多巴胺能神经元在低温刺激下调节肌肉兴奋的机制研究

过度的寒冷刺激，轻则导致动物和人类发生组织损伤（冻伤）和引起疼痛，重则导致体温难以维持而危及生命。大约有4%的人口，遇到低温时，四肢末端会出现血管内皮痉挛导致缺血现象，严重时会造成末端组织坏死，这种疾病叫做雷诺氏综合征。目前雷诺氏综合征的致病机制尚不清楚，尚无有效的治疗方法。我们发现模式动物秀丽隐杆线虫在低温条件下会迅速发生肌肉痉挛，这一行为学特征是通过多巴胺能神经元PDE感受低温刺激后分泌神经递质多巴胺，并作用于下游的运动神经元上的多巴胺受体dop-3，进而调节肌肉的兴奋性，产生肌肉痉挛反应。以上预实验结果提示多巴胺能神经元很可能直接参与低温信号感受和传递。我们拟运用分子遗传学、膜片钳电生理、胞内钙成像、药理和行为学分析等技术，系统性研究多巴胺能神经元在低温刺激下调节肌肉兴奋的机制与神经网络。本研究将有助于雷诺氏综合征的致病机制和其药物新靶点的开发提供理论基础。

Excessive cold stimulation can cause tissue damage and pain in animals and human, and can cause low body temperature that leads to life-threatening. Approximately 4% of the population suffer from vascular endothelial spasm leaded ischemia at the extremities when exposed to low temperature and cause necrosis of the extremities in some severe cases. This disease is called Raynaud's syndrome. At present, the pathogenesis of Raynaud's syndrome is unclear, and there is no effective treatment. We found that the model animal Caenorhabditis elegans can rapidly cause muscle spasm under low temperature conditions. This behavioral characteristic is that the dopaminergic neuron PDE secretes the neurotransmitter dopamine after being stimulated by low temperature, and acts on the downstream motor neurons that express the dopamine receptor dop-3, which in turn regulates the excitability of muscles, produces a muscle spasm response. The above pre-experimental results suggest that dopaminergic neurons are likely to directly participate in the sensing and transmission of cold signals. We plan to use techniques such as molecular genetics, patch-clamp electrophysiology, intracellular calcium imaging, pharmacology, and behavioral analysis to systematically study the mechanisms and neural networks of dopaminergic neurons that regulate muscle excitation under low-temperature stimulation. This study will help to provide a theoretical basis for the pathogenesis of Raynaud's syndrome and the development of new drug targets.