Orexin as a modulator of fear-related behavior: Hypothalamic control of noradrenaline circuit.
Orexin as a modulator of fear-related behavior: Hypothalamic control of noradrenaline circuit.
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食欲素作为恐惧相关行为的调节剂：下丘脑对去甲肾上腺素回路的控制。
DOI：
10.1016/j.brainres.2018.11.032
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发表时间：
2018
期刊：
影响因子：
2.9
通讯作者：
Sakurai T
中科院分区：
文献类型：
--
作者：
Soya S;Sakurai T
恐惧是生存的重要生理功能。它出现在动物或人类面临环境威胁时。杏仁核已经被证明在恐惧的出现中起着非常重要的作用。下丘脑食欲素神经元被恐惧刺激激活，以唤起“防御反应”，提高唤醒水平和交感神经流出，以应对迫在眉睫的危险。然而，这个系统如何促成与恐惧相关的行为的出现还没有得到很好的理解。下丘脑中的食欲素神经元向蓝斑（NALC）中的去甲肾上腺素能神经元发送兴奋性神经支配，所述去甲肾上腺素能神经元表达食欲素受体1（OX 1 R）并向外侧杏仁核（LA）发送投射。通过药理学或光/化学遗传学方法抑制这种双突触食欲素→ NALC→ LA途径可以减少线索诱导的恐惧表达。对这条通路的兴奋性操纵会导致冻结，这是一种与恐惧有关的行为，只有当环境包含一些暗示危险的元素时才会发生。虽然恐惧记忆有助于动物对先前与厌恶刺激配对的背景或线索做出反应，但即使在包含一些相似元素的不同背景下，有时也会诱发与恐惧相关的行为，这被称为恐惧泛化。我们最近的观察表明，食欲素→ NALC→ LA通路可能有助于这种反应。本文就下丘脑增食欲素神经元在行为恐惧表达中的作用作一综述。我们还讨论了食欲素受体拮抗剂治疗焦虑症和创伤后应激障碍（PTSD）中过度恐惧反应或过度概括的潜在有效性。
Fear is an important physiological function for survival. It appears when animals or humans are confronted with an environmental threat. The amygdala has been shown to play a highly important role in emergence of fear. Hypothalamic orexin neurons are activated by fearful stimuli to evoke a ‘defense reaction’ with an increase in arousal level and sympathetic outflow to deal with the imminent danger. However, how this system contributes to the emergence of fear-related behavior is not well understood. Orexin neurons in the hypothalamus send excitatory innervations to noradrenergic neurons in the locus coeruleus (NALC) which express orexin receptor 1 (OX1R) and send projections to the lateral amygdala (LA). Inhibition of this di-synaptic orexin → NALC→ LA pathway by pharmacological or opto/chemogenetic methods reduces cue-induced fear expression. Excitatory manipulation of this pathway induces freezing, a fear-related behavior that only occurs when the environment contains some elements suggestive of danger. Although, fear memory helps animals respond to a context or cue previously paired with an aversive stimulus, fear-related behavior is sometimes evoked even in a distinct context containing some similar elements, which is known as fear generalization. Our recent observation suggests that the orexin → NALC→ LA pathway might contribute to this response. This review focuses on recent advances regarding the role of hypothalamic orexin neurons in behavioral fear expression. We also discuss the potential effectiveness of orexin receptor antagonists for treating excessive fear response or overgeneralization seen in anxiety disorder and post-traumatic stress disorder (PTSD).