Caccavano Adam P, Vlachos Anna, McLean Nadiya, Kimmel Sarah, Kim June Hoan, Vargish Geoffrey, Mahadevan Vivek, Hewitt Lauren, Rossi Anthony M, Spineux Ilona, Wu Sherry Jingjing, Furlanis Elisabetta, Dai Min, Leyva Garcia Brenda, Wang Yating, Chittajallu Ramesh, London Edra, Yuan Xiaoqing, Hunt Steven, Abebe Daniel, Eldridge Mark A G, Cummins Alex C, Hines Brendan E, Plotnikova Anya, Mohanty Arya, Averbeck Bruno B, Zaghloul Kareem A, Dimidschstein Jordane, Fishell Gord, Pelkey Kenneth A, McBain Chris J
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Section on Cellular and Synaptic Physiology, National Institutes of Health (NIH), Bethesda, MD 20892, USA.
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Section on Cellular and Synaptic Physiology, National Institutes of Health (NIH), Bethesda, MD 20892, USA.
Neuron. 2025 Jun 4;113(11):1805-1822.e7. doi: 10.1016/j.neuron.2025.03.005. Epub 2025 Mar 26.
Within adult rodent hippocampus (HPC), opioids suppress inhibitory parvalbumin-expressing interneurons (PV-INs), disinhibiting local microcircuits. However, it is unknown whether this disinhibitory motif is conserved across cortical regions, species, or development. We observed that PV-IN-mediated inhibition is robustly suppressed by opioids in HPC proper but not primary neocortex in mice and non-human primates, with spontaneous inhibitory tone in resected human tissue also following a consistent dichotomy. This hippocampal disinhibitory motif is established in early development when PV-INs and opioids regulate early population activity. Morphine pretreatment partially occludes this acute opioid-mediated suppression, with implications for the effects of opioids on hippocampal network activity important for learning and memory. Our findings demonstrate that PV-INs exhibit divergent opioid sensitivity across brain regions, which is remarkably conserved over evolution, and highlight the underappreciated role of opioids acting through immature PV-INs in shaping hippocampal development.
在成年啮齿动物的海马体（HPC）中，阿片类物质会抑制表达小白蛋白的抑制性中间神经元（PV-INs），从而解除对局部微回路的抑制。然而，这种去抑制模式在不同皮质区域、物种或发育阶段是否保守尚不清楚。我们观察到，在小鼠和非人灵长类动物中，阿片类物质能强烈抑制HPC本身的PV-IN介导的抑制作用，但对初级新皮质则无此作用，切除的人体组织中的自发抑制性活动也呈现出一致的二分法。这种海马体去抑制模式在早期发育过程中就已确立，此时PV-INs和阿片类物质调节早期群体活动。吗啡预处理部分阻断了这种急性阿片类物质介导的抑制作用，这对阿片类物质对海马体网络活动的影响具有重要意义，而海马体网络活动对学习和记忆至关重要。我们的研究结果表明，PV-INs在不同脑区表现出不同的阿片类物质敏感性，这种敏感性在进化过程中显著保守，并突出了通过未成熟的PV-INs起作用的阿片类物质在塑造海马体发育中未被充分认识的作用。
