Central Neural Mechanisms of the Defense Response against Stressor

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We previously showed that the defense response elicited by stressors was attenuated in prepro-orexin knockout mice and in orexin neuron-ablated mice, and we proposed that orexin serves as a master switch within multiple efferent pathways that mediate the defense response. In this study we sought to determine whether excitation of the amygdala (AMG) or the bed nucleus of stria terminalis (BNST) activates orexin-containing neurons and whether those neurons are essential in eliciting cardiorespiratory responses to the stimulus. In urethane-anesthetized mice, the GABA-A receptor antagonist bicuculline was microinjected into the AMG or BNST at sites where electrical stimulation induced simultaneous increases in blood pressure, heart rate, respiratory frequency, and tidal volume. Injection of bicuculline in either site induced long-lasting dose-dependent cardiorespiratory excitation in wild-type mice. In contrast, mice in which orexin neurons had been ablated demonstrated no such response after activation of the AMG and only a small response after activation of the BNST. Double immunohistochemical staining for orexin and c-Fos, an indicator of neural activation, revealed that an injection of bicuculline induced significantly larger numbers of orexin positive neurons that expressed c-Fos in the medial portion of the hypothalamus (58.2 ± 6.4 % into AMG and 66.4 ± 6.6 % into BNST, n=3 each) than did vehicle (18.2 ± 4.4 % into AMG and 28.3 ± 2.1 % into BNST). We conclude that the AMG and the BNST provide afferent input to the orexin-containing neurons that are involved in mediating the cardiorespiratory responses through the perifornical and dorsomedial hypothalamus.