Myers Brent, McKlveen Jessica M, Morano Rachel, Ulrich-Lai Yvonne M, Solomon Matia B, Wilson Steven P, Herman James P
Biomedical Sciences, Colorado State University, Fort Collins, Colorado 80523.
Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, Ohio 45237.
Endocrinology. 2017 Oct 1;158(10):3579-3591. doi: 10.1210/en.2017-00426.
Chronic stress-associated pathologies frequently associate with alterations in the structure and activity of the medial prefrontal cortex (mPFC). However, the influence of infralimbic cortex (IL) projection neurons on hypothalamic-pituitary-adrenal (HPA) axis activity is unknown, as is the involvement of these cells in chronic stress-induced endocrine alterations. In the current study, a lentiviral-packaged vector coding for a small interfering RNA (siRNA) targeting vesicular glutamate transporter (vGluT) 1 messenger RNA (mRNA) was microinjected into the IL of male rats. vGluT1 is responsible for presynaptic vesicular glutamate packaging in cortical neurons, and knockdown reduces the amount of glutamate available for synaptic release. After injection, rats were either exposed to chronic variable stress (CVS) or remained in the home cage as unstressed controls. Fifteen days after the initiation of CVS, all animals were exposed to a novel acute stressor (30-minute restraint) with blood collection for the analysis of adrenocorticotropic hormone (ACTH) and corticosterone. Additionally, brains were collected for in situ hybridization of corticotrophin-releasing hormone mRNA. In previously unstressed rats, vGluT1 siRNA significantly enhanced ACTH and corticosterone secretion. Compared with CVS animals receiving the green fluorescent protein control vector, the vGluT1 siRNA further increased basal and stress-induced corticosterone release. Further analysis revealed enhanced adrenal responsiveness in CVS rats treated with vGluT1 siRNA. Collectively, our results suggest that IL glutamate output inhibits HPA responses to acute stress and restrains corticosterone secretion during chronic stress, possibly at the level of the adrenal. Together, these findings pinpoint a neurochemical mechanism linking mPFC dysfunction with aberrant neuroendocrine responses to chronic stress.
慢性应激相关的病理状况常常与内侧前额叶皮质（mPFC）的结构和活动改变相关。然而，边缘下皮质（IL）投射神经元对下丘脑-垂体-肾上腺（HPA）轴活动的影响尚不清楚，这些细胞在慢性应激诱导的内分泌改变中的作用也不清楚。在本研究中，将编码靶向囊泡谷氨酸转运体（vGluT）1信使核糖核酸（mRNA）的小干扰RNA（siRNA）的慢病毒包装载体微量注射到雄性大鼠的IL中。vGluT1负责皮质神经元中突触前囊泡谷氨酸的包装，敲低会减少可用于突触释放的谷氨酸量。注射后，将大鼠暴露于慢性可变应激（CVS）中，或作为未受应激的对照留在饲养笼中。在开始CVS 15天后，所有动物都暴露于一种新的急性应激源（30分钟束缚），并采集血液以分析促肾上腺皮质激素（ACTH）和皮质酮。此外，收集大脑用于促肾上腺皮质激素释放激素mRNA的原位杂交。在先前未受应激的大鼠中，vGluT1 siRNA显著增强了ACTH和皮质酮的分泌。与接受绿色荧光蛋白对照载体的CVS动物相比，vGluT1 siRNA进一步增加了基础和应激诱导的皮质酮释放。进一步分析显示，用vGluT1 siRNA处理的CVS大鼠的肾上腺反应性增强。总的来说，我们的结果表明，IL谷氨酸输出抑制HPA对急性应激的反应，并在慢性应激期间抑制皮质酮分泌，可能是在肾上腺水平。总之，这些发现确定了一种神经化学机制，将mPFC功能障碍与对慢性应激的异常神经内分泌反应联系起来。
