Orexin对前庭内侧核突触传递的调节及其在前庭相关运动疾病中的作用

Vestibular dysfunction, characterized by posture imbalance and vestibular vertigo, seriously affects the patient’s quality of life. As existing drugs alleviate vestibular symptoms simply by their sedative effect, new drugs contributing to the restoration of vestibular function remain to be developed. Orexin is a newly found neuropeptide. And for its key position in the regulation of various physiological functions, such as sleep/wake cycle, feeding and reward, orexin has attracted much attention. It’s worth noting that medial vestibular nucleus (MVN), the most critical central target for the treatment of vestibular disease, receives direct hypothalamic orexinergic projections. And high densities of orexin receptors are distributed throughout the MVN. It is well-known that plasticity of synaptic transmission in the MVN is the most significant physiological basis for vestibular compensation, i.e., the restoration of vestibular function in numerous peripheral vestibular diseases. Therefore, by combined using the methods of molecular biology, immunohistochemistry, electrophysiology, neuropharmacology, molecular genetics and behavioral study, we propose to investigate the effects of orexin on the MVN neuronal activities, especially on the synaptic transmission of MVN and its role in vestibular disease (rat models of motion sickness and unilateral labyrinthectomy) from the molecular, cellular as well as behavior level. The results of this study will reveal the physiological and pathological regulation of central orexinergic system in vestibular function. In addition, it will also benefit for the development of new drugs for vestibular disease treatment.

与前庭功能紊乱相关的疾病主要表现为姿势失衡和前庭性眩晕，严重影响患者的生活质量。现有药物仅通过镇定作用缓解前庭症状，前庭功能修复类药物亟待开发。Orexin是新近发现的一种神经肽，因在睡眠/觉醒、摄食、奖赏等生理功能中发挥重要作用而备受关注。值得注意的是，前庭内侧核（MVN）这一前庭疾病治疗的重要中枢靶点接受下丘脑orexin能纤维的直接投射，并表达大量orexin受体。考虑到MVN突触传递效能的变化是外周前庭疾病进行自身功能修复，即前庭代偿的重要生理基础，本项目拟采用分子生物学、免疫组织化学、电生理学、神经药理学、分子遗传学和行为学相结合的方法，从分子、细胞、行为水平上，深入研究orexin对MVN突触传递的调节及其在前庭疾病（运动症和单侧迷路切除模型）中的作用。研究结果将揭示中枢orexin能系统在前庭功能中的生理和病理性调控。同时，对于新型治疗前庭疾病药物的开发也极具指导意义。

Orexin是新近发现的一种神经肽，在睡眠/觉醒、摄食、奖赏以及运动等生理功能中发挥重要作用。值得注意的是，前庭内侧核（MVN）这一前庭疾病治疗的重要中枢靶点接受下丘脑orexin能纤维的直接投射，并表达大量orexin受体。然而，orexin对MVN的调控作用及其在前庭疾病中的作用尚不清楚。因此，本项目在我们先前工作的基础上，采用分子生物学、免疫组织化学、电生理学、神经药理学、分子遗传学和行为学相结合的方法，从分子、细胞、行为水平上，深入研究orexin对MVN神经元兴奋性和突触传递的调节及其在单侧迷路损伤和运动症等前庭疾病中的作用。结果表明，orexin可以降低MVN神经元接受的抑制性突触传递效能，并通过直接的突触后效应兴奋MVN神经元，进而提高经MVN介导的躯体运动和平衡协调能力，参与单侧迷路损伤后的前庭代偿进程和运动症的发生发展机制。项目已发表SCI研究论文9篇，核心期刊研究论文1篇。项目研究成果将有助于我们深入理解前庭功能障碍及自身修复的生理和病理学机制，orexin受体及其下游耦联离子机制很可能作为新型前庭疾病治疗药物靶点用于临床前庭疾病的防治。