Oh Hyunjung, Newton Dwight, Lewis David, Sibille Etienne
Campbell Family Mental Health Research Institute of CAMH, Toronto, ON, Canada.
Departments of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.
Front Psychiatry. 2022 Feb 25;13:827972. doi: 10.3389/fpsyt.2022.827972. eCollection 2022.
A previous transcriptome meta-analysis revealed significantly lower levels of corticotropin-releasing hormone (CRH) mRNA in corticolimbic brain regions in major depressive disorder (MDD) subjects, suggesting that cortical CRH-expressing (CRH+) cells are affected in MDD. Rodent studies show that cortical CRH is mostly expressed in GABAergic interneurons; however, the characteristic features of CRH+ cells in human brain cortex and their association with MDD are largely unknown.
Subgenual anterior cingulate cortex (sgACC) of human subjects without brain disorders were labeled using fluorescent hybridization (FISH) for CRH and markers of excitatory (SLC17A7), inhibitory (GAD1) neurons, as well as markers of other interneuron subpopulations (PVALB, SST, VIP). MDD-associated changes in CRH+ cell density and cellular CRH expression ( = 6/group) were analyzed. RNA-sequencing was performed on sgACC CRH+ interneurons from comparison and MDD subjects ( = 6/group), and analyzed for group differences. The effect of reduced BDNF on CRH expression was tested in mice with blocked TrkB function.
About 80% of CRH+ cells were GABAergic and 17.5% were glutamatergic. CRH+ GABAergic interneurons co-expressed VIP (52%), SST (7%), or PVALB (7%). MDD subjects displayed lower CRH mRNA levels in GABAergic interneurons relative to comparison subjects without changes in cell density. CRH+ interneurons show transcriptomic profile suggesting lower excitability and less GABA release and reuptake. Further analyses suggested that these molecular changes are not mediated by altered glucocorticoid feedback and potentially occur downstream for a common modulator of neurotrophic function.
CRH+ cells in human sgACC are a heterogeneous population of GABAergic interneurons, although largely co-expressing VIP. Our data suggest that MDD is associated with reduced markers of inhibitory function in sgACC CRH+ interneurons, and provide further evidence for impaired GABAergic function in the cortex in MDD.
先前的转录组荟萃分析显示，重度抑郁症（MDD）患者的皮质边缘脑区促肾上腺皮质激素释放激素（CRH）mRNA水平显著降低，这表明表达CRH的皮质（CRH+）细胞在MDD中受到影响。啮齿动物研究表明，皮质CRH主要在GABA能中间神经元中表达；然而，人类大脑皮质中CRH+细胞的特征及其与MDD的关联在很大程度上尚不清楚。
使用荧光原位杂交（FISH）对无脑部疾病的人类受试者的膝下前扣带回皮质（sgACC）进行CRH以及兴奋性（SLC17A7）、抑制性（GAD1）神经元标志物，以及其他中间神经元亚群标志物（PVALB、SST、VIP）的标记。分析了MDD相关的CRH+细胞密度和细胞CRH表达的变化（每组n = 6）。对来自对照组和MDD患者（每组n = 6）的sgACC CRH+中间神经元进行RNA测序，并分析组间差异。在TrkB功能被阻断的小鼠中测试脑源性神经营养因子（BDNF）减少对CRH表达的影响。
约80%的CRH+细胞是GABA能的，17.5%是谷氨酸能的。CRH+ GABA能中间神经元共表达VIP（52%）、SST（7%）或PVALB（7%）。与对照组相比，MDD患者的GABA能中间神经元中CRH mRNA水平较低，而细胞密度没有变化。CRH+中间神经元显示出转录组图谱，表明其兴奋性较低，GABA释放和再摄取较少。进一步分析表明，这些分子变化不是由糖皮质激素反馈改变介导的，可能发生在神经营养功能的共同调节因子的下游。
人类sgACC中的CRH+细胞是GABA能中间神经元的异质群体，尽管在很大程度上共表达VIP。我们的数据表明，MDD与sgACC CRH+中间神经元中抑制功能标志物的减少有关，并为MDD中皮质GABA能功能受损提供了进一步的证据。
