Inui A, Okita M, Nakajima M, Momose K, Ueno N, Teranishi A, Miura M, Hirosue Y, Sano K, Sato M, Watanabe M, Sakai T, Watanabe T, Ishida K, Silver J, Baba S, Kasuga M
Second Department of Internal Medicine, Kobe University School of Medicine, Japan.
Proc Assoc Am Physicians. 1998 May-Jun;110(3):171-82.
Neuropeptide Y (NPY), one of the most abundant peptide transmitters in the mammalian brain, is assumed to play an important role in behavior and its disorders. To understand the long-term modulation of neuronal functions by NPY, we raised transgenic mice created with a novel central nervous system (CNS) neuron-specific expression vector of human Thy- gene fragment linked to mouse NPY cDNA. In situ hybridization analysis demonstrated transgene-derived NPY expression in neurons (e.g., in the hippocampus, cerebral cortex, and the arcuate nucleus of the hypothalamus) in the transgenic mice. The modest increase of NPY protein in the brain was demonstrated by semiquantitative immunohistochemical analysis and by radioreceptor assay (115% in transgenic mice compared to control littermates). Double-staining experiments indicated colocalization of the transgene-derived NPY message and NPY protein in the same neurons, such as in the arcuate nucleus. The transgenic mice displayed behavioral signs of anxiety and hypertrophy of adrenal zona fasciculata cells, but no change in food intake was observed. The anxiety-like behavior of transgenic mice was reversed, at least in part, by administration of corticotropin-releasing factor (CRF) antagonists, alpha-helical CRF9-41, into the third cerebral ventricle. These results suggest that NPY has a role in anxiety and behavioral responses to stress partly via the CRF neuronal system. This genetic model may provide a unique opportunity to study human anxiety and emotional disorders.
神经肽Y（NPY）是哺乳动物大脑中含量最为丰富的肽类递质之一，被认为在行为及其紊乱中发挥重要作用。为了解NPY对神经元功能的长期调节作用，我们培育了转基因小鼠，其构建方法是将人类Thy基因片段与小鼠NPY cDNA连接，构建一种新型的中枢神经系统（CNS）神经元特异性表达载体。原位杂交分析显示，转基因小鼠的神经元（如海马体、大脑皮层和下丘脑弓状核中的神经元）中有转基因衍生的NPY表达。通过半定量免疫组织化学分析和放射受体测定法证实，大脑中NPY蛋白有适度增加（与对照同窝小鼠相比，转基因小鼠中增加了115%）。双重染色实验表明，转基因衍生的NPY信息和NPY蛋白在同一神经元中共定位，如下丘脑弓状核中的神经元。转基因小鼠表现出焦虑行为迹象以及肾上腺束状带细胞肥大，但未观察到食物摄入量有变化。向第三脑室注射促肾上腺皮质激素释放因子（CRF）拮抗剂α-螺旋CRF9-41后，转基因小鼠的焦虑样行为至少部分得到逆转。这些结果表明，NPY至少部分通过CRF神经元系统在焦虑和对应激的行为反应中发挥作用。这种遗传模型可能为研究人类焦虑和情绪障碍提供独特的机会。
