗传学操纵可双向调节幼稚雄性小鼠的痛觉。这种投射的光遗传学抑制在由坐骨神经慢性收缩性损伤（CCI）和完全弗氏佐剂引起的持续性炎性疼痛引起的病理性疼痛的小鼠中产生了镇痛作用。跨突触病毒示踪揭示了LHGABA能神经元和VTAGABA能神经元之间的单突触联系。功能上,体内钙/神经递质成像显示DA神经元活性增加，VTA中GABA能神经元活性降低，增加了NAc中的多巴胺释放，响应LHGABA→VTA投影的光遗传学激活。此外，LHGABA→VTA投影的重复激活足以增加中胚层BDNF蛋白的表达，在患有神经性疼痛的小鼠中看到的效果。该回路的抑制诱导了CCI小鼠中脑边缘BDNF表达的降低。有趣的是,LHGABA→VTA投射激活引起的疼痛行为可以通过NAc内给药TrkB受体拮抗剂ANA-12进行预处理来预防。这些结果表明，LHGABA→VTA投射通过靶向局部GABA能中间神经元来抑制中胚层DA回路并调节伏隔BDNF释放，从而调节痛觉。意义陈述中脑边缘多巴胺（DA）系统的脑源性神经营养因子（BDNF）信号与疼痛调节有关，然而,潜在的机制仍然知之甚少。下丘脑外侧（LH）将不同的传入纤维送入并强烈影响中脑边缘DA系统的功能。这里,利用细胞类型和投射特异性病毒追踪，光遗传学,体内钙和神经递质成像，我们目前的研究确定LHGABA-VTA投影是一种新型的疼痛调节神经回路，可能通过靶向VTAGABA能神经元来抑制中胚层通路特异性DA释放和BDNF信号传导。这项研究提供了更好地了解LH和中脑边缘DA系统在生理和病理性疼痛中的作用。
