EFFERENT MECHANISMS OF DEFENSE RESPONSE FROM THE HYPOTHALAMUS

下丘脑穹隆周围区域一直被称为防御反应中心，其特征是伴随着动脉血压(AP)、心率(HR)和呼吸频率(RF)的升高。我们利用食欲素基因敲除小鼠研究了食欲素，一种最近发现的下丘脑神经肽，是否有助于防御反应和基础心血管调节。将GABA-A受体拮抗剂甲基荷包牡丹碱微量注射到氨基甲酸乙酯麻醉的野生型小鼠的穹窿周围区域，可引起AP、HR和RF的剂量依赖性增加。虽然在食欲素基因敲除小鼠中也观察到了类似的变化，但强度和持续时间都比野生型小鼠小，而且在清醒和自由活动的条件下，在居民-入侵者测试中，遥测仪携带的食欲素基因敲除小鼠对情绪应激的心血管和行为反应减弱。我们还发现，在麻醉和清醒条件下，食欲素基因敲除小鼠的基础AP显著降低约20毫米汞柱。α-肾上腺素能受体阻滞剂哌唑嗪或神经节阻滞剂六甲基托溴铵可消除基础AP的差异。超声心动图测定的心率和心脏收缩参数在两个品系的小鼠之间没有差异。这些结果表明，基因敲除小鼠的交感血管收缩张力较低。本研究提示穹隆周围区含食欲素的神经元作为防御反应的传出通路之一起重要作用，并通过激活交感神经流出而在基础状态下作为AP的调节器发挥作用。

The perifornical area of the hypothalamus has been known as the center for defense response, or "fight or flight" response, which is characterized by concomitant rise in arterial blood pressure (AP), heart rate (HR), and respiratory frequency (Rf). We examined whether orexin, a recently identified hypothalamic neuropeptide, contributes to the defense response and basal cardiovascular regulation using orexin knockout mice. Microinjection of a GABA-A receptor antagonist, bicuculline methiodide, to the perifornical area in urethane-anesthetized wild-type mice elicited dose-dependent increases in AP, HR, and Rf. Although similar changes were observed in orexin knockout mice, intensities were smaller and duration was shorter than those in wild-type mice.Moreover, in an awake and freely moving condition, telemeter-indwelling orexin knockout mice showed diminished cardiovascular and behavioral responses to emotional stress in the resident-intruder test. We also found that basal AP in orexin knockout mice was significantly lower by 〜20 mmHg in both anesthetized and awake conditions. Alpha-adrenergic blockade with prazosin or ganglion blockade with hexamethonium cancelled the difference in basal AP. HR and cardiac contractile parameters by echocardiography did not differ between the two strains of mice. These results indicate lower sympathetic vasoconstrictor tone in knockout mice. The present study suggests that orexin-containing neurons in the perifornical area play a crucial role as one of the efferent pathways of defense response and also operate as a regulator of AP at basal condition by activating sympathetic outflow.