Department of Pharmacology, and the Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta T6G 2H7, Canada, and.
Center for the Neurobiology of Stress Resilience and Psychiatric Disorders, Discipline of Physiology and Biophysics, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois 60064.
J Neurosci. 2020 Apr 15;40(16):3231-3249. doi: 10.1523/JNEUROSCI.2621-19.2020. Epub 2020 Mar 6.
Endogenous neuropeptide Y (NPY) and corticotrophin-releasing factor (CRF) modulate the responses of the basolateral amygdala (BLA) to stress and are associated with the development of stress resilience and vulnerability, respectively. We characterized persistent effects of repeated NPY and CRF treatment on the structure and function of BLA principal neurons in a novel organotypic slice culture (OTC) model of male rat BLA, and examined the contributions of specific NPY receptor subtypes to these neural and behavioral effects. In BLA principal neurons within the OTCs, repeated NPY treatment caused persistent attenuation of excitatory input and induced dendritic hypotrophy via Y receptor activation; conversely, CRF increased excitatory input and induced hypertrophy of BLA principal neurons. Repeated treatment of OTCs with NPY followed by an identical treatment with CRF, or vice versa, inhibited or reversed all structural changes in OTCs. These structural responses to NPY or CRF required calcineurin or CaMKII, respectively. Finally, repeated intra-BLA injections of NPY or a Y receptor agonist increased social interaction, a validated behavior for anxiety, and recapitulated structural changes in BLA neurons seen in OTCs, while a Y receptor antagonist prevented NPY's effects both on behavior and on structure. These results implicate the Y receptor in the long-term, anxiolytic-like effects of NPY in the BLA, consistent with an intrinsic role in stress buffering, and highlight a remarkable mechanism by which BLA neurons may adapt to different levels of stress. Moreover, BLA OTCs offer a robust model to study mechanisms associated with resilience and vulnerability to stress in BLA. Within the basolateral amygdala (BLA), neuropeptide Y (NPY) is associated with buffering the neural stress response induced by corticotropin releasing factor, and promoting stress resilience. We used a novel organotypic slice culture model of BLA, complemented with studies, to examine the cellular mechanisms associated with the actions of NPY. In organotypic slice cultures, repeated NPY treatment reduces the complexity of the dendritic extent of anxiogenic BLA principal neurons, making them less excitable. NPY, via activation of Y5 receptors, additionally inhibits and reverses the increases in dendritic extent and excitability induced by the stress hormone, corticotropin releasing factor. This NPY-mediated neuroplasticity indicates that resilience or vulnerability to stress may thus involve neuropeptide-mediated dendritic remodeling in BLA principal neurons.
内源性神经肽 Y（NPY）和促肾上腺皮质释放因子（CRF）调节外侧杏仁核（BLA）对压力的反应，分别与压力的适应能力和脆弱性的发展有关。我们在雄性大鼠 BLA 的新型器官型切片培养（OTC）模型中，描述了重复 NPY 和 CRF 处理对 BLA 主神经元结构和功能的持久影响，并研究了特定 NPY 受体亚型对这些神经和行为影响的贡献。在 OTC 中的 BLA 主神经元中，重复的 NPY 处理通过 Y 受体激活导致兴奋性输入持续减弱，并诱导树突萎缩；相反，CRF 增加了 BLA 主神经元的兴奋性输入并诱导了其肥大。用 NPY 重复处理 OTC 后再用 CRF 进行相同处理，或反之亦然，可抑制或逆转 OTC 中的所有结构变化。这些对 NPY 或 CRF 的结构反应分别需要钙调神经磷酸酶或 CaMKII。最后，重复的 BLA 内注射 NPY 或 Y 受体激动剂增加了社交互动，这是一种焦虑的验证行为，并重现了 OTC 中观察到的 BLA 神经元的结构变化，而 Y 受体拮抗剂则阻止了 NPY 对行为和结构的影响。这些结果表明 Y 受体在 NPY 在 BLA 中的长期、抗焦虑样作用中起作用，这与内在的应激缓冲作用一致，并突出了 BLA 神经元可能适应不同应激水平的显著机制。此外，BLA OTC 为研究 BLA 中应激适应能力和脆弱性相关的机制提供了一个强大的模型。在内侧杏仁核（BLA）中，神经肽 Y（NPY）与缓冲促肾上腺皮质释放因子诱导的神经应激反应以及促进应激适应能力有关。我们使用了一种新型的 BLA 器官型切片培养模型，并辅以研究，以研究与 NPY 作用相关的细胞机制。在器官型切片培养中，重复的 NPY 处理会降低焦虑 BLA 主神经元树突复杂性，使它们兴奋性降低。NPY 通过激活 Y5 受体，还可以抑制和逆转应激激素促肾上腺皮质释放因子诱导的树突范围和兴奋性的增加。这种 NPY 介导的神经可塑性表明，应激的适应能力或脆弱性可能涉及 BLA 主神经元中的神经肽介导的树突重塑。
