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The kappa opioid receptor modulates GABA neuron excitability and synaptic transmission in midbrainprojections from the insular cortex.
Neuropharmacology ( IF 4.7 ) Pub Date : 2019-12-21 , DOI: 10.1016/j.neuropharm.2019.107831
Melanie M Pina 1 , Dipanwita Pati 1 , Lara S Hwa 1 , Sarah Y Wu 2 , Alexandra A Mahoney 2 , Chiazam G Omenyi 2 , Montserrat Navarro 3 , Thomas L Kash 1
Affiliation  

As an integrative hub, the insular cortex (IC) translates external cues into interoceptive states that generate complex physiological, affective, and behavioral responses. However, the precise circuit and signaling mechanisms in the IC that modulate these processes are unknown. Here, we describe a midbrain-projecting microcircuit in the medial aspect of the agranular IC that signals through the Gαi/o-coupled kappa opioid receptor (KOR) and its endogenous ligand dynorphin (Dyn). Within this microcircuit, Dyn is robustly expressed in layer 2/3, while KOR is localized to deep layer 5, which sends a long-range projection to the substantia nigra (SN). Using ex vivo electrophysiology, we evaluated the functional impact of KOR signaling in layer 5 of the IC. We found that bath application of dynorphin decreased GABA release and increased glutamate release on IC-SN neurons, but did not alter their excitability. Conversely, dynorphin decreased the excitability of GABA neurons without altering synaptic transmission. Pretreatment with the KOR antagonist nor-BNI blocked the effects of dynorphin in IC-SN neurons and GABA neurons, indicating that the changes in synaptic transmission and excitability were selectively mediated through KOR. Selective inhibition of IC GABA neurons using a KOR-derived DREADD recapitulated these effects. This work provides insight into IC microcircuitry and indicates that Dyn/KOR signaling may act to directly reduce activity of layer 5 GABA neurons. In turn, KOR-driven inhibition of GABA promotes disinhibition of IC-SN neurons, which can modulate downstream circuits. Our findings present a potential mechanism whereby chronic upregulation of IC Dyn/KOR signaling can lead to altered subcortical function and downstream activity.

中文翻译:

κ阿片受体可调节GABA神经元的兴奋性和离岛皮层中脑突触的突触传递。

作为一个综合枢纽,岛状皮质(IC)将外部线索转换为感受态,从而产生复杂的生理,情感和行为反应。但是,IC中用于调制这些过程的精确电路和信号机制尚不清楚。在这里,我们在颗粒状IC的内侧描述了一个中脑投射微电路,该信号通过Gαi/ o耦合的阿片受体(KOR)及其内源性配体强啡肽(Dyn)发出信号。在此微电路中,Dyn在第2/3层中稳健表示,而KOR定位在第5层深层,该层将长距离投影发送到黑质(SN)。使用离体电生理学,我们评估了IC第5层中KOR信号传导的功能影响。我们发现强啡肽的洗澡应用减少了IC-SN神经元上的GABA释放并增加了谷氨酸盐的释放,但并未改变它们的兴奋性。相反,强啡肽在不改变突触传递的情况下降低了GABA神经元的兴奋性。用KOR拮抗剂nor-BNI进行的预处理可阻断强啡肽对IC-SN神经元和GABA神经元的作用,表明突触传递和兴奋性的变化是通过KOR选择性介导的。使用KOR衍生的DREADD对IC GABA神经元的选择性抑制概括了这些作用。这项工作提供了对IC微电路的深入了解,并表明Dyn / KOR信号传导可能直接降低了第5层GABA神经元的活性。反过来,KOR驱动的GABA抑制作用会促进IC-SN神经元的去抑制作用,从而可以调节下游回路。
更新日期:2019-12-21
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