Plagemann A, Harder T, Rake A, Janert U, Melchior K, Rohde W, Dörner G
Institute of Experimental Endocrinology, Humboldt University Medical School (Charité), Berlin, Germany.
Int J Dev Neurosci. 1999 Feb;17(1):37-44. doi: 10.1016/s0736-5748(98)00064-1.
In former studies, a temporary, intrahypothalamically localized hyperinsulinism during brain development was shown to result in overweight and metabolic disturbances during later life in rats. Therefore, we tested the hypothesis whether intrahypothalamic insulin treatment during early postnatal life may lead to hypothalamic morphological alterations, i.e., of numerical density of neurons and area of neuronal nuclei or area of neuronal cytoplasm, in this animal model. For this purpose, on the 8th day of age in Wistar rats a long-acting insulin was bilaterally applicated stereotactically into the hypothalamus (12 mIU on each side), while in controls the insulin-free agar-vehicle was given only. By computer-assisted morphometric analysis on the 15th day of life a decrease of the mean area of neuronal nuclei and the mean nucleus-cytoplasm-ratio within the VMN of the insulin-treated animals was observed, as compared to control rats (P < 0.05), while no significant alterations were found in the lateral hypothalamic area (LHA). Analysis of topographically distinct parts of the VMN revealed significant reductions of the mean area of neuronal nuclei (P < 0.001) and nucleus-cytoplasm-ratio (P < 0.05) in the anterior part of the VMN (VMNpa). Furthermore, in the ventrolateral part (VMNpv) a decreased mean neuronal density was observed in the insulin group (P < 0.01). In contrast, the dorsomedial part of the VMN (VMNpd) displayed an increased mean neuronal density in the insulin-treated animals (P < 0.05). In the dorsomedial hypothalamic nucleus (DMN) a significant increase of the mean area of neuronal nuclei (P < 0.01) and the area of neuronal cytoplasm were observed (P < 0.001). These alterations were accompanied by a significantly elevated mean numerical density of astrocytes (positive for glial fibriallary acidic protein; GFAP+) within the periventricular hypothalamic area (PER) of the insulin-treated rats (P < 0.05). These observations speak for a varying vulnerability of LHA, DMN and distinct parts of the VMN to hyperinsulinism during early development, possibly leading to a disturbed organization and, consecutively, permanent dysfunction of these morphologically connected and functionally interacting hypothalamic nuclei.
在以往的研究中，已表明大脑发育过程中下丘脑局部短暂性高胰岛素血症会导致大鼠成年后体重超重和代谢紊乱。因此，在该动物模型中，我们检验了出生后早期进行下丘脑内胰岛素治疗是否可能导致下丘脑形态学改变的假说，即神经元数量密度、神经元细胞核面积或神经元细胞质面积的改变。为此，在Wistar大鼠出生第8天时，通过立体定位法将长效胰岛素双侧注入下丘脑（每侧12 mIU），而对照组仅给予不含胰岛素的琼脂载体。在出生第15天时通过计算机辅助形态计量分析发现，与对照大鼠相比，胰岛素治疗组动物的VMN内神经元细胞核平均面积和平均核质比降低（P < 0.05），而下丘脑外侧区（LHA）未发现明显改变。对VMN不同地形部位的分析显示，VMN前部（VMNpa）的神经元细胞核平均面积（P < 0.001）和核质比（P < 0.05）显著降低。此外，在胰岛素组的腹外侧部（VMNpv）观察到平均神经元密度降低（P < 0.01）。相反，胰岛素治疗组动物的VMN背内侧部（VMNpd）平均神经元密度增加（P < 0.05）。在背内侧下丘脑核（DMN）观察到神经元细胞核平均面积（P < 0.01）和神经元细胞质面积显著增加（P < 0.001）。这些改变伴随着胰岛素治疗大鼠下丘脑室周区（PER）内星形胶质细胞（胶质纤维酸性蛋白阳性；GFAP+）平均数量密度显著升高（P < 0.05）。这些观察结果表明，在早期发育过程中，LHA、DMN和VMN的不同部位对高胰岛素血症的易感性不同，这可能导致这些形态相连且功能相互作用的下丘脑核团组织紊乱，并继而导致永久性功能障碍。
