Caughey S, Harris A P, Seckl J R, Holmes M C, Yau J L W
UoE/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
J Neuroendocrinol. 2017 Jan;29(1). doi: 10.1111/jne.12447.
Mice lacking the intracellular glucocorticoid-regenerating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) are protected from age-related spatial memory deficits. 11β-HSD1 is expressed predominantly in the brain, liver and adipose tissue. Reduced glucocorticoid levels in the brain in the absence of 11β-HSD1 may underlie the improved memory in aged 11β-HSD1 deficient mice. However, the improved glucose tolerance, insulin sensitisation and cardioprotective lipid profile associated with reduced peripheral glucocorticoid regeneration may potentially contribute to the cognitive phenotype of aged 11β-HSD1 deficient mice. In the present study, transgenic mice with forebrain-specific overexpression of 11β-HSD1 (Tg) were intercrossed with global 11β-HSD1 knockout mice (HSD1KO) to examine the influence of forebrain and peripheral 11β-HSD1 activity on spatial memory in aged mice. Transgene-mediated delivery of 11β-HSD1 to the hippocampus and cortex of aged HSD1KO mice reversed the improved spatial memory retention in the Y-maze but not spatial learning in the watermaze. Brain-derived neurotrophic factor (BDNF) mRNA levels in the hippocampus of aged HSD1KO mice were increased compared to aged wild-type mice. Rescue of forebrain 11β-HSD1 reduced BDNF mRNA in aged HSD1KO mice to levels comparable to aged wild-type mice. These findings indicate that 11β-HSD1 regenerated glucocorticoids in the forebrain and decreased levels of BDNF mRNA in the hippocampus play a role in spatial memory deficits in aged wild-type mice, although 11β-HSD1 activity in peripheral tissues may also contribute to spatial learning impairments in aged mice.
缺乏细胞内糖皮质激素再生酶11β-羟基类固醇脱氢酶1型（11β-HSD1）的小鼠可免受与年龄相关的空间记忆缺陷影响。11β-HSD1主要在脑、肝脏和脂肪组织中表达。在缺乏11β-HSD1的情况下，脑中糖皮质激素水平降低可能是11β-HSD1基因缺陷老年小鼠记忆力改善的基础。然而，与外周糖皮质激素再生减少相关的葡萄糖耐量改善、胰岛素敏感性增加和心脏保护脂质谱可能潜在地导致了11β-HSD1基因缺陷老年小鼠的认知表型。在本研究中，将前脑特异性过表达11β-HSD1的转基因小鼠（Tg）与全身11β-HSD1基因敲除小鼠（HSD1KO）杂交，以研究前脑和外周11β-HSD1活性对老年小鼠空间记忆的影响。通过转基因介导将11β-HSD1递送至老年HSD1KO小鼠的海马体和皮质，可逆转Y迷宫中改善的空间记忆保持能力，但不能逆转水迷宫中的空间学习能力。与老年野生型小鼠相比，老年HSD1KO小鼠海马体中脑源性神经营养因子（BDNF）的mRNA水平升高。恢复前脑11β-HSD1可使老年HSD1KO小鼠的BDNF mRNA水平降至与老年野生型小鼠相当的水平。这些发现表明，前脑中再生糖皮质激素的11β-HSD1以及海马体中BDNF mRNA水平降低在老年野生型小鼠的空间记忆缺陷中起作用，尽管外周组织中的11β-HSD1活性也可能导致老年小鼠的空间学习障碍。
