Neural basis for fasting activation of the hypothalamic-pituitary-adrenal axis
Neural basis for fasting activation of the hypothalamic-pituitary-adrenal axis
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下丘脑-垂体-肾上腺轴禁食激活的神经基础
DOI：
10.1038/s41586-023-06358-0
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发表时间：
2023-07-26
期刊：
影响因子：
64.8
通讯作者：
Lowell, Bradford B.
中科院分区：
文献类型：
--
作者：
Douglass, Amelia M.;Resch, Jon M.;Lowell, Bradford B.
禁食启动了多种适应以允许生存。下丘脑-垂体-肾上腺（HPA）轴的激活和随后糖皮质激素的释放是调动燃料储存以满足能量需求的关键反应1 -5。尽管HPA轴反应的重要性，但在能量不足时驱动其激活的神经机制尚不清楚。在这里，我们表明，禁食激活下丘脑刺豚鼠相关肽（AgRP）表达神经元触发，是必不可少的禁食诱导HPA轴激活。AgRP神经元通过投射到室旁下丘脑（PVH）来实现这一点，在PVH中，AgRP神经元以先前未描述的机制突触前抑制来自终纹床核（BNST）的紧张性活性GABA能传入的末梢，否则这些末梢抑制促肾上腺皮质激素释放激素（CRH）表达神经元的活性。PVHCrh神经元的这种去抑制需要。-氨基丁酸（GABA）/GABA-B受体信号传导并有效激活HPA轴。值得注意的是，刺激HPA轴的AgRP神经元是独立的诱导饥饿，表明这些典型的“饥饿神经元”驱动许多明显不同的适应禁食状态。总之，我们的研究结果确定了禁食诱导HPA轴激活的神经基础，并揭示了AgRP神经元激活下游神经元的独特方式：通过突触前抑制GABA能传入。考虑到这种对紧张性活性BNST传入的解除抑制的效力，HPA轴的其他激活剂，例如心理应激，也可以通过减少BNST对PVHCrh神经元的抑制性紧张来起作用。
Fasting initiates a multitude of adaptations to allow survival. Activation of the hypothalamic-pituitary-adrenal (HPA) axis and subsequent release of glucocorticoid hormones is a key response that mobilizes fuel stores to meet energy demands1-5. Despite the importance of the HPA axis response, the neural mechanisms that drive its activation during energy deficit are unknown. Here, we show that fasting-activated hypothalamic agouti-related peptide (AgRP)-expressing neurons trigger and are essential for fasting-induced HPA axis activation. AgRP neurons do so through projections to the paraventricular hypothalamus (PVH), where, in a mechanism not previously described for AgRP neurons, they presynaptically inhibit the terminals of tonically active GABAergic afferents from the bed nucleus of the stria terminalis (BNST) that otherwise restrain activity of corticotrophin-releasing hormone (CRH)expressing neurons. This disinhibition of PVHCrh neurons requires.-aminobutyric acid (GABA)/GABA-B receptor signalling and potently activates the HPA axis. Notably, stimulation of the HPA axis by AgRP neurons is independent of their induction of hunger, showing that these canonical 'hunger neurons' drive many distinctly different adaptations to the fasted state. Together, our findings identify the neural basis for fasting-induced HPA axis activation and uncover a unique means by which AgRP neurons activate downstream neurons: through presynaptic inhibition of GABAergic afferents. Given the potency of this disinhibition of tonically active BNST afferents, other activators of the HPA axis, such as psychological stress, may also work by reducing BNST inhibitory tone onto PVHCrh neurons.