Maniscalco James W, Zheng Huiyuan, Gordon Patrick J, Rinaman Linda
Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania 15260.
Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania 15260
J Neurosci. 2015 Jul 29;35(30):10701-14. doi: 10.1523/JNEUROSCI.3464-14.2015.
Previous reports indicate that caloric restriction attenuates anxiety and other behavioral responses to acute stress, and blunts the ability of stress to increase anterior pituitary release of adrenocorticotropic hormone. Since hindbrain glucagon-like peptide-1 (GLP-1) neurons and noradrenergic prolactin-releasing peptide (PrRP) neurons participate in behavioral and endocrine stress responses, and are sensitive to the metabolic state, we examined whether overnight food deprivation blunts stress-induced recruitment of these neurons and their downstream hypothalamic and limbic forebrain targets. A single overnight fast reduced anxiety-like behavior assessed in the elevated-plus maze and acoustic startle test, including marked attenuation of light-enhanced startle. Acute stress [i.e., 30 min restraint (RES) or 5 min elevated platform exposure] robustly activated c-Fos in GLP-1 and PrRP neurons in fed rats, but not in fasted rats. Fasting also significantly blunted the ability of acute stress to activate c-Fos expression within the anterior ventrolateral bed nucleus of the stria terminalis (vlBST). Acute RES stress suppressed dark-onset food intake in rats that were fed ad libitum, whereas central infusion of a GLP-1 receptor antagonist blocked RES-induced hypophagia, and reduced the ability of RES to activate PrRP and anterior vlBST neurons in ad libitum-fed rats. Thus, an overnight fast "silences" GLP-1 and PrRP neurons, and reduces both anxiety-like and hypophagic responses to acute stress. The partial mimicking of these fasting-induced effects in ad libitum-fed rats after GLP-1 receptor antagonism suggests a potential mechanism by which short-term negative energy balance attenuates neuroendocrine and behavioral responses to acute stress.
The results from this study reveal a potential central mechanism for the "metabolic tuning" of stress responsiveness. A single overnight fast, which markedly reduces anxiety-like behavior in rats, reduces or blocks the ability of acute stress to activate hindbrain neurons that are immunoreactive for either prolactin-releasing peptide or glucagon-like peptide 1, and attenuates the activation of their stress-sensitive projection targets in the limbic forebrain. In nonfasted rats, central antagonism of glucagon-like peptide 1 receptors partially mimics the effect of an overnight fast by blocking the ability of acute stress to inhibit food intake, and by attenuating stress-induced activation of hindbrain and limbic forebrain neurons. We propose that caloric restriction attenuates behavioral and physiological responses to acute stress by "silencing" central glucagon-like peptide 1 signaling pathways.
先前的报告表明，热量限制可减轻焦虑及对急性应激的其他行为反应，并削弱应激增加垂体前叶促肾上腺皮质激素释放的能力。由于后脑胰高血糖素样肽-1（GLP-1）神经元和去甲肾上腺素能催乳素释放肽（PrRP）神经元参与行为和内分泌应激反应，且对代谢状态敏感，我们研究了过夜禁食是否会减弱应激诱导的这些神经元及其下游下丘脑和边缘前脑靶点的募集。单次过夜禁食可减轻在高架十字迷宫和听觉惊吓试验中评估的焦虑样行为，包括显著减弱光增强惊吓反应。急性应激[即30分钟束缚（RES）或5分钟高架平台暴露]可强烈激活喂食大鼠中GLP-1和PrRP神经元中的c-Fos，但在禁食大鼠中则不然。禁食还显著减弱了急性应激激活终纹床核腹外侧前部（vlBST）内c-Fos表达的能力。急性RES应激抑制了随意进食大鼠的暗期食物摄入，而中枢注射GLP-1受体拮抗剂可阻断RES诱导的摄食减少，并降低RES激活随意进食大鼠中PrRP和vlBST前部神经元的能力。因此，过夜禁食“沉默”了GLP-1和PrRP神经元，并减少了对急性应激的焦虑样和摄食减少反应。在GLP-1受体拮抗后，在随意进食大鼠中部分模拟这些禁食诱导的效应，提示了一种潜在机制，通过该机制短期负能量平衡可减弱对急性应激的神经内分泌和行为反应。
本研究结果揭示了应激反应性“代谢调节”的潜在中枢机制。单次过夜禁食可显著减轻大鼠的焦虑样行为，降低或阻断急性应激激活对催乳素释放肽或胰高血糖素样肽1免疫反应阳性的后脑神经元的能力，并减弱其在边缘前脑的应激敏感投射靶点的激活。在非禁食大鼠中，胰高血糖素样肽1受体的中枢拮抗作用通过阻断急性应激抑制食物摄入的能力以及减弱应激诱导的后脑和边缘前脑神经元激活，部分模拟了过夜禁食的效果。我们提出，热量限制通过“沉默”中枢胰高血糖素样肽1信号通路来减弱对急性应激的行为和生理反应。
