Morphological alterations of hypothalamic nucleidue to intrahypothalamic hyperinsulinism in newborn rats

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In former studies, a temporary, intrahypothalamically localized hyperinsulinism duringbrain development was shown to result in overweight and metabolic disturbances during later lifein rats. Therefore, we tested the hypothesis whether intrahypothalamic insulin treatment duringearly postnatal life may lead to hypothalamic morphological alterations, i.e., of numerical densityof neurons and area of neuronal nuclei or area of neuronal cytoplasm, in this animal model. Forthis purpose, on the 8th day of age in Wistar rats a long-acting insulin was bilaterally applicatedstereotactically into the hypothalamus (12 mIU on each side), while in controls the insulin-freeagar-vehicle was given only. By computer-assisted morphometric analysis on the 15th day of life adecrease of the mean area of neuronal nuclei and the mean nucleus-cytoplasm-ratio within theVMN 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). Analysisof topographically distinct parts of the VMN revealed significant reductions of the mean area ofneuronal nuclei (P < 0.001) and nucleus-cytoplasm-ratio (P < 0.05) inthe anterior part of the VMN (VMNpa). Furthermore, in the ventrolateral part (VMNpv) adecreased mean neuronal density was observed in the insulin group (P < 0.01). Incontrast, the dorsomedial part of the VMN (VMNpd) displayed an increased mean neuronaldensity in the insulin-treated animals (P < 0.05). In the dorsomedial hypothalamicnucleus (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 alterationswere accompanied by a significantly elevated mean numerical density of astrocytes (positive forglial fibriallary acidic protein ; GFAP+) within the periventricular hypothalamic area (PER) of theinsulin-treated rats (P < 0.05). These observations speak for a varying vulnerabilityof LHA, DMN and distinct parts of the VMN to hyperinsulinism during early development,possibly leading to a disturbed organization and, consecutively, permanent dysfunction of thesemorphologically connected and functionally interacting hypothalamic nuclei.