Reeves Jacob M, Arias-Hervert Erwin, Kmiec Gracianne E, Birdsong William T
Neuroscience Graduate Program, University of Michigan, Ann Arbor, Michigan 48109.
Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109.
eNeuro. 2025 Aug 18;12(8). doi: 10.1523/ENEURO.0219-25.2025. Print 2025 Aug.
The anterior cingulate cortex (ACC) plays a pivotal role in processing pain and emotion, communicating with both cortical and subcortical regions involved in these functions. The claustrum (CLA), a subcortical region with extensive connectivity to the ACC, also plays a critical role in pain perception and consciousness. Both ACC and CLA express Kappa (KOR), Mu (MOR), and Delta (DOR) opioid receptors, yet whether and how opioid receptors modulate this circuit are poorly understood. This study investigates the effects of opioid receptor activation on glutamatergic signaling in CLA→ACC circuitry using spatial transcriptomics, brain slice electrophysiology, optogenetics, and pharmacological approaches in mice of both sexes. Our results demonstrated that excitatory synaptic transmission generated by the CLA onto Layer 5 pyramidal (L5 PYR) cells in the ACC are reduced by KOR, MOR, and DOR agonists. However, only KOR agonists reduce monosynaptic transmission from the CLA onto L5 ACC PYR cells, highlighting the unique role of KOR in modulating the CLA→ACC pathway. MOR and DOR agonists only reduced slower, longer-latency recurrent excitatory responses. These findings provide new insights into how opioid receptors regulate the claustrocingulate circuit and demonstrate the distinct, receptor-specific modulation of synaptic transmission within this network.
前扣带回皮质（ACC）在处理疼痛和情绪方面起着关键作用，与参与这些功能的皮质和皮质下区域进行通信。屏状核（CLA）是一个与ACC有广泛连接的皮质下区域，在疼痛感知和意识方面也起着关键作用。ACC和CLA都表达κ（KOR）、μ（MOR）和δ（DOR）阿片受体，但阿片受体是否以及如何调节这个神经回路却知之甚少。本研究使用空间转录组学、脑片电生理学、光遗传学和药理学方法，研究阿片受体激活对CLA→ACC神经回路中谷氨酸能信号传导的影响，实验对象为雌雄小鼠。我们的结果表明，CLA对ACC中第5层锥体（L5 PYR）细胞产生的兴奋性突触传递会被KOR、MOR和DOR激动剂所减少。然而，只有KOR激动剂会减少从CLA到L5 ACC PYR细胞的单突触传递，这突出了KOR在调节CLA→ACC通路中的独特作用。MOR和DOR激动剂只会减少较慢、潜伏期较长的反复兴奋性反应。这些发现为阿片受体如何调节屏状核 - 扣带回神经回路提供了新的见解，并证明了该网络内突触传递的独特的、受体特异性调节。
