University of Alabama at Birmingham, Department of Neurobiology, 1825 University Blvd, SHEL 971, Birmingham, AL 35294, United States of America; University of Alabama at Birmingham, Department of Biology, 1670 University Blvd., VH G133B, Birmingham, AL 35233, United States of America.
University of Alabama at Birmingham, Department of Neurobiology, 1825 University Blvd, SHEL 971, Birmingham, AL 35294, United States of America.
Neuropeptides. 2020 Feb;79:101979. doi: 10.1016/j.npep.2019.101979. Epub 2019 Nov 7.
Neuropeptide Y (NPY) is an endogenous neuropeptide that is abundantly expressed in the central nervous system. NPY is involved in various neurological processes and neuropsychiatric disorders, including fear learning and anxiety disorders. Reduced levels of NPY are reported in Post-Traumatic Stress Disorder (PTSD) patients, and NPY has been proposed as a potential therapeutic target for PTSD. It is therefore important to understand the effects of chronic enhancement of NPY on anxiety and fear learning. Previous studies have shown that acute elevation of NPY reduces anxiety, fear learning and locomotor activity. Models of chronic NPY overexpression have produced mixed results, possibly caused by ectopic NPY expression. NPY is expressed primarily by a subset of GABAergic interneurons, providing specific spatiotemporal release patterns. Administration of exogenous NPY throughout the brain, or overexpression in cells that do not normally release NPY, can have detrimental side effects, including memory impairment. In order to determine the effects of boosting NPY only in the cells that normally release it, we utilized a transgenic mouse line that overexpresses NPY only in NPY+ cells. We tested for effects on anxiety related behaviors in adolescent mice, an age with high incidence of anxiety disorders in humans. Surprisingly, we did not observe the expected reduction in anxiety-like behavior in NPY overexpression mice. There was no change in fear learning behavior, although there was a deficit in nest building. The effect of exogenous NPY on synaptic transmission in acute hippocampal slices was also diminished, indicating that the function of NPY receptors is impaired. Reduced NPY receptor function could contribute to the unexpected behavioral outcomes. We conclude that overexpression of NPY, even in cells that normally express it, can lead to reduced responsiveness of NPY receptors, potentially affecting the ability of NPY to function as a long-term therapeutic.
神经肽 Y（NPY）是一种内源性神经肽，在中枢神经系统中大量表达。NPY 参与各种神经过程和神经精神疾病，包括恐惧学习和焦虑症。创伤后应激障碍（PTSD）患者的 NPY 水平降低，NPY 已被提出作为 PTSD 的潜在治疗靶点。因此，了解慢性增强 NPY 对焦虑和恐惧学习的影响非常重要。先前的研究表明，NPY 的急性升高可降低焦虑、恐惧学习和运动活性。慢性 NPY 过表达模型产生了混合结果，这可能是由于异位 NPY 表达引起的。NPY 主要由 GABA 能中间神经元表达，提供特定的时空释放模式。外源性 NPY 在整个大脑中的给药，或在通常不释放 NPY 的细胞中过表达，可能会产生有害的副作用，包括记忆损伤。为了确定仅在正常释放 NPY 的细胞中增强 NPY 的效果，我们利用了一种仅在 NPY+细胞中过表达 NPY 的转基因小鼠系。我们测试了 NPY 过表达对青少年小鼠焦虑相关行为的影响，这一年龄段人类焦虑症的发病率很高。令人惊讶的是，我们没有观察到 NPY 过表达小鼠的预期焦虑样行为减少。恐惧学习行为没有变化，尽管筑巢行为有缺陷。外源性 NPY 对急性海马切片中突触传递的影响也减弱了，表明 NPY 受体的功能受损。NPY 受体功能的降低可能导致了出乎意料的行为结果。我们得出结论，即使在正常表达 NPY 的细胞中过表达 NPY，也会导致 NPY 受体的反应性降低，可能会影响 NPY 作为长期治疗的功能。
