DataSheet_3_Lateral parabrachial nucleus astrocytes control food intake.pdf

Food intake behavior is under the tight control of the central nervous system. Most studies to date focus on the contribution of neurons to this behavior. However, although previously overlooked, astrocytes have recently been implicated to play a key role in feeding control. Most of the recent literature has focused on astrocytic contribution in the hypothalamus or the dorsal vagal complex. The contribution of astrocytes located in the lateral parabrachial nucleus (lPBN) to feeding behavior control remains poorly understood. Thus, here, we first investigated whether activation of lPBN astrocytes affects feeding behavior in male and female rats using chemogenetic activation. Astrocytic activation in the lPBN led to profound anorexia in both sexes, under both ad-libitum feeding schedule and after a fasting challenge. Astrocytes have a key contribution to glutamate homeostasis and can themselves release glutamate. Moreover, lPBN glutamate signaling is a key contributor to potent anorexia, which can be induced by lPBN activation. Thus, here, we determined whether glutamate signaling is necessary for lPBN astrocyte activation-induced anorexia, and found that pharmacological N-methyl D-aspartate (NMDA) receptor blockade attenuated the food intake reduction resulting from lPBN astrocyte activation. Since astrocytes have been shown to contribute to feeding control by modulating the feeding effect of peripheral feeding signals, we further investigated whether lPBN astrocyte activation is capable of modulating the anorexic effect of the gut/brain hormone, glucagon like peptide -1, as well as the orexigenic effect of the stomach hormone - ghrelin, and found that the feeding effect of both signals is modulated by lPBN astrocytic activation. Lastly, we found that lPBN astrocyte activation-induced anorexia is affected by a diet-induced obesity challenge, in a sex-divergent manner. Collectively, current findings uncover a novel role for lPBN astrocytes in feeding behavior control.

进食行为受中枢神经系统的精密调控。迄今为止，多数相关研究均聚焦于神经元对该行为的调控作用。然而，尽管星形胶质细胞（astrocytes）此前长期被忽视，近来却被证实可在进食调控中发挥关键作用。现有近期研究多关注星形胶质细胞在下丘脑或迷走背核（dorsal vagal complex）中的调控功能，而位于外侧臂旁核（lateral parabrachial nucleus, lPBN）的星形胶质细胞对进食行为的调控作用，目前仍鲜为人知。为此，本研究首先利用化学遗传学激活手段，探究了外侧臂旁核星形胶质细胞的激活对雌雄大鼠进食行为的影响。研究发现，无论处于自由进食（ad-libitum）状态还是禁食应激后，激活外侧臂旁核的星形胶质细胞均可导致雌雄大鼠出现显著的厌食反应。星形胶质细胞对谷氨酸稳态具有关键调控作用，且可自主释放谷氨酸。此外，外侧臂旁核的谷氨酸信号通路是强效厌食反应的关键介导因子，该通路可通过激活外侧臂旁核而被诱导激活。为此，本研究进一步明确了谷氨酸信号通路是否是外侧臂旁核星形胶质细胞激活诱发厌食反应的必要条件，并发现通过药理学手段阻断N-甲基-D-天冬氨酸（N-methyl D-aspartate, NMDA）受体，可减弱外侧臂旁核星形胶质细胞激活所导致的进食量减少。鉴于已有研究证实星形胶质细胞可通过调控外周进食信号的进食效应参与进食调控，本研究进一步探究了外侧臂旁核星形胶质细胞的激活是否能够调控肠脑激素胰高血糖素样肽-1（glucagon like peptide-1, GLP-1）的厌食效应，以及胃激素饥饿素（ghrelin）的促食欲效应，结果发现这两种信号分子的进食调控效应均受外侧臂旁核星形胶质细胞激活的调控。最后，本研究发现，饮食诱导肥胖应激可影响外侧臂旁核星形胶质细胞激活诱发的厌食反应，且该影响存在性别差异。综上，本研究的发现揭示了外侧臂旁核星形胶质细胞在进食行为调控中的全新作用。