外侧下丘脑电刺激对脑外伤昏迷大鼠的促醒作用及机制研究

Neural electrical stimulation is the latest clinical treatment for comatose awakening. The domestic and foreign related research has confirmed wake-promoting effects of median nerve electrical stimulation.Recent work in our laboratory has shown that the coma-promoting mechanism is related to upregulated expression levels of Orexin-A in lateral hypothalamus.In view of existence of large number of orexin neurons in the lateral hypothalamic areas which have extensive connection with cortex and others arousal centers, and the preliminary experiments also showed that electrical stimulation of the lateral hypothalamus could improve the state of consciousness and increased the expression of orexin-A in prefrontal cortex of coma rats after traumatic brain injury, so we hypothesized that the lateral hypothalamus may be a potential target for awaking. For this purpose, we established coma model using controlled cortical impact mothod,(1) to study the coma promoting effects of lateral hypothalamus electrical stimulation of rats;(2) to investigate whether these effects have connection with the prefrontal cortex and nucleus tuberomammillary ; and (3) to elucidate whether orexin neurons mediate wake-promoting effect of electrical stimulation of lateral hypothalamus and regulate others arousal brain regions.The aim of this project is to investigate the awaking effects and mechanism by stimulating lateral hypothalamus of rats with traumatic brain injury induced coma in a whole animal level,Which can help clarify whether the lateral hypothalamic area can be a potential target for electrical stimulation, and open up new ideas and methods for clinical treatment of coma.

神经电刺激是临床上昏迷促醒的最新治疗手段。国内外研究发现：正中神经电刺激具有促醒作用，我们前期研究表明其促醒机制与上调下丘脑Orexin-A的含量相关。鉴于下丘脑外侧区存在大量orexin能神经元，与皮层及其它觉醒中枢有广泛联系，且预实验也表明外侧下丘脑电刺激可改善昏迷大鼠意识状态和上调前额叶皮层orexin-A受体的表达水平，因此我们推测下丘脑外侧区可能是潜在的促醒靶点。为此，我们通过控制性皮质撞击法建立脑外伤昏迷大鼠模型，1）研究外侧下丘脑电刺激对大鼠的促醒作用；2）探讨上述效应是否与前额叶皮层及结节乳头体核有关；3）明确orexin神经元是否介导外侧下丘脑电刺激的促醒作用及对其他觉醒脑区的调控。本课题拟从整体动物水平上探讨外侧下丘脑电刺激治疗脑外伤昏迷的促醒作用及机理，有助于明确下丘脑外侧区是否可能作为神经电刺激治疗昏迷的潜在靶点，为临床上昏迷促醒治疗开辟新的思路和方法。

神经电刺激是临床上昏迷促醒的最新治疗手段。国内外研究发现：正中神经电刺激具有促醒作用，我们前期研究表明其促醒机制与上调下丘脑Orexin-A的含量相关。鉴于下丘脑外侧区存在大量orexin能神经元，与皮层及其它觉醒中枢有广泛联系，且预实验也表明外侧下丘脑电刺激可改善昏迷大鼠意识状态和上调前额叶皮层orexin-A受体的表达水平，因此我们推测下丘脑外侧区可能是潜在的促醒靶点。为了验证这一假说，本课题拟从整体动物水平上探讨外侧下丘脑电刺激治疗脑外伤昏迷的促醒作用及机理，检测orexin-A 水平的变化及相关信号通路中物质的表达，明确Orexin-A在神经电刺激促醒中的关键作用，从而探讨神经电刺激促醒作用的分子机制。.研究结果表明：1）首次发现外侧下丘脑电刺激能够提高TBI昏迷大鼠的意识状态水平；2）LHA-DBS可上调TBI昏迷大鼠前额叶和下丘脑兴奋性递质受体OX1R、α1-AR的表达水平，下调抑制性递质受体GABAbR的表达水平；3）Orexins在LHA-DBS调节α1-AR和GABAbR 途径中扮演者关键作用，即存在“LHA-DBS/Orexins/神经递质”通路。.该成果为临床上LHA-DBS治疗TBI后昏迷患者奠定了理论基础，为临床上昏迷促醒提供了新的思路。此外，本研究有利于促进昏迷患者觉醒，减少致残率和提高患者的生活质量，使其真正重返家庭、回归社会，对促进社会和谐具有重要的经济和社会意义。