Anxiolytic function of the orexin 2/hypocretin A receptor in the basolateral amygdala.
Anxiolytic function of the orexin 2/hypocretin A receptor in the basolateral amygdala.
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DOI：
10.1016/j.psyneuen.2013.10.010
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发表时间：
2014-02
影响因子：
3.7
通讯作者：
Summers, Cliff H.
中科院分区：
文献类型：
--
作者：
Arendt, David H.;Hassell, James;Li, Hao;Achua, Justin K.;Guarnieri, Douglas J.;DiLeone, Ralph J.;Ronan, Patrick J.;Summers, Cliff H.
食欲素/下丘脑分泌素系统与许多导致抑郁和焦虑等压力相关疾病的相同回路相互作用。这些包括与促肾上腺皮质激素释放因子（CRF）神经元的潜在相互联系，该神经元驱动下丘脑-垂体-肾上腺（HPA）内分泌反应，并在中央杏仁核（CeA）中具有焦虑效应。下丘脑中食欲素1型受体（Orx1）的拮抗作用也被证明可以阻止恐慌发作。然而，很少有研究调查了负责情境恐惧的基底外侧杏仁核（BLA）中食欲能信号的作用，并调节CeA的活性。为此，我们对社会性失败的c57bl/6小鼠进行了长期应激，并检测了BLA中食欲素受体的基因表达。我们发现，在易受慢性失败影响的动物中，BLA中Orx1和Orx2受体的转录本出现分化，Orx1增加，Orx2减少。这些变化在向BLA发送传出信号的前边缘皮层（PrL）中未见。然后，我们试图利用腺相关病毒传递的短发夹干扰序列来敲除食欲素受体，从而在BLA中概括这些表达模式。虽然Orx1基因敲低确实减少了运动活动，但它并没有减少抑郁或焦虑行为。降低BLA中的Orx2受体会增加焦虑行为，这可以通过降低社会偏好和减少在开阔场地中心停留的时间来衡量。由于这两种受体在慢性应激反应中的表达模式不同，BLA中的食欲能活性可能是焦虑行为的双向调节。此外，这些数据提高了Orx2激动剂可能作为治疗焦虑症的有效手段的可能性。
The orexin/hypocretin system interacts with many of the same circuitries contributing to stress-associated disorders like depression and anxiety. These include potentially reciprocal connections with corticotropin releasing factor (CRF) neurons which drive the hypothalamic–pituitary–adrenal (HPA) endocrine response in addition to having an anxiogenic effect in the central amygdala (CeA). Antagonism of the orexin type 1 receptor (Orx1) in the hypothalamus has also been shown to block panic attacks. However, few studies have investigated the effect of orexinergic signaling in the basolateral amygdala (BLA) which is responsible for contextual fear, and modulates the activity of the CeA. To this end, we chronically stressed c57bl/6 mice with social defeat and examined the gene expression of the orexin receptors in the BLA. We found that the transcripts for the Orx1 and Orx2 receptors diverged in the BLA with Orx1 increasing and Orx2 decreasing in animals that were susceptible to the chronic defeat. These changes were not seen in the prelimbic cortex (PrL) which sends efferents to the BLA. We then tried to recapitulate these expression patterns in the BLA using short hairpin interfering sequences delivered by adeno-associated viruses to knock down the orexin receptors. While the Orx1 knockdown did reduce locomotor activity, it did not decrease depressive or anxious behaviors. Knocking down the Orx2 receptors in the BLA increased anxious behavior as measured by reduced social preference and reduced time spent in the center of an open field. Due to the divergent expression patterns of the two receptors in response to chronic stress, orexinergic activity in the BLA may be responsible for bidirectional modulation of anxious behavior. Furthermore, these data raise the possibility that an Orx2 agonist may serve as an effective means to treat anxiety disorders.
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