Overexpression of neuropeptide Y decreases responsiveness to neuropeptide Y
Overexpression of neuropeptide Y decreases responsiveness to neuropeptide Y
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DOI：
10.1016/j.npep.2019.101979
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发表时间：
2020-02-01
期刊：
影响因子：
2.9
通讯作者：
Dobrunz, Lynn E.
中科院分区：
文献类型：
--
作者：
Corder, Katelynn M.;Li, Qin;Dobrunz, Lynn E.
神经肽Y（neuropeptide Y，NPY）是一种在中枢神经系统中大量表达的内源性神经肽。NPY参与各种神经过程和神经精神障碍，包括恐惧学习和焦虑障碍。据报道，在创伤后应激障碍（PTSD）患者中，NPY水平降低，并且已经提出NPY作为PTSD的潜在治疗靶点。因此，重要的是要了解慢性增强神经肽Y对焦虑和恐惧学习的影响。先前的研究表明，急性升高的NPY减少焦虑，恐惧学习和运动活动。慢性NPY过表达的模型产生了混合的结果，可能是由异位NPY表达引起的。NPY主要由GABA能中间神经元的子集表达，提供特定的时空释放模式。在整个大脑中施用外源性NPY，或在通常不释放NPY的细胞中过度表达，可能具有有害的副作用，包括记忆障碍。为了确定仅在正常释放NPY的细胞中加强NPY的效果，我们利用了仅在NPY +细胞中过表达NPY的转基因小鼠系。我们测试了对青春期小鼠焦虑相关行为的影响，青春期小鼠是人类焦虑症的高发年龄。令人惊讶的是，我们没有观察到预期的减少焦虑样行为在NPY过表达小鼠。尽管在筑巢方面存在缺陷，但在恐惧学习行为方面没有变化。外源性NPY对急性海马脑片突触传递的影响也减弱，表明NPY受体的功能受损。NPY受体功能降低可能导致意外的行为结果。我们的结论是，即使在正常表达它的细胞中，NPY的过表达也会导致NPY受体的反应性降低，从而可能影响NPY作为长期治疗剂的能力。
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.