INSERM, U1215 NeuroCentre Magendie, Endocannabinoids and Neuroadaptation, Bordeaux, France; University of Bordeaux, Bordeaux, France; Department of Neurosciences, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Leioa, Spain; Achucarro Basque Center for Neuroscience, Leioa, Spain; IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.
INSERM, U1215 NeuroCentre Magendie, Endocannabinoids and Neuroadaptation, Bordeaux, France; University of Bordeaux, Bordeaux, France.
Neuron. 2021 May 5;109(9):1513-1526.e11. doi: 10.1016/j.neuron.2021.03.007. Epub 2021 Mar 25.
Recent advances in neuroscience have positioned brain circuits as key units in controlling behavior, implying that their positive or negative modulation necessarily leads to specific behavioral outcomes. However, emerging evidence suggests that the activation or inhibition of specific brain circuits can actually produce multimodal behavioral outcomes. This study shows that activation of a receptor at different subcellular locations in the same neuronal circuit can determine distinct behaviors. Pharmacological activation of type 1 cannabinoid (CB) receptors in the striatonigral circuit elicits both antinociception and catalepsy in mice. The decrease in nociception depends on the activation of plasma membrane-residing CB receptors (pmCB), leading to the inhibition of cytosolic PKA activity and substance P release. By contrast, mitochondrial-associated CB receptors (mtCB) located at the same terminals mediate cannabinoid-induced catalepsy through the decrease in intra-mitochondrial PKA-dependent cellular respiration and synaptic transmission. Thus, subcellular-specific CB receptor signaling within striatonigral circuits determines multimodal control of behavior.
神经科学的最新进展将大脑回路定位为控制行为的关键单元，这意味着它们的正或负调节必然会导致特定的行为结果。然而，新出现的证据表明，特定大脑回路的激活或抑制实际上可能产生多模态的行为结果。本研究表明，同一神经元回路中不同亚细胞位置的受体的激活可以决定不同的行为。在纹状体黑质回路中激活 1 型大麻素 (CB) 受体可在小鼠中引起镇痛和僵直。疼痛减轻取决于质膜驻留 CB 受体 (pmCB) 的激活，导致细胞质 PKA 活性和 P 物质释放的抑制。相比之下，位于相同末端的线粒体相关 CB 受体 (mtCB) 通过减少线粒体 PKA 依赖性细胞呼吸和突触传递来介导大麻素诱导的僵直。因此，纹状体黑质回路中的亚细胞特异性 CB 受体信号决定了行为的多模态控制。
