Insulin Bidirectionally Alters NAc Glutamatergic Transmission: Interactions between Insulin Receptor Activation, Endogenous Opioids, and Glutamate Release.
Insulin Bidirectionally Alters NAc Glutamatergic Transmission: Interactions between Insulin Receptor Activation, Endogenous Opioids, and Glutamate Release.
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胰岛素双向改变NAC谷氨酸能传播：胰岛素受体激活，内源性阿片类药物和谷氨酸释放之间的相互作用。
DOI：
10.1523/jneurosci.3216-18.2021
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发表时间：
2021-03-17
期刊：
影响因子：
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通讯作者：
Ferrario CR
中科院分区：
文献类型：
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作者：
Fetterly TL;Oginsky MF;Nieto AM;Alonso-Caraballo Y;Santana-Rodriguez Z;Ferrario CR
人类功能性磁共振成像研究表明，胰岛素影响大脑中调节奖励和动机的区域的活动，包括丘脑核（NAc）。胰岛素受体由NAc中等多刺神经元（MSN）表达，培养的皮质和海马神经元的研究表明，胰岛素通过突触前和突触后机制影响兴奋性传递。然而，没有什么是已知的胰岛素如何影响兴奋性传输的NAc。人类功能性磁共振成像研究表明，胰岛素影响大脑中调节奖励和动机的区域的活动，包括丘脑核（NAc）。胰岛素受体由NAc中等多刺神经元（MSN）表达，培养的皮质和海马神经元的研究表明，胰岛素通过突触前和突触后机制影响兴奋性传递。然而，没有什么是已知的胰岛素如何影响兴奋性传输的NAc。此外，肥胖伴随的胰岛素调节障碍与依赖NAc兴奋性传递的认知能力下降、抑郁、焦虑和动机改变有关。利用全细胞膜片钳和生物化学方法，我们确定了胰岛素如何影响非肥胖和肥胖雄性大鼠的NAc神经递质传递及其潜在机制。我们发现，胰岛素对兴奋性传递有浓度依赖性的双向作用，胰岛素受体激活增加，IGF受体激活减少NAc兴奋性传递。兴奋性传递的增加是通过激活位于MSN上的突触后胰岛素受体介导的。然而，这种效应是由于突触前谷氨酸释放的增加。这表明从MSN到突触前末梢的反馈。在另外的实验中，我们发现胰岛素诱导的突触前谷氨酸释放增加是由阿片受体依赖性去抑制介导的。此外，肥胖导致胰岛素受体介导的兴奋性传递增加的损失和NAc胰岛素受体表面表达的减少，同时保持IGF受体介导的传递减少。这些结果提供了第一次深入了解胰岛素如何影响成人大脑中的兴奋性传递，以及以前未识别的阿片受体依赖性NAc神经元能传递去抑制形式的证据。重要性声明这里的数据提供了关于胰岛素如何影响成人大脑兴奋性传递的第一个见解，并确定了胰岛素受体激活，阿片类药物和多巴胺能传递之间先前未知的相互作用。这些数据有助于我们从根本上了解胰岛素对大脑动机系统的影响，并对胰岛素作为认知增强剂的使用以及靶向胰岛素受体和IGF受体以改变动机产生影响。
Human fMRI studies show that insulin influences brain activity in regions that mediate reward and motivation, including the nucleus accumbens (NAc). Insulin receptors are expressed by NAc medium spiny neurons (MSNs), and studies of cultured cortical and hippocampal neurons suggest that insulin influences excitatory transmission via presynaptic and postsynaptic mechanisms. However, nothing is known about how insulin influences excitatory transmission in the NAc. Human fMRI studies show that insulin influences brain activity in regions that mediate reward and motivation, including the nucleus accumbens (NAc). Insulin receptors are expressed by NAc medium spiny neurons (MSNs), and studies of cultured cortical and hippocampal neurons suggest that insulin influences excitatory transmission via presynaptic and postsynaptic mechanisms. However, nothing is known about how insulin influences excitatory transmission in the NAc. Furthermore, insulin dysregulation accompanying obesity is linked to cognitive decline, depression, anxiety, and altered motivation that rely on NAc excitatory transmission. Using whole-cell patch-clamp and biochemical approaches, we determined how insulin affects NAc glutamatergic transmission in nonobese and obese male rats and the underlying mechanisms. We find that there are concentration-dependent, bidirectional effects of insulin on excitatory transmission, with insulin receptor activation increasing and IGF receptor activation decreasing NAc excitatory transmission. Increases in excitatory transmission were mediated by activation of postsynaptic insulin receptors located on MSNs. However, this effect was due to an increase in presynaptic glutamate release. This suggested feedback from MSNs to presynaptic terminals. In additional experiments, we found that insulin-induced increases in presynaptic glutamate release are mediated by opioid receptor-dependent disinhibition. Furthermore, obesity resulted in a loss of insulin receptor-mediated increases in excitatory transmission and a reduction in NAc insulin receptor surface expression, while preserving reductions in transmission mediated by IGF receptors. These results provide the first insights into how insulin influences excitatory transmission in the adult brain, and evidence for a previously unidentified form of opioid receptor-dependent disinhibition of NAc glutamatergic transmission. SIGNIFICANCE STATEMENT Data here provide the first insights into how insulin influences excitatory transmission in the adult brain, and identify previously unknown interactions between insulin receptor activation, opioids, and glutamatergic transmission. These data contribute to our fundamental understanding of insulin's influence on brain motivational systems and have implications for the use of insulin as a cognitive enhancer and for targeting of insulin receptors and IGF receptors to alter motivation.