Department of Physiology and Pharmacology, Hotchkiss Brain Institute, The University of Calgary, 3330 Hospital Dr. NW, Calgary, Alberta T2N 4N1, Canada.
Department of Physiology and Pharmacology, Hotchkiss Brain Institute, The University of Calgary, 3330 Hospital Dr. NW, Calgary, Alberta T2N 4N1, Canada.
Cell Rep. 2021 Aug 17;36(7):109563. doi: 10.1016/j.celrep.2021.109563.
Overconsumption of highly palatable, energy-dense food is considered a key driver of the obesity pandemic. The orbitofrontal cortex (OFC) is critical for reward valuation of gustatory signals, yet how the OFC adapts to obesogenic diets is poorly understood. Here, we show that extended access to a cafeteria diet impairs astrocyte glutamate clearance, which leads to a heterosynaptic depression of GABA transmission onto pyramidal neurons of the OFC. This decrease in GABA tone is due to an increase in extrasynaptic glutamate, which acts via metabotropic glutamate receptors to liberate endocannabinoids. This impairs the induction of endocannabinoid-mediated long-term plasticity. The nutritional supplement, N-acetylcysteine rescues this cascade of synaptic impairments by restoring astrocytic glutamate transport. Together, our findings indicate that obesity targets astrocytes to disrupt the delicate balance between excitatory and inhibitory transmission in the OFC.
过度摄入美味、高热量的食物被认为是肥胖流行的一个关键驱动因素。眶额皮层（OFC）对于味觉信号的奖赏估值至关重要，但眶额皮层如何适应致肥胖饮食还知之甚少。在这里，我们表明，长期摄入 cafeteria 饮食会损害星形胶质细胞对谷氨酸的清除能力，从而导致 GABA 传递到 OFC 锥体神经元的异突触抑制。这种 GABA 张力的下降是由于突触外谷氨酸的增加，通过代谢型谷氨酸受体释放内源性大麻素。这会损害内源性大麻素介导的长时程可塑性的诱导。营养补充剂 N-乙酰半胱氨酸通过恢复星形胶质细胞谷氨酸转运来挽救这种突触损伤级联反应。总之，我们的研究结果表明，肥胖以星形胶质细胞为靶点，破坏了 OFC 中兴奋性和抑制性传递之间的微妙平衡。
