Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada T6G 2H7.
Department of Physiology and Biophysics, and.
J Neurosci. 2018 May 9;38(19):4505-4520. doi: 10.1523/JNEUROSCI.3528-17.2018. Epub 2018 Apr 12.
Neuropeptide Y (NPY) expression is tightly linked with the development of stress resilience in rodents and humans. Local NPY injections targeting the basolateral amygdala (BLA) produce long-term behavioral stress resilience in male rats via an unknown mechanism. Previously, we showed that activation of NPY Y receptors hyperpolarizes BLA principal neurons (PNs) through inhibition of the hyperpolarization-activated, depolarizing H-current, The present studies tested whether NPY treatment induces stress resilience by modulating NPY (10 pmol) was delivered daily for 5 d bilaterally into the BLA to induce resilience; thereafter, the electrophysiological properties of PNs and the expression of in the BLA were characterized. As reported previously, increases in social interaction (SI) times persisted weeks after completion of NPY administration. intracellular recordings showed that repeated intra-BLA NPY injections resulted in hyperpolarization of BLA PNs at 2 weeks (2W) and 4 weeks (4W) after NPY treatment. At 2W, spontaneous IPSC frequencies were increased, whereas at 4W, resting was markedly reduced and accompanied by decreased levels of HCN1 mRNA and protein expression in BLA. Knock-down of HCN1 channels in the BLA with targeted delivery of lentivirus containing HCN1-shRNA increased SI beginning 2W after injection and induced stress resilience. NPY treatment induced sequential, complementary changes in the inputs to BLA PNs and their postsynaptic properties that reduce excitability, a mechanism that contributes to less anxious behavior. Furthermore, HCN1 knock-down mimicked the increases in SI and stress resilience observed with NPY, indicating the importance of in stress-related behavior. Resilience improves mental health outcomes in response to adverse situations. Neuropeptide Y (NPY) is associated with decreased stress responses and the expression of resilience in rodents and humans. Single or repeated injections of NPY into the basolateral amygdala (BLA) buffer negative behavioral effects of stress and induce resilience in rats, respectively. Here, we demonstrate that repeated administration of NPY into the BLA unfolds several cellular mechanisms that decrease the activity of pyramidal output neurons. One key mechanism is a reduction in levels of the excitatory ion channel HCN1. Moreover, shRNA knock-down of HCN1 expression in BLA recapitulates some of the actions of NPY and causes potent resilience to stress, indicating that this channel may be a possible target for therapy.
神经肽 Y（NPY）的表达与啮齿动物和人类应激适应能力的发展密切相关。局部注射 NPY 到基底外侧杏仁核（BLA）会通过未知的机制在雄性大鼠中产生长期的行为应激适应能力。以前，我们已经证明，通过抑制超极化激活的去极化 H 电流，NPY Y 受体的激活使 BLA 主神经元（PNs）超极化。本研究测试了 NPY 治疗是否通过调节 BLA 中的 HCN1 表达来诱导应激适应能力。每天双侧向 BLA 内注射 10 pmol 的 NPY 5 天以诱导适应能力；此后，表征 PNs 的电生理特性和 BLA 中的 表达。正如之前报道的，社交互动（SI）时间的增加在 NPY 给药完成后持续数周。细胞内记录显示，重复的 BLA 内 NPY 注射导致 NPY 处理后 2 周（2W）和 4 周（4W）BLA PNs 超极化。在 2W 时，自发 IPSC 频率增加，而在 4W 时，静息 明显降低，同时 BLA 中的 HCN1 mRNA 和蛋白表达水平降低。用含有 HCN1-shRNA 的慢病毒靶向递送至 BLA 中的 HCN1 通道敲低增加了注射后 2W 开始的 SI，并诱导了应激适应能力。NPY 处理诱导了 BLA PNs 输入和它们的突触后特性的顺序、互补变化，降低了兴奋性，这是一种导致焦虑行为减少的机制。此外，HCN1 敲低模拟了 NPY 观察到的 SI 增加和应激适应能力，表明 在应激相关行为中的重要性。适应能力提高了对不利情况的心理健康结果。神经肽 Y（NPY）与啮齿动物和人类的应激反应降低和适应能力的表达有关。单次或重复注射 NPY 到基底外侧杏仁核（BLA）分别缓冲应激的负面行为影响并诱导大鼠适应能力。在这里，我们证明了 BLA 中重复给予 NPY 会产生几种降低锥体神经元活性的细胞机制。一个关键机制是兴奋性离子通道 HCN1 水平降低。此外，BLA 中 HCN1 表达的 shRNA 敲低重现了 NPY 的一些作用，并导致对压力的强烈适应能力，表明该通道可能是治疗的一个可能靶点。
