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GABAergic CaMKII{alpha}+ Amygdala Output Attenuates Pain and Modulates Emotional-Motivational Behavior via Parabrachial Inhibition
Journal of Neuroscience ( IF 4.4 ) Pub Date : 2022-07-06 , DOI: 10.1523/jneurosci.2067-21.2022
Roni Hogri 1 , Hannah Luise Teuchmann 2 , Bernhard Heinke 2 , Raphael Holzinger 2 , Lidia Trofimova 2 , Jürgen Sandkühler 2
Affiliation  

Pain and emotion are strongly regulated by neurons in the central nucleus of the amygdala (CeA), a major output of the limbic system; yet, the neuronal signaling pathways underlying this modulation are incompletely understood. Here, we characterized a subpopulation of CeA neurons that express the CaMKIIα gene (CeACAM neurons) and project to the lateral parabrachial nucleus (LPBN), a brainstem region known for its critical role in distributing nociceptive and other aversive signals throughout the brain. In male Sprague Dawley rats, we show that CeACAM-LPBN neurons are GABAergic and mostly express somatostatin. In anaesthetized rats, optogenetic stimulation of CeACAM-LPBN projections inhibited responses of LPBN neurons evoked by electrical activation of A- and C-fiber primary afferents; this inhibition could be blocked by intra-LPBN application of the GABAA receptor antagonist bicuculline. CeACAM-LPBN stimulation also dampened LPBN responses to noxious mechanical, thermal, and chemical stimuli. In behaving rats, optogenetic stimulation of CeACAM-LPBN projections attenuated nocifensive responses to mechanical pressure and radiant heat, disrupted the ability of a noxious shock to drive aversive learning, reduced the defensive behaviors of thigmotaxis and freezing, induced place preference, and promoted food consumption in sated rats. Thus, we suggest that CeACAM-LPBN projections mediate a form of analgesia that is accompanied by a shift toward the positive-appetitive pole of the emotional-motivational continuum. Since the affective state of pain patients strongly influences their prognosis, we envision that recruitment of this pathway in a clinical setting could potentially promote pain resilience and recovery.

SIGNIFICANCE STATEMENT Pain and emotion interact on multiple levels of the nervous system. Both positive and negative emotion may have analgesic effects. However, while the neuronal mechanisms underlying "stress-induced analgesia" have been the focus of many studies, the neuronal substrates underlying analgesia accompanied by appetitive emotional-motivational states have received far less attention. The current study focuses on a subpopulation of amygdala neurons that form inhibitory synapses within the brainstem lateral parabrachial nucleus (LPBN). We show that activation of these amygdalo-parabrachial projections inhibits pain processing, while also reducing behaviors related to negative affect and enhancing behaviors related to positive affect. We propose that recruitment of this pathway would benefit pain patients, many of whom suffer from psychological comorbidities such as anxiety and depression.



中文翻译:


GABAergic CaMKII{alpha}+ 杏仁核输出通过臂旁抑制减轻疼痛并调节情绪动机行为



疼痛和情绪受到杏仁核中央核 (CeA) 神经元的强烈调节,杏仁核是边缘系统的主要输出;然而,这种调节背后的神经信号通路尚不完全清楚。在这里,我们表征了表达 CaMKIIα 基因的 CeA 神经元亚群(CeA CAM神经元)并投射到臂旁外侧核(LPBN),这是一个脑干区域,以其在整个大脑中分布伤害性和其他厌恶信号的关键作用而闻名。在雄性 Sprague Dawley 大鼠中,我们发现 CeA CAM -LPBN 神经元具有 GABA 能,并且主要表达生长抑素。在麻醉大鼠中,CeA CAM -LPBN 投射的光遗传学刺激抑制了 A 纤维和 C 纤维初级传入神经元的电激活引起的 LPBN 神经元的反应;这种抑制作用可以通过在 LPBN 内应用 GABA A受体拮抗剂荷包牡丹碱来阻断。 CeA CAM -LPBN 刺激还抑制 LPBN 对有害机械、热和化学刺激的反应。在行为大鼠中,CeA CAM -LPBN 投射的光遗传学刺激减弱了对机械压力和辐射热的伤害性反应,破坏了伤害性休克驱动厌恶性学习的能力,减少了趋触性和冻结的防御行为,诱导了位置偏好,并促进了食物饱腹大鼠的消耗。因此,我们认为 CeA CAM -LPBN 投射介导一种镇痛形式,伴随着向情绪动机连续体的积极食欲极的转变。 由于疼痛患者的情感状态强烈影响他们的预后,我们预计在临床环境中招募该通路可能会促进疼痛恢复和恢复。


意义陈述疼痛和情绪在神经系统的多个层面上相互作用。积极和消极情绪都可能具有镇痛作用。然而,虽然“压力诱导镇痛”背后的神经元机制一直是许多研究的焦点,但伴随食欲情绪动机状态的镇痛背后的神经元底物受到的关注却少得多。目前的研究重点是在脑干外侧旁臂核(LPBN)内形成抑制性突触的杏仁核神经元亚群。我们发现,这些杏仁核臂旁投射的激活会抑制疼痛处理,同时还减少与负面情绪相关的行为并增强与正面情绪相关的行为。我们建议,招募这条通路将有利于疼痛患者,他们中的许多人患有焦虑和抑郁等心理并发症。

更新日期:2022-07-07
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